Abstract
Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.
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References
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3:e442.
Organization WH. 2012 [updated 2012]; Available from: http://www.who.int/diabetes/fact/en.
DeFronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–95.
Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989;321:337–43.
DeFronzo RA. Lilly lecture 1987. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes. 1988;37:667–87.
Cersosimo E, Triplitt C, Mandarino LJ, DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth: MDText.com; 2000.
Bergman RN, Finegood DT, Kahn SE. The evolution of beta-cell dysfunction and insulin resistance in type 2 diabetes. Eur J Clin Investig. 2002;32(Suppl 3):35–45.
Bergman RN. Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal model approach. Diabetes. 1989;38:1512–27.
Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia. 2004;47:31–9.
Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90:493–500.
Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the veterans administration genetic epidemiology study. Diabetes. 2006;55:1430–5.
Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care. 2006;29:1130–9.
Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 2003;88:2300–8.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.
Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type II diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340:925–9.
Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373:2215–21.
James WP. The fundamental drivers of the obesity epidemic. Obes Rev Off J Int Assoc Study Obes. 2008;9(Suppl 1):6–13.
DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 1997;5:177–269.
Groop L, Lyssenko V. Genes and type 2 diabetes mellitus. Curr Diabetes Rep. 2008;8:192–7.
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jorgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjogren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40:638–45.
Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H, Mahajan A, Prokopenko I, Kang HM, Dina C, Esko T, Fraser RM, Kanoni S, Kumar A, Lagou V, Langenberg C, Luan J, Lindgren CM, Muller-Nurasyid M, Pechlivanis S, Rayner NW, Scott LJ, Wiltshire S, Yengo L, Kinnunen L, Rossin EJ, Raychaudhuri S, Johnson AD, Dimas AS, Loos RJ, Vedantam S, Chen H, Florez JC, Fox C, Liu CT, Rybin D, Couper DJ, Kao WH, Li M, Cornelis MC, Kraft P, Sun Q, van Dam RM, Stringham HM, Chines PS, Fischer K, Fontanillas P, Holmen OL, Hunt SE, Jackson AU, Kong A, Lawrence R, Meyer J, Perry JR, Platou CG, Potter S, Rehnberg E, Robertson N, Sivapalaratnam S, Stancakova A, Stirrups K, Thorleifsson G, Tikkanen E, Wood AR, Almgren P, Atalay M, Benediktsson R, Bonnycastle LL, Burtt N, Carey J, Charpentier G, Crenshaw AT, Doney AS, Dorkhan M, Edkins S, Emilsson V, Eury E, Forsen T, Gertow K, Gigante B, Grant GB, Groves CJ, Guiducci C, Herder C, Hreidarsson AB, Hui J, James A, Jonsson A, Rathmann W, Klopp N, Kravic J, Krjutskov K, Langford C, Leander K, Lindholm E, Lobbens S, Mannisto S, Mirza G, Muhleisen TW, Musk B, Parkin M, Rallidis L, Saramies J, Sennblad B, Shah S, Sigurethsson G, Silveira A, Steinbach G, Thorand B, Trakalo J, Veglia F, Wennauer R, Winckler W, Zabaneh D, Campbell H, van Duijn C, Uitterlinden AG, Hofman A, Sijbrands E, Abecasis GR, Owen KR, Zeggini E, Trip MD, Forouhi NG, Syvanen AC, Eriksson JG, Peltonen L, Nothen MM, Balkau B, Palmer CN, Lyssenko V, Tuomi T, Isomaa B, Hunter DJ, Qi L, Shuldiner AR, Roden M, Barroso I, Wilsgaard T, Beilby J, Hovingh K, Price JF, Wilson JF, Rauramaa R, Lakka TA, Lind L, Dedoussis G, Njolstad I, Pedersen NL, Khaw KT, Wareham NJ, Keinanen-Kiukaanniemi SM, Saaristo TE, Korpi-Hyovalti E, Saltevo J, Laakso M, Kuusisto J, Metspalu A, Collins FS, Mohlke KL, Bergman RN, Tuomilehto J, Boehm BO, Gieger C, Hveem K, Cauchi S, Froguel P, Baldassarre D, Tremoli E, Humphries SE, Saleheen D, Danesh J, Ingelsson E, Ripatti S, Salomaa V, Erbel R, Jockel KH, Moebus S, Peters A, Illig T, De Fair U, Hamsten A, Morris AD, Donnelly PJ, Frayling TM, Hattersley AT, Boerwinkle E, Melander O, Kathiresan S, Nilsson PM, Deloukas P, Thorsteinsdottir U, Groop LC, Stefansson K, Hu F, Pankow JS, Dupuis J, Meigs JB, Altshuler D, Boehnke M, McCarthy MI. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–90.
Mahajan A, Go MJ, Zhang W, Below JE, Gaulton KJ, Ferreira T, Horikoshi M, Johnson AD, Ng MC, Prokopenko I, Saleheen D, Wang X, Zeggini E, Abecasis GR, Adair LS, Almgren P, Atalay M, Aung T, Baldassarre D, Balkau B, Bao Y, Barnett AH, Barroso I, Basit A, Been LF, Beilby J, Bell GI, Benediktsson R, Bergman RN, Boehm BO, Boerwinkle E, Bonnycastle LL, Burtt N, Cai Q, Campbell H, Carey J, Cauchi S, Caulfield M, Chan JC, Chang LC, Chang TJ, Chang YC, Charpentier G, Chen CH, Chen H, Chen YT, Chia KS, Chidambaram M, Chines PS, Cho NH, Cho YM, Chuang LM, Collins FS, Cornelis MC, Couper DJ, Crenshaw AT, van Dam RM, Danesh J, Das D, De Faire U, Dedoussis G, Deloukas P, Dimas AS, Dina C, Doney AS, Donnelly PJ, Dorkhan M, van Duijn C, Dupuis J, Edkins S, Elliott P, Emilsson V, Erbel R, Eriksson JG, Escobedo J, Esko T, Eury E, Florez JC, Fontanillas P, Forouhi NG, Forsen T, Fox C, Fraser RM, Frayling TM, Froguel P, Frossard P, Gao Y, Gertow K, Gieger C, Gigante B, Grallert H, Grant GB, Grrop LC, Groves CJ, Grundberg E, Guiducci C, Hamsten A, Han BG, Hara K, Hassanali N, Hattersley AT, Hayward C, Hedman AK, Herder C, Hofman A, Holmen OL, Hovingh K, Hreidarsson AB, Hu C, Hu FB, Hui J, Humphries SE, Hunt SE, Hunter DJ, Hveem K, Hydrie ZI, Ikegami H, Illig T, Ingelsson E, Islam M, Isomaa B, Jackson AU, Jafar T, James A, Jia W, Jockel KH, Jonsson A, Jowett JB, Kadowaki T, Kang HM, Kanoni S, Kao WH, Kathiresan S, Kato N, Katulanda P, Keinanen-Kiukaanniemi KM, Kelly AM, Khan H, Khaw KT, Khor CC, Kim HL, Kim S, Kim YJ, Kinnunen L, Klopp N, Kong A, Korpi-Hyovalti E, Kowlessur S, Kraft P, Kravic J, Kristensen MM, Krithika S, Kumar A, Kumate J, Kuusisto J, Kwak SH, Laakso M, Lagou V, Lakka TA, Langenberg C, Langford C, Lawrence R, Leander K, Lee JM, Lee NR, Li M, Li X, Li Y, Liang J, Liju S, Lim WY, Lind L, Lindgren CM, Lindholm E, Liu CT, Liu JJ, Lobbens S, Long J, Loos RJ, Lu W, Luan J, Lyssenko V, Ma RC, Maeda S, Magi R, Mannisto S, Matthews DR, Meigs JB, Melander O, Metspalu A, Meyer J, Mirza G, Mihailov E, Moebus S, Mohan V, Mohlke KL, Morris AD, Muhleisen TW, Muller-Nurasyid M, Musk B, Nakamura J, Nakashima E, Navarro P, Ng PK, Nica AC, Nilsson PM, Njolstad I, Nothen MM, Ohnaka K, Ong TH, Owen KR, Palmer CN, Pankow JS, Park KS, Parkin M, Pechlivanis S, Pedersen NL, Peltonen L, Perry JR, Peters A, Pinidiyapathirage JM, Platou CG, Potter S, Price JF, Qi L, Radha V, Rallidis L, Rasheed A, Rathman W, Rauramaa R, Raychaudhuri S, Rayner NW, Rees SD, Rehnberg E, Ripatti S, Robertson N, Roden M, Rossin EJ, Rudan I, Rybin D, Saaristo TE, Salomaa V, Saltevo J, Samuel M, Sanghera DK, Saramies J, Scott J, Scott LJ, Scott RA, Segre AV, Sehmi J, Sennblad B, Shah N, Shah S, Shera AS. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014;46:234–44.
Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, McCarthy MI. Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes. 2006;55:2640–4.
Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445:881–5.
Mohlke KL, Boehnke M. Recent advances in understanding the genetic architecture of type 2 diabetes. Hum Mol Genet. 2015;24:R85–92.
Billings LK, Florez JC. The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci. 2010;1212:59–77.
Hong KW, Chung M, Cho SB. Meta-analysis of genome-wide association study of homeostasis model assessment beta cell function and insulin resistance in an East Asian population and the European results. Mol Gen Genet MGG. 2014;289:1247–55.
Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proenca C, Bacot F, Balkau B, Belisle A, Borch-Johnsen K, Charpentier G, Dina C, Durand E, Elliott P, Hadjadj S, Jarvelin MR, Laitinen J, Lauritzen T, Marre M, Mazur A, Meyre D, Montpetit A, Pisinger C, Posner B, Poulsen P, Pouta A, Prentki M, Ribel-Madsen R, Ruokonen A, Sandbaek A, Serre D, Tichet J, Vaxillaire M, Wojtaszewski JF, Vaag A, Hansen T, Polychronakos C, Pedersen O, Froguel P, Sladek R. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet. 2009;41:1110.
Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, Lyssenko V, Chen WM, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, de Geus EJ, Dehghan A, Deloukas P, Doney AS, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT, Mohlke KL, Morris AD, Naitza S, Orru M, Palmer CN, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann HE, Willemsen G, Witteman JC, Yuan X, Zhao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma DI, Uda M, Spector TD, Penninx BW, Altshuler D, Vollenweider P, Jarvelin MR, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, Van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2009;41:77–81.
Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, Sparso T, Holmkvist J, Marchand M, Delplanque J, Lobbens S, Rocheleau G, Durand E, De Graeve F, Chevre JC, Borch-Johnsen K, Hartikainen AL, Ruokonen A, Tichet J, Marre M, Weill J, Heude B, Tauber M, Lemaire K, Schuit F, Elliott P, Jorgensen T, Charpentier G, Hadjadj S, Cauchi S, Vaxillaire M, Sladek R, Visvikis-Siest S, Balkau B, Levy-Marchal C, Pattou F, Meyre D, Blakemore AI, Jarvelin MR, Walley AJ, Hansen T, Dina C, Pedersen O, Froguel P. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009;41:89–94.
Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet. 2009;41:82–8.
Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, Ma C, Fontanillas P, Moutsianas L, McCarthy DJ, Rivas MA, Perry JR, Sim X, Blackwell TW, Robertson NR, Rayner NW, Cingolani P, Locke AE, Fernandez Tajes J, Highland HM, Dupuis J, Chines PS, Lindgren CM, Hartl C, Jackson AU, Chen H, Huyghe JR, van de Bunt M, Pearson RD, Kumar A, Muller-Nurasyid M, Grarup N, Stringham HM, Gamazon ER, Lee J, Chen Y, Scott RA, Below JE, Chen P, Huang J, Go MJ, Stitzel ML, Pasko D, Parker SC, Varga TV, Green T, Beer NL, Day-Williams AG, Ferreira T, Fingerlin T, Horikoshi M, Hu C, Huh I, Ikram MK, Kim BJ, Kim Y, Kim YJ, Kwon MS, Lee J, Lee S, Lin KH, Maxwell TJ, Nagai Y, Wang X, Welch RP, Yoon J, Zhang W, Barzilai N, Voight BF, Han BG, Jenkinson CP, Kuulasmaa T, Kuusisto J, Manning A, Ng MC, Palmer ND, Balkau B, Stancakova A, Abboud HE, Boeing H, Giedraitis V, Prabhakaran D, Gottesman O, Scott J, Carey J, Kwan P, Grant G, Smith JD, Neale BM, Purcell S, Butterworth AS, Howson JM, Lee HM, Lu Y, Kwak SH, Zhao W, Danesh J, Lam VK, Park KS, Saleheen D, So WY, Tam CH, Afzal U, Aguilar D, Arya R, Aung T, Chan E, Navarro C, Cheng CY, Palli D, Correa A, Curran JE, Rybin D, Farook VS, Fowler SP, Freedman BI, Griswold M, Hale DE, Hicks PJ, Khor CC, Kumar S, Lehne B, Thuillier D, Lim WY, Liu J, van der Schouw YT, Loh M, Musani SK, Puppala S, Scott WR, Yengo L, Tan ST, Taylor Jr HA, Thameem F, Wilson Sr G, Wong TY, Njolstad PR, Levy JC, Mangino M, Bonnycastle LL, Schwarzmayr T, Fadista J, Surdulescu GL, Herder C, Groves CJ, Wieland T, Bork-Jensen J, Brandslund I, Christensen C, Koistinen HA, Doney AS, Kinnunen L, Esko T, Farmer AJ, Hakaste L, Hodgkiss D, Kravic J, Lyssenko V, Hollensted M, Jorgensen ME, Jorgensen T, Ladenvall C, Justesen JM, Karajamaki A, Kriebel J, Rathmann W, Lannfelt L, Lauritzen T, Narisu N, Linneberg A, Melander O, Milani L, Neville M, Orho-Melander M, Qi L, Qi Q, Roden M, Rolandsson O, Swift A, Rosengren AH, Stirrups K, Wood AR, Mihailov E, Blancher C, Carneiro MO, Maguire J, Poplin R, Shakir K, Fennell T, De Pristo M, Hrabe de Angelis M, Deloukas P, Gjesing AP, Jun G, Nilsson P, Murphy J, Onofrio R, Thorand B, Hansen T, Meisinger C, Hu FB, Isomaa B, Karpe F, Liang L, Peters A, Huth C, O’ Rahilly SP, Palmer CN, Pedersen O, Rauramaa R, Tuomilehto J, Salomaa V, Watanabe RM, Syvanen AC, Bergman RN, Bharadwaj D, Bottinger EP, Cho YS, Chandak GR, Chan JC, Chia KS, Daly MJ, Ebrahim SB, Langenberg C, Elliott P, Jablonski KA, Lehman DM, Jia W, Ma RC, Pollin TI, Sandhu M, Tandon N, Froguel P, Barroso I, Teo YY, Zeggini E, Loos RJ, Small KS, Ried JS, DeFronzo RA, Grallert H, Glaser B, Metspalu A, Wareham NJ, Walker M, Banks E, Gieger C, Ingelsson E, Im HK, Illig T, Franks PW, Buck G, Trakalo J, Buck D, Prokopenko I, Magi R, Lind L, Farjoun Y, Owen KR, Gloyn AL, Strauch K, Tuomi T, Kooner JS, Lee JY, Park T, Donnelly P, Morris AD, Hattersley AT, Bowden DW, Collins FS, Atzmon G, Chambers JC, Spector TD, Laakso M, Strom TM, Bell GI, Blangero J, Duggirala R, Tai ES, McVean G, Hanis CL, Wilson JG, Seielstad M, Frayling TM, Meigs JB, Cox NJ, Sladek R, Lander ES, Gabriel S, Burtt NP, Mohlke KL, Meitinger T, Groop L, Abecasis G, Florez JC, Scott LJ, Morris AP, Kang HM, Boehnke M, Altshuler D, McCarthy MI. The genetic architecture of type 2 diabetes. Nature. 2016;536:41–7.
Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Mandel G, DeFronzo RA, Kahn CR, Mandarino LJ. Insulin resistance differentially affects the PI 3-kinase-and MAP kinase – mediated signaling in human muscle. J Clin Invest. 2000;105:311–20.
Rome S, Clement K, Rabasa-Lhoret R, Loizon E, Poitou C, Barsh GS, Riou JP, Laville M, Vidal H. Microarray profiling of human skeletal muscle reveals that insulin regulates ~ 800 genes during an hyperinsulinemic clamp. J Biol Chem. 2003;278:18063.
Zierath JR, He L, Guma A, Odegoard Wahlstrom E, Klip A, Wallberg-Henriksson H. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia. 1996;39:1180–9.
Liao J, Barthel A, Nakatani K, Roth RA. Activation of protein kinase B/Akt is sufficient to repress the glucocorticoid and cAMP induction of phosphoenolpyruvate carboxykinase gene. J Biol Chem. 1998;273:27320–4.
Hall RK, Yamasaki T, Kucera T, O'Brien RM, Granner DK. Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor binding protein-1 gene expression by insulin. J Biol Chem. 2000;275:30169–75.
Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279:32345–53.
Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes. 2011;18:139–43.
Suganami T, Tanaka M, Ogawa Y. Adipose tissue inflammation and ectopic lipid accumulation. Endocr J. 2012;59:849–57.
Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17.
Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293:E444–52.
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360:1518–25.
Chondronikola M, Volpi E, Borsheim E, Porter C, Annamalai P, Enerback S, Lidell ME, Saraf MK, Labbe SM, Hurren NM, Yfanti C, Chao T, Andersen CR, Cesani F, Hawkins H, Sidossis LS. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014;63:4089–99.
Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, Goodyear LJ. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123:215–23.
Marino JS, Xu Y, Hill JW. Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab. 2011;22:275–85.
Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central melanocortin receptors regulate insulin action. J Clin Invest. 2001;108:1079–85.
Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002;5:566–72.
Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–65.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.
Meier JJ, Nauck MA. Incretins and the development of type 2 diabetes. Curr Diab Rep. 2006;6:194–201.
Rask E, Olsson T, Soderberg S, Johnson O, Seckl J, Holst JJ, Ahren B. Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Diabetes Care. 2001;24:1640–5.
Starkov AA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci. 2008;1147:37–52.
Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13.
Murgia M, Giorgi C, Pinton P, Rizzuto R. Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. J Mol Cell Cardiol. 2009;46:781–8.
Santulli G, Marks AR. Essential roles of intracellular calcium release channels in muscle, brain, metabolism, and aging. Curr Mol Pharmacol. 2015;8:206–22.
Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961;191:144–8.
Puigserver P, Wu A, Park CW, Graves R, Wright M, Spiegelman BR. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–39.
Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88:611–38.
Liesa M, Palacin M, Zorzano A. Mitochondrial dynamics in Mammalian health and disease. Physiol Rev. 2009;89:799–845.
Twig G, Hyde B, Shirihai OS. Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta. 2008;1777:1092–7.
Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011;13:589–98.
Molina AJ, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A, Walzer G, Twig G, Katz S, Corkey BE, Shirihai OS. Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes. 2009;58:2303–15.
Arnoult D, Grodet A, Lee YJ, Estaquier J, Blackstone C. Release of OPA1 during apoptosis participates in the rapid and complete release of cytochrome c and subsequent mitochondrial fragmentation. J Biol Chem. 2005;280:35742–50.
Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160:189–200.
Eura Y, Ishihara N, Yokota S, Mihara K. Two mitofusin proteins, mammalian homologues of FZO, with distinct functions are both required for mitochondrial fusion. J Biochem. 2003;134:333–44.
Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacin M, Vidal H, Rivera F, Brand M, Zorzano A. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem. 2003;278:17190–7.
de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008;456:605–10.
Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004;101:15927–32.
Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007;178:749–55.
Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001;1:515–25.
Pitts KR, Yoon Y, Krueger EW, McNiven MA. The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol Biol Cell. 1999;10:4403–17.
James DI, Parone PA, Mattenberger Y, Martinou JC. hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem. 2003;278:36373–9.
Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT. Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci. 2004;117:1201–10.
Tondera D, Santel A, Schwarzer R, Dames S, Giese K, Klippel A, Kaufmann J. Knockdown of MTP18, a novel phosphatidylinositol 3-kinase-dependent protein, affects mitochondrial morphology and induces apoptosis. J Biol Chem. 2004;279:31544–55.
Tondera D, Czauderna F, Paulick K, Schwarzer R, Kaufmann J, Santel A. The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells. J Cell Sci. 2005;118:3049–59.
Dumas JF, Simard G, Flamment M, Ducluzeau PH, Ritz P. Is skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of insulin resistance in humans? Diabetes Metab. 2009;35:159–67.
Pagel-Langenickel I, Bao J, Pang L, Sack MN. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Endocr Rev. 2010;31:25–51.
Hanson M. Understanding the origins of diabetes. JAMA. 2014;311:575–6.
Goodpaster BH. Mitochondrial deficiency is associated with insulin resistance. Diabetes. 2013;62:1032–5.
Holloszy JO. “Deficiency” of mitochondria in muscle does not cause insulin resistance. Diabetes. 2013;62:1036–40.
Vondra K, Rath R, Bass A, Slabochova Z, Teisinger J, Vitek V. Enzyme activities in quadriceps femoris muscle of obese diabetic male patients. Diabetologia. 1977;13:527–9.
Kelley DE, Goodpaster B, Wing RR, Simoneau JA. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Phys. 1999;277:E1130–41.
Simoneau JA, Veerkamp JH, Turcotte LP, Kelley DE. Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J. 1999;13:2051–60.
He J, Watkins S, Kelley DE. Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity. Diabetes. 2001;50:817–23.
Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51:2944–50.
Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003;300:1140–2.
Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–73.
Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA. 2003;100:8466–71.
Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664–71.
Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005;115:3587–93.
Miller WC, Bryce GR, Conlee RK. Adaptations to a high-fat diet that increase exercise endurance in male rats. J Appl Physiol Respir Environ Exerc Physiol. 1984;56:78–83.
McAinch AJ, Lee JS, Bruce CR, Tunstall RJ, Hawley JA, Cameron-Smith D. Dietary regulation of fat oxidative gene expression in different skeletal muscle fiber types. Obes Res. 2003;11:1471–9.
Han DH, Nolte LA, Ju JS, Coleman T, Holloszy JO, Semenkovich CF. UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction. Am J Physiol Endocrinol Metab. 2004;286:E347–53.
Wredenberg A, Freyer C, Sandstrom ME, Katz A, Wibom R, Westerblad H, Larsson NG. Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochem Biophys Res Commun. 2006;350:202–7.
Han DH, Hancock CR, Jung SR, Higashida K, Kim SH, Holloszy JO. Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance. PLoS One. 2011;6:e19739.
Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD, Ebersberger I, Nakashima T, Sarao R, Neely G, Esterbauer H, Kozlov A, Kahn CR, Kroemer G, Rustin P, Burcelin R, Penninger JM. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell. 2007;131:1–16.
Zechner C, Lai L, Zechner JF, Geng T, Yan Z, Rumsey JW, Collia D, Chen Z, Wozniak DF, Leone TC, Kelly DP. Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab. 2010;12:633–42.
Garcia-Roves P, Huss JM, Han DH, Hancock CR, Iglesias-Gutierrez E, Chen M, Holloszy JO. Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci USA. 2007;104:10709–13.
Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes. 2007;56:2085–92.
Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA. 2008;105:7815–20.
Toledo FG, Menshikova EV, Azuma K, Radikova Z, Kelley CA, Ritov VB, Kelley DE. Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes. 2008;57:987–94.
Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM, Klaus KA, Guo ZK, Sreekumar R, Irving BA. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes. 2008;57:1166–75.
Jin W, Goldfine AB, Boes T, Henry RR, Ciaraldi TP, Kim EY, Emecan M, Fitzpatrick C, Sen A, Shah A, Mun E, Vokes V, Schroeder J, Tatro E, Jimenez-Chillaron J, Patti ME. Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance. J Clin Invest. 2011;121:918–29.
Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev. 2011;91:1447–531.
DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981;30:1000–7.
Sasson S, Cerasi E. Substrate regulation of the glucose transport system in skeletal muscle. J Biol Chem. 1986;261:16827–33.
DeFronzo RA, Ferrannini E, Hendler R, Wahren J, Felig P. Influence of hyperinsulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci U S A. 1978;75:5173–7.
DeFronzo RA, Gunnarson R, Biorkman O, Olsson M, Warren J. Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent (Type II) diabetes mellitus. J Clin Invest. 1985;76:149–55.
Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990;39:1381–90.
Shulman GI, Rothman DL, Jue R, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990;322:223–8.
Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini B, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989;84:205–13.
Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, Shulman GI. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA. 1995;92:983–7.
Bajaj M, Defronzo RA. Metabolic and molecular basis of insulin resistance. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol. 2003;10:311–23.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.
Musi N, Goodyear LJ. Insulin resistance and improvements in signal transduction. Endocrine. 2006;29:73–80.
Kashyap SR, Roman LJ, Lamont J, Masters BS, Bajaj M, Suraamornkul S, Belfort R, Berria R, Kellogg Jr DL, Liu Y, DeFronzo RA. Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects. J Clin Endocrinol Metab. 2005;90:1100–5.
Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem. 2001;276:30392–8.
Kashyap SR, Belfort R, Berria R, Suraamornkul S, Pratipranawatr T, Finlayson J, Barrentine A, Bajaj M, Mandarino L, DeFronzo R, Cusi K. Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287:537–46.
Pratipanawatr W, Pratipanawatr T, Cusi K, Berria R, Adams JM, Jenkinson CP, Maezono K, DeFronzo RA, Mandarino LJ. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes. 2001;50:2572–8.
Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002;277:50230–6.
Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277:1531–7.
Folli F, Saad MJA, Backer JM, Kahn CR. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest. 1993;92:1787–94.
Befroy D, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman D, Shulman G. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes. 2007;56:1376–81.
Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes. 2005;54:8–14.
Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, van Engelshoven JM, Mensink M, Schrauwen P. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia. 2007;50:113–20.
Kacerovsky-Bielesz G, Chmelik M, Ling C, Pokan R, Szendroedi J, Farukuoye M, Kacerovsky M, Schmid AI, Gruber S, Wolzt M, Moser E, Pacini G, Smekal G, Groop L, Roden M. Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes. Diabetes. 2009;58:1333–41.
Phielix E, Schrauwen-Hinderling VB, Mensink M, Lenaers E, Meex R, Hoeks J, Kooi ME, Moonen-Kornips E, Sels JP, Hesselink MK, Schrauwen P. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes. 2008;57:2943–9.
Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia. 2007;50:790–6.
Ritov VB, Menshikova EV, Azuma K, Wood R, Toledo FG, Goodpaster BH, Ruderman NB, Kelley DE. Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity. Am J Physiol Endocrinol Metab. 2010;298:E49–58.
Mogensen M, Sahlin K, Fernstrom M, Glintborg D, Vind BF, Beck-Nielsen H, Hojlund K. Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes. 2007;56:1592–9.
Szendroedi J, Schmid AI, Chmelik M, Toth C, Brehm A, Krssak M, Nowotny P, Wolzt M, Waldhausl W, Roden M. Muscle Mitochondrial atp synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med. 2007;4:e154.
Gnaiger E. Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol. 2009;41:1837–45.
Lefort N, Glancy B, Bowen B, Willis WT, Bailowitz Z, De Filippis EA, Brophy C, Meyer C, Hojlund K, Yi Z, Mandarino LJ. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes. 2010;59:2444–52.
Chomentowski P, Coen PM, Radikova Z, Goodpaster BH, Toledo FG. Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. J Clin Endocrinol Metab. 2011;96:494–503.
Heilbronn LK, Gan SK, Turner N, Campbell LV, Chisholm DJ. Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab. 2007;92:1467–73.
Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004;101:6570–5.
Karlsson HK, Ahlsen M, Zierath JR, Wallberg-Henriksson H, Koistinen HA. Insulin signaling and glucose transport in skeletal muscle from first-degree relatives of type 2 diabetic patients. Diabetes. 2006;55:1283–8.
Nisoli E, Carruba MO. Nitric oxide and mitochondrial biogenesis. J Cell Sci. 2006;119:2855–62.
Lodi R, Tonon C, Valentino ML, Iotti S, Clementi V, Malucelli E, Barboni P, Longanesi L, Schimpf S, Wissinger B, Baruzzi A, Barbiroli B, Carelli V. Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy. Ann Neurol. 2004;56:719–23.
Jheng HF, Tsai PJ, Guo SM, Kuo LH, Chang CS, Su IJ, Chang CR, Tsai YS. Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol. 2012;32:309–19.
Holmstrom MH, Iglesias-Gutierrez E, Zierath JR, Garcia-Roves PM. Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes. Am J Physiol Endocrinol Metab. 2012;302:E731–9.
Karakelides H, Irving BA, Short KR, O’Brien P, Nair KS. Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes. 2010;59:89–97.
Holmstrom MH, Tom RZ, Bjornholm M, Garcia-Roves PM, Zierath JR. Effect of leptin treatment on mitochondrial function in obese leptin-deficient ob/ob mice. Metabolism. 2013;62:1258–67.
Lenaers E, De Feyter HM, Hoeks J, Schrauwen P, Schaart G, Nabben M, Nicolay K, Prompers JJ, Hesselink MK. Adaptations in mitochondrial function parallel, but fail to rescue, the transition to severe hyperglycemia and hyperinsulinemia: a study in Zucker diabetic fatty rats. Obesity (Silver Spring). 2010;18:1100–7.
van den Broek NM, Ciapaite J, De Feyter HM, Houten SM, Wanders RJ, Jeneson JA, Nicolay K, Prompers JJ. Increased mitochondrial content rescues in vivo muscle oxidative capacity in long-term high-fat-diet-fed rats. FASEB J. 2010;24:1354–64.
Zhang D, Liu ZX, Choi CS, Tian L, Kibbey R, Dong J, Cline GW, Wood PA, Shulman GI. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci USA. 2007;104:17075–80.
Quintens R, Singh S, Lemaire K, De Bock K, Granvik M, Schraenen A, Vroegrijk IO, Costa V, Van Noten P, Lambrechts D, Lehnert S, Van Lommel L, Thorrez L, De Faudeur G, Romijn JA, Shelton JM, Scorrano L, Lijnen HR, Voshol PJ, Carmeliet P, Mammen PP, Schuit F. Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance. PLoS One. 2013;8:e56719.
Dela F, Helge JW. Insulin resistance and mitochondrial function in skeletal muscle. Int J Biochem Cell Biol. 2013;45:11–5.
Yki-Jarvinen H. Ectopic fat accumulation: an important cause of insulin resistance in humans. J R Soc Med. 2002;95(Suppl 42):39–45.
Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375:2267–77.
Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148:852–71.
Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest. 2002;32(Suppl 3):14–23.
Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes. 1999;48:1600–6.
Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Phys. 1999;276:E977–89.
Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, Boselli L, Barbetta G, Allen K, Rife F, Savoye M, Dziura J, Sherwin R, Shulman GI, Caprio S. Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet. 2003;362:951–7.
Wang H, Knaub LA, Jensen DR, Young Jung D, Hong EG, Ko HJ, Coates AM, Goldberg IJ, de la Houssaye BA, Janssen RC, McCurdy CE, Rahman SM, Soo Choi C, Shulman GI, Kim JK, Friedman JE, Eckel RH. Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues. Diabetes. 2009;58:116–24.
Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ, Fillmore JJ, Liu ZX, Dong J, Cline G, Stahl A, Lodish HF, Shulman GI. Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. J Clin Invest. 2004;113:756–63.
Goudriaan JR, Dahlmans VE, Teusink B, Ouwens DM, Febbraio M, Maassen JA, Romijn JA, Havekes LM, Voshol PJ. CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice. J Lipid Res. 2003;44:2270–7.
Hajri T, Han XX, Bonen A, Abumrad NA. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest. 2002;109:1381–9.
Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA. 2001;98:7522–7.
Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253–9.
Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999;48:1270–4.
Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Liu ZX, Soos TJ, Cline GW, O'Brien WR, Littman DR, Shulman GI. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest. 2004;114:823–7.
Krssak M, Petersen KF, Bergeron R, Price T, Laurent D, Rothman DL, Roden M, Shulman GI. Intramuscular glycogen and intramyocellular lipid utilization during prolonged exercise and recovery in man: a 13C and 1H nuclear magnetic resonance spectroscopy study. J Clin Endocrinol Metab. 2000;85:748–54.
Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001;86:5755–61.
Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes. 1997;46:169–78.
Dube JJ, Amati F, Toledo FG, Stefanovic-Racic M, Rossi A, Coen P, Goodpaster BH. Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia. 2011;54:1147–56.
Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002;51:2005–11.
Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674–82.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–25.
Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res. 2007;100:1589–96.
Senn JJ. Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. J Biol Chem. 2006;281:26865–75.
Coen PM, Dube JJ, Amati F, Stefanovic-Racic M, Ferrell RE, Toledo FG, Goodpaster BH. Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes. 2010;59:80–8.
Adams 2nd JM, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards MC, Mandarino LJ. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes. 2004;53:25–31.
Ara I, Larsen S, Stallknecht B, Guerra B, Morales-Alamo D, Andersen JL, Ponce-Gonzalez JG, Guadalupe-Grau A, Galbo H, Calbet JA, Helge JW. Normal mitochondrial function and increased fat oxidation capacity in leg and arm muscles in obese humans. Int J Obes (Lond). 2011;35:99–108.
Goodpaster BH, Wolfe RR, Kelley DE. Effects of obesity on substrate utilization during exercise. Obes Res. 2002;10:575–84.
Groop LC, Saloranta C, Shank M, Bonadonna RC, Ferrannini E, DeFronzo RA. The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1991;72(1):96–107.
Boon H, Blaak EE, Saris WH, Keizer HA, Wagenmakers AJ, van Loon LJ. Substrate source utilisation in long-term diagnosed type 2 diabetes patients at rest, and during exercise and subsequent recovery. Diabetologia. 2007;50:103–12.
Petersen KF, Dufour S, Shulman GI. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med. 2005;2:e233.
Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7.
Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW, Romanelli AJ, Rossbacher JC, Moore IK, Regittnig W, Munoz DS, Kim JH, Shulman GI. n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner. Diabetes. 2007;56:1034–41.
Brehm A, Krssak M, Schmid AI, Nowotny P, Waldhausl W, Roden M. Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes. 2006;55:136–40.
Holloway GP, Thrush AB, Heigenhauser GJ, Tandon NN, Dyck DJ, Bonen A, Spriet LL. Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. Am J Physiol Endocrinol Metab. 2007;292:E1782–9.
Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM. Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes. 2006;55:2277–85.
Brehm A, Krssak M, Schmid AI, Nowotny P, Waldhausl W, Roden M. Acute elevation of plasma lipids does not affect ATP synthesis in human skeletal muscle. Am J Physiol Endocrinol Metab. 2010;299:E33–8.
Chavez AO, Kamath S, Jani R, Sharma LK, Monroy A, Abdul-Ghani MA, Centonze VE, Sathyanarayana P, Coletta DK, Jenkinson CP, Bai Y, Folli F, Defronzo RA, Tripathy D. Effect of short-term free fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J Clin Endocrinol Metab. 2010;95:422–9.
Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:92–103.
van de Weijer T, Sparks LM, Phielix E, Meex RC, van Herpen NA, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB. Relationships between mitochondrial function and metabolic flexibility in type 2 diabetes mellitus. PLoS One. 2013;8:e51648.
De Feyter HM, Lenaers E, Houten SM, Schrauwen P, Hesselink MK, Wanders RJ, Nicolay K, Prompers JJ. Increased intramyocellular lipid content but normal skeletal muscle mitochondrial oxidative capacity throughout the pathogenesis of type 2 diabetes. FASEB J. 2008;22:3947–55.
Holloway GP, Benton CR, Mullen KL, Yoshida Y, Snook LA, Han XX, Glatz JF, Luiken JJ, Lally J, Dyck DJ, Bonen A. In obese rat muscle transport of palmitate is increased and is channeled to triacylglycerol storage despite an increase in mitochondrial palmitate oxidation. Am J Physiol Endocrinol Metab. 2009;296:E738–47.
Abu-Elheiga L, Oh W, Kordari P, Wakil SJ. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. Proc Natl Acad Sci U S A. 2003;100:10207–12.
Rabol R, Svendsen PF, Skovbro M, Boushel R, Haugaard SB, Schjerling P, Schrauwen P, Hesselink MK, Nilas L, Madsbad S, Dela F. Reduced skeletal muscle mitochondrial respiration and improved glucose metabolism in nondiabetic obese women during a very low calorie dietary intervention leading to rapid weight loss. Metabolism. 2009;58:1145–52.
Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, Schaart G, Mensink M, Phielix E, van de Weijer T, Sels JP, Schrauwen P, Hesselink MK. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes. 2010;59:572–9.
Phielix E, Jelenik T, Nowotny P, Szendroedi J, Roden M. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial. Diabetologia. 2014;57:572–81.
Makimura H, Stanley TL, Suresh C, De Sousa-Coelho AL, Frontera WR, Syu S, Braun LR, Looby SE, Feldpausch MN, Torriani M, Lee H, Patti ME, Grinspoon SK. Metabolic effects of long-term reduction in free fatty acids with acipimox in obesity: a randomized trial. J Clin Endocrinol Metab. 2016;101:1123–33.
Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL, Brand MD. Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biol. 2013;1:304–12.
Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19:757–66.
Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose-Response Publ Int Hormesis Soc. 2014;12:288–341.
Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price III JW, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest. 2009;119:573–81.
Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944–8.
Curtis JM, Grimsrud PA, Wright WS, Xu X, Foncea RE, Graham DW, Brestoff JR, Wiczer BM, Ilkayeva O, Cianflone K, Muoio DE, Arriaga EA, Bernlohr DA. Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction. Diabetes. 2010;59:1132–42.
Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest. 2008;118:789.
Boudina S, Sena S, Sloan C, Tebbi A, Han YH, O’Neill BT, Cooksey RC, Jones D, Holland WL, McClain DA, Abel ED. Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity. Endocrinology. 2012;153:2677–88.
Abdul-Ghani MA, Jani R, Chavez A, Molina-Carrion M, Tripathy D, Defronzo RA. Mitochondrial reactive oxygen species generation in obese non-diabetic and type 2 diabetic participants. Diabetologia. 2009;52:574–82.
Hey-Mogensen M, Hojlund K, Vind BF, Wang L, Dela F, Beck-Nielsen H, Fernstrom M, Sahlin K. Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes. Diabetologia. 2010;53:1976–85.
Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Andersen JL, Madsbad S, Worm D, Helge JW, Dela F. Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes. Diabetologia. 2011;54:1427–36.
Nishikawa T, Araki E. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal. 2007;9:343–53.
Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes. 2003;52:1–8.
Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S, Bruce C, Shields BJ, Skiba B, Ooms LM, Stepto N, Wu B, Mitchell CA, Tonks NK, Watt MJ, Febbraio MA, Crack PJ, Andrikopoulos S, Tiganis T. Reactive oxygen species enhance insulin sensitivity. Cell Metab. 2009;10:260–72.
Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, Zhang D, Woo DK, Shadel GS, Ladiges W, Rabinovitch PS, Santos JH, Petersen KF, Samuel VT, Shulman GI. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab. 2010;12:668–74.
Boden MJ, Brandon AE, Tid-Ang JD, Preston E, Wilks D, Stuart E, Cleasby ME, Turner N, Cooney GJ, Kraegen EW. Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle. Am J Physiol Endocrinol Metab. 2012;303:E798–805.
Hoppeler H, Howald H, Conley K, Lindstedt SL, Claassen H, Vock P, Weibel ER. Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol. 1985;59:320–7.
Phielix E, Meex R, Moonen-Kornips E, Hesselink MK, Schrauwen P. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia. 2010;53:1714–21.
Toledo FG, Menshikova EV, Ritov VB, Azuma K, Radikova Z, DeLany J, Kelley DE. Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes. 2007;56:2142–7.
Irving BA, Short KR, Nair KS, Stump CS. Nine days of intensive exercise training improves mitochondrial function but not insulin action in adult offspring of mothers with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:E1137–41.
Pihlajamaki J, Boes T, Kim EY, Dearie F, Kim BW, Schroeder J, Mun E, Nasser I, Park PJ, Bianco AC, Goldfine AB, Patti ME. Thyroid hormone-related regulation of gene expression in human fatty liver. J Clin Endocrinol Metab. 2009;94:3521–9.
Takamura T, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T, Shimizu A, Kurita S, Takeshita Y, Ando H, Honda M, Kaneko S. Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity (SilverSpring). 2008;16:2601–9.
Iossa S, Lionetti L, Mollica MP, Crescenzo R, Botta M, Barletta A, Liverini G. Effect of high-fat feeding on metabolic efficiency and mitochondrial oxidative capacity in adult rats. Br J Nutr. 2003;90:953–60.
Raffaella C, Francesca B, Italia F, Marina P, Giovanna L, Susanna I. Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. Obesity (Silver Spring). 2008;16:958–64.
Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, Doeller JE, Kraus DW, Darley-Usmar VM, Bailey SM. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem J. 2009;417:183–93.
Wang Y, Lam KS, Lam JB, Lam MC, Leung PT, Zhou M, Xu A. Overexpression of angiopoietin-like protein 4 alters mitochondria activities and modulates methionine metabolic cycle in the liver tissues of db/db diabetic mice. Mol Endocrinol. 2007;21:972–86.
Flamment M, Arvier M, Gallois Y, Simard G, Malthiery Y, Ritz P, Ducluzeau PH. Fatty liver and insulin resistance in obese Zucker rats: no role for mitochondrial dysfunction. Biochimie. 2008;90:1407–13.
Brady LJ, Brady PS, Romsos DR, Hoppel CL. Elevated hepatic mitochondrial and peroxisomal oxidative capacities in fed and starved adult obese (ob/ob) mice. Biochem J. 1985;231:439–44.
Ferreira FM, Palmeira CM, Seica R, Santos MS. Alterations of liver mitochondrial bioenergetics in diabetic Goto-Kakizaki rats. Metabolism. 1999;48:1115–9.
Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121:2094–101.
Rasouli N, Kern PA. Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab. 2008;93:S64–73.
Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134:933–44.
Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 2008;7:410–20.
Carey VJ, Walters EE, Colditz GA, Solomon CG, Willett WC, Rosner BA, Speizer FE, Manson JE. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The nurses’ health study. Am J Epidemiol. 1997;145:614–9.
Wang Y, Rimm EB, Stampfer MJ, Willett WC, Hu FB. Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr. 2005;81:555–63.
Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation. 2008;117:1658–67.
Gil A, Olza J, Gil-Campos M, Gomez-Llorente C, Aguilera CM. Is adipose tissue metabolically different at different sites? Int J Pediatr Obes. 2011;6(Suppl 1):13–20.
O’Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II, Jobe BA, Roberts Jr CT, Slifka MK, Marks DL. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes. 2009;33:978–90.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.
Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.
GS H. Inflammation and metabolic disorders. Nature. 2006;444:860–7.
Heilbronn LK, Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des. 2008;14:1225–30.
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.
Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest. 2008;118:2992–3002.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.
Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280:745–51.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111–9.
Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010;316:129–39.
Feingold KR, Soued M, Staprans I, Gavin LA, Donahue ME, Huang BJ, Moser AH, Gulli R, Grunfeld C. Effect of tumor necrosis factor (TNF) on lipid metabolism in the diabetic rat. Evidence that inhibition of adipose tissue lipoprotein lipase activity is not required for TNF-induced hyperlipidemia. J Clin Invest. 1989;83:1116–21.
Grunfeld C, Feingold KR. The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy. 1991;3:143–58.
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.
Lane T, Flam B, Lockey R, Kolliputi N. TXNIP shuttling: missing link between oxidative stress and inflammasome activation. Front Physiol. 2013;4:50.
Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179–88.
Yu J, Novgorodov SA, Chudakova D, Zhu H, Bielawska A, Bielawski J, Obeid LM, Kindy MS, Gudz TI. JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J Biol Chem. 2007;282:25940–9.
Lu RH, Ji H, Chang ZG, Su SS, Yang GS. Mitochondrial development and the influence of its dysfunction during rat adipocyte differentiation. Mol Biol Rep. 2010;37:2173–82.
Gao CL, Zhu C, Zhao YP, Chen XH, Ji CB, Zhang CM, Zhu JG, Xia ZK, Tong ML, Guo XR. Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol. 2010;320:25–33.
Maclaren R, Cui W, Simard S, Cianflone K. Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissue. J Lipid Res. 2008;49:308–23.
Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S, Czech M, Corvera S. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol. 2003;23:1085–94.
Boudina S, Graham TE. Mitochondrial function/dysfunction in white adipose tissue. Exp Physiol. 2014;99:1168–78.
Tormos KV, Anso E, Hamanaka RB, Eisenbart J, Joseph J, Kalyanaraman B, Chandel NS. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 2011;14:537–44.
Shi X, Burkart A, Nicoloro SM, Czech MP, Straubhaar J, Corvera S. Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells. J Biol Chem. 2008;283:30658–67.
Asterholm IW, Mundy DI, Weng J, Anderson RG, Scherer PE. Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell Metab. 2012;15:171–85.
Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol Metab. 2012;23:435–43.
Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E. TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Invest. 2006;116:2791–8.
Laye MJ, Rector RS, Warner SO, Naples SP, Perretta AL, Uptergrove GM, Laughlin MH, Thyfault JP, Booth FW, Ibdah JA. Changes in visceral adipose tissue mitochondrial content with type 2 diabetes and daily voluntary wheel running in OLETF rats. J Physiol. 2009;587:3729–39.
Sutherland LN, Capozzi LC, Turchinsky NJ, Bell RC, Wright DC. Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance. Am J Physiol Endocrinol Metab. 2008;295:E1076–83.
Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes. 2005;54:1392–9.
Kaaman M, Sparks LM, van Harmelen V, Smith SR, Sjolin E, Dahlman I, Arner P. Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue. Diabetologia. 2007;50:2526–33.
Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S, Mirtschink P, Ukropcova B, Gasperikova D, Pedrazzini T, Krek W. Dietary obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev. 2012;26:259–70.
Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR. Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab. 2005;90:6650–6.
Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab. 2014;99:E209–16.
Mustelin L, Pietilainen KH, Rissanen A, Sovijarvi AR, Piirila P, Naukkarinen J, Peltonen L, Kaprio J, Yki-Jarvinen H. Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity. Am J Physiol Endocrinol Metab. 2008;295:E148.
Deveaud C, Beauvoit B, Salin B, Schaeffer J, Rigoulet M. Regional differences in oxidative capacity of rat white adipose tissue are linked to the mitochondrial content of mature adipocytes. Mol Cell Biochem. 2004;267:157–66.
Kraunsoe R, Boushel R, Hansen CN, Schjerling P, Qvortrup K, Stockel M, Mikines KJ, Dela F. Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. J Physiol. 2010;588:2023–32.
Dahlman I, Forsgren M, Sjogren A, Nordstrom EA, Kaaman M, Naslund E, Attersand A, Arner P. Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-alpha. Diabetes. 2006;55:1792–9.
Ost A, Svensson K, Ruishalme I, Brannmark C, Franck N, Krook H, Sandstrom P, Kjolhede P, Stralfors P. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med. 2010;16:235–46.
Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J, Straubhaar J, Czech MP, Corvera S. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest. 2004;114:1281–9.
Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS, Yoon YS, Yoon G, Choi KM, Ko YG. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia. 2006;49:784–91.
Rong JX, Qiu Y, Hansen MK, Zhu L, Zhang V, Xie M, Okamoto Y, Mattie MD, Higashiyama H, Asano S, Strum JC, Ryan TE. Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. Diabetes. 2007;56:1751–60.
Keller MP, Attie AD. Physiological insights gained from gene expression analysis in obesity and diabetes. Annu Rev Nutr. 2010;30:341–64.
Cummins TD, Holden CR, Sansbury BE, Gibb AA, Shah J, Zafar N, Tang Y, Hellmann J, Rai SN, Spite M, Bhatnagar A, Hill BG. Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab. 2014;307:E262–77.
De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol. 2009;175:927–39.
Chen XH, Zhao YP, Xue M, Ji CB, Gao CL, Zhu JG, Qin DN, Kou CZ, Qin XH, Tong ML, Guo XR. TNF-alpha induces mitochondrial dysfunction in 3T3-L1 adipocytes. Mol Cell Endocrinol. 2010;328:63–9.
Wang T, Si Y, Shirihai OS, Si H, Schultz V, Corkey RF, Hu L, Deeney JT, Guo W, Corkey BE. Respiration in adipocytes is inhibited by reactive oxygen species. Obesity (Silver Spring). 2010;18:1493–502.
Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE. The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem. 2005;280:4617–26.
Mahadev K, Motoshima H, Wu X, Ruddy JM, Arnold RS, Cheng G, Lambeth JD, Goldstein BJ. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol. 2004;24:1844–54.
Goldstein BJ, Mahadev K, Wu X, Zhu L, Motoshima H. Role of insulin-induced reactive oxygen species in the insulin signaling pathway. Antioxid Redox Signal. 2005;7:1021–31.
van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500–8.
Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J. 2000;345:161–79.
Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for different functions? Endocrinology. 2013;154:2992–3000.
Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest. 2015;125:478–86.
Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 2013;5:1196–203.
Okamatsu-Ogura Y, Fukano K, Tsubota A, Uozumi A, Terao A, Kimura K, Saito M. Thermogenic ability of uncoupling protein 1 in beige adipocytes in mice. PLoS One. 2013;8:e84229.
Nedergaard J, Cannon B. The browning of white adipose tissue: some burning issues. Cell Metab. 2014;20:396–407.
Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerback S, Virtanen KA. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14:272–9.
Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F, Turcotte EE, Richard D, Carpentier AC. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012;122:545–52.
Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.
Lopez-Soriano FJ, Fernandez-Lopez JA, Mampel T, Villarroya F, Iglesias R, Alemany M. Amino acid and glucose uptake by rat brown adipose tissue. Effect of cold-exposure and acclimation. Biochem J. 1988;252:843–9.
Cannon B, Nedergaard J. The physiological role of pyruvate carboxylation in hamster brown adipose tissue. Eur J Biochem. 1979;94:419–26.
Buckley MG, Rath EA. Regulation of fatty acid synthesis and malonyl-CoA content in mouse brown adipose tissue in response to cold-exposure, starvation or re-feeding. Biochem J. 1987;243:437–42.
Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmuller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–5.
Inokuma K, Ogura-Okamatsu Y, Toda C, Kimura K, Yamashita H, Saito M. Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue. Diabetes. 2005;54:1385–91.
Jia JJ, Tian YB, Cao ZH, Tao LL, Zhang X, Gao SZ, Ge CR, Lin QY, Jois M. The polymorphisms of UCP1 genes associated with fat metabolism, obesity and diabetes. Mol Biol Rep. 2010;37:1513–22.
Del Mar Gonzalez-Barroso M, Ricquier D, Cassard-Doulcier AM. The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research. Obes Rev Off J Int Assoc Study Obes. 2000;1:61–72.
Keipert S, Kutschke M, Lamp D, Brachthauser L, Neff F, Meyer CW, Oelkrug R, Kharitonenkov A, Jastroch M. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol Metab. 2015;4:537–42.
Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med. 2011;17:736–40.
Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem. 2011;286:12983–90.
Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–35.
Rachid B, van de Sande-Lee S, Rodovalho S, Folli F, Beltramini GC, Morari J, Amorim BJ, Pedro T, Ramalho AF, Bombassaro B, Tincani AJ, Chaim E, Pareja JC, Geloneze B, Ramos CD, Cendes F, Saad MJ, Velloso LA. Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity. Int J Obes (Lond). 2015;39:1515–22.
Williams KW, Elmquist JK. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci. 2012;15:1350–5.
Schneeberger M, Dietrich MO, Sebastian D, Imbernon M, Castano C, Garcia A, Esteban Y, Gonzalez-Franquesa A, Rodriguez IC, Bortolozzi A, Garcia-Roves PM, Gomis R, Nogueiras R, Horvath TL, Zorzano A, Claret M. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell. 2013;155:172–87.
Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116:1761–6.
Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122–5.
Schwartz MW, Woods SC, Porte Jr D, Baskin RJ, Baskin DG. Cental nervous system control of food intake. Nature. 2000;404:661–71.
Plum L, Schubert M, Bruning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab. 2005;16:59–65.
Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2002;8:1376–82.
Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers Jr MG, Rhodes CJ, Schwartz MW. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab. 2006;3:67–73.
Perrin C, Knauf C, Burcelin R. Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis. Endocrinology. 2004;145:4025–33.
Koch L, Wunderlich FT, Seibler J, Konner AC, Hampel B, Irlenbusch S, Brabant G, Kahn CR, Schwenk F, Bruning JC. Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest. 2008;118:2132–47.
Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab. 2005;2:411–20.
De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005;146:4192–9.
Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145:4880–9.
Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002;51:271–5.
Morgan K, Obici S, Rossetti L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem. 2004;279:31139–48.
Contreras C, Gonzalez-Garcia I, Martinez-Sanchez N, Seoane-Collazo P, Jacas J, Morgan DA, Serra D, Gallego R, Gonzalez F, Casals N, Nogueiras R, Rahmouni K, Dieguez C, Lopez M. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep. 2014;9:366–77.
Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell. 2013;152:673–84.
Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers Jr MG, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9:35–51.
Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron. 1999;22:221–32.
Quaresma PG, Reencober N, Zanotto TM, Santos AC, Weissmann L, de Matos AH, Lopes-Cendes I, Folli F, Saad MJ, Prada PO. Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway. Int J Obes. 2016;40:138–46.
Benani A, Barquissau V, Carneiro L, Salin B, Colombani AL, Leloup C, Casteilla L, Rigoulet M, Penicaud L. Method for functional study of mitochondria in rat hypothalamus. J Neurosci Methods. 2009;178:301–7.
Colombani AL, Carneiro L, Benani A, Galinier A, Jaillard T, Duparc T, Offer G, Lorsignol A, Magnan C, Casteilla L, Penicaud L, Leloup C. Enhanced hypothalamic glucose sensing in obesity: alteration of redox signaling. Diabetes. 2009;58:2189–97.
Dietrich MO, Liu ZW, Horvath TL. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell. 2013;155:188–99.
Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med. 2011;17:1121–7.
Horvath TL, Andrews ZB, Diano S. Fuel utilization by hypothalamic neurons: roles for ROS. Trends Endocrinol Metab. 2009;20:78–87.
Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschop MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature. 2008;454:846–51.
Campanucci V, Krishnaswamy A, Cooper E. Diabetes depresses synaptic transmission in sympathetic ganglia by inactivating nAChRs through a conserved intracellular cysteine residue. Neuron. 2010;66:827–34.
Woo M, Isganaitis E, Cerletti M, Fitzpatrick C, Wagers A, Jimenez-Chillaron J, Patti ME. Early life nutrition modulates muscle stem cell number: implications for muscle mass and repair. Stem Cells Dev. 2011;20:1763.
Iovino S, Burkart AM, Kriauciunas K, Warren L, Hughes KJ, Molla M, Lee YK, Patti ME, Kahn CR. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells. Diabetes. 2014;63:4130–42.
Burkart AM, Tan K, Warren L, Iovino S, Hughes KJ, Kahn CR, Patti ME. Insulin resistance in human iPS cells reduces mitochondrial size and function. Sci Rep. 2016;6:22788.
Turner N, Robker RL. Developmental programming of obesity and insulin resistance: does mitochondrial dysfunction in oocytes play a role? Mol Hum Reprod. 2015;21:23–30.
Rando OJ, Simmons RA. I’m eating for two: parental dietary effects on offspring metabolism. Cell. 2015;161:93–105.
Richter EA, Garetto LP, Goodman MN, Ruderman NB. Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. J Clin Invest. 1982;69:785–93.
Ren JM, Semenkovich CF, Gulve EA, Gao J, Holloszy JO. Exercise induces rapid increases in GLUT4 expression, glucose transport capacity, and insulin-stimulated glycogen storage in muscle. J Biol Chem. 1994;269:14396–401.
Hansen PA, Nolte LA, Chen MM, Holloszy JO. Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise. J Appl Physiol (1985). 1998;85:1218–22.
Wallberg-Henriksson H, Holloszy JO. Activation of glucose transport in diabetic muscle: responses to contraction and insulin. Am J Phys. 1985;249:C233–7.
Ojuka EO, Nolte LA, Holloszy JO. Increased expression of GLUT-4 and hexokinase in rat epitrochlearis muscles exposed to AICAR in vitro. J Appl Physiol (1985). 2000;88:1072–5.
Hevener AL, Reichart D, Olefsky J. Exercise and thiazolidinedione therapy normalize insulin action in the obese Zucker fatty rat. Diabetes. 2000;49:2154–9.
Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17:884–6.
Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8:457–65.
Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985). 2007;103:1093–8.
Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88:1379–406.
Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98:1154–62.
Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem. 1967;242:2278–82.
Larsen S, Nielsen J, Hansen CN, Nielsen LB, Wibrand F, Stride N, Schroder HD, Boushel R, Helge JW, Dela F, Hey-Mogensen M. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol. 2012;590:3349–60.
Dela F, Larsen JJ, Mikines KJ, Ploug T, Petersen LN, Galbo H. Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes. 1995;44:1010–20.
Hawley JA, Gibala MJ. What’s new since Hippocrates? Preventing type 2 diabetes by physical exercise and diet. Diabetologia. 2012;55:535–9.
Asterholm IW, Scherer PE. Enhanced metabolic flexibility associated with elevated adiponectin levels. Am J Pathol. 2010;176:1364–76.
Nabben M, Hoeks J, Briede JJ, Glatz JF, Moonen-Kornips E, Hesselink MK, Schrauwen P. The effect of UCP3 overexpression on mitochondrial ROS production in skeletal muscle of young versus aged mice. FEBS Lett. 2008;582:4147–52.
Holten MK, Zacho M, Gaster M, Juel C, Wojtaszewski JF, Dela F. Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes. 2004;53:294–305.
Senechal M, Rempel M, Duhamel TA, MacIntosh AC, Hay J, Wicklow B, Wittmeier K, Shen GX, McGavock JM. Fitness is a determinant of the metabolic response to endurance training in adolescents at risk of type 2 diabetes mellitus. Obesity (Silver Spring). 2015;23:823–32.
Rao X, Zhong J, Xu X, Jordan B, Maurya S, Braunstein Z, Wang TY, Huang W, Aggarwal S, Periasamy M, Rajagopalan S, Mehta K, Sun Q. Exercise protects against diet-induced insulin resistance through downregulation of protein kinase Cbeta in mice. PLoS One. 2013;8:e81364.
Tsuzuki T, Shinozaki S, Nakamoto H, Kaneki M, Goto S, Shimokado K, Kobayashi H, Naito H. Voluntary exercise can ameliorate insulin resistance by reducing iNOS-mediated S-nitrosylation of Akt in the liver in obese rats. PLoS One. 2015;10:e0132029.
Goncalves IO, Maciel E, Passos E, Torrella JR, Rizo D, Viscor G, Rocha-Rodrigues S, Santos-Alves E, Domingues MR, Oliveira PJ, Ascensao A, Magalhaes J. Exercise alters liver mitochondria phospholipidomic profile and mitochondrial activity in non-alcoholic steatohepatitis. Int J Biochem Cell Biol. 2014;54:163–73.
Ronn T, Volkov P, Tornberg A, Elgzyri T, Hansson O, Eriksson KF, Groop L, Ling C. Extensive changes in the transcriptional profile of human adipose tissue including genes involved in oxidative phosphorylation after a 6-month exercise intervention. Acta Physiol (Oxford). 2014;211:188–200.
King DE, Carek P, Mainous 3rd AG, Pearson WS. Inflammatory markers and exercise: differences related to exercise type. Med Sci Sports Exerc. 2003;35:575–81.
Abramson JL, Vaccarino V. Relationship between physical activity and inflammation among apparently healthy middle-aged and older US adults. Arch Intern Med. 2002;162:1286–92.
Geffken DF, Cushman M, Burke GL, Polak JF, Sakkinen PA, Tracy RP. Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol. 2001;153:242–50.
Mattusch F, Dufaux B, Heine O, Mertens I, Rost R. Reduction of the plasma concentration of C-reactive protein following nine months of endurance training. Int J Sports Med. 2000;21:21–4.
Stallknecht B, Vinten J, Ploug T, Galbo H. Increased activities of mitochondrial enzymes in white adipose tissue in trained rats. Am J Phys. 1991;261:E410–4.
Trevellin E, Scorzeto M, Olivieri M, Granzotto M, Valerio A, Tedesco L, Fabris R, Serra R, Quarta M, Reggiani C, Nisoli E, Vettor R. Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms. Diabetes. 2014;63:2800–11.
Stanford KI, Middelbeek RJ, Goodyear LJ. Exercise effects on white adipose tissue: beiging and metabolic adaptations. Diabetes. 2015;64:2361–8.
Mahoney DJ, Parise G, Melov S, Safdar A, Tarnopolsky MA. Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. FASEB J. 2005;19:1498–500.
Gollisch KS, Brandauer J, Jessen N, Toyoda T, Nayer A, Hirshman MF, Goodyear LJ. Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats. Am J Physiol Endocrinol Metab. 2009;297:E495–504.
Craig BW, Hammons GT, Garthwaite SM, Jarett J, Holloszy JO. Adaptation of fat cells to exercise: response of glucose uptake and oxidation to insulin. J Appl Physiol. 1981;51:1500–6.
Sutherland LN, Bomhof MR, Capozzi LC, Basaraba SA, Wright DC. Exercise and adrenaline increase PGC-1{alpha} mRNA expression in rat adipose tissue. J Physiol. 2009;587:1607–17.
Stanford KI, Middelbeek RJ, Townsend KL, Lee MY, Takahashi H, So K, Hitchcox KM, Markan KR, Hellbach K, Hirshman MF, Tseng YH, Goodyear LJ. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes. 2015;64:2002–14.
Vernochet C, Mourier A, Bezy O, Macotela Y, Boucher J, Rardin MJ, An D, Lee KY, Ilkayeva OR, Zingaretti CM, Emanuelli B, Smyth G, Cinti S, Newgard CB, Gibson BW, Larsson NG, Kahn CR. Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab. 2012;16:765–76.
Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000;49:677–83.
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603–8.
Suga T, Kinugawa S, Takada S, Kadoguchi T, Fukushima A, Homma T, Masaki Y, Furihata T, Takahashi M, Sobirin MA, Ono T, Hirabayashi K, Yokota T, Tanaka S, Okita K, Tsutsui H. Combination of exercise training and diet restriction normalizes limited exercise capacity and impaired skeletal muscle function in diet-induced diabetic mice. Endocrinology. 2014;155:68–80.
Snel M, Gastaldelli A, Ouwens DM, Hesselink MK, Schaart G, Buzzigoli E, Frolich M, Romijn JA, Pijl H, Meinders AE, Jazet IM. Effects of adding exercise to a 16-week very low-calorie diet in obese, insulin-dependent type 2 diabetes mellitus patients. J Clin Endocrinol Metab. 2012;97:2512–20.
Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006;55:924–8.
Nakatani T, Kim HJ, Kaburagi Y, Yasuda K, Ezaki O. A low fish oil inhibits SREBP-1 proteolytic cascade, while a high-fish-oil feeding decreases SREBP-1 mRNA in mice liver: relationship to anti-obesity. J Lipid Res. 2003;44:369–79.
Lionetti L, Mollica MP, Donizzetti I, Gifuni G, Sica R, Pignalosa A, Cavaliere G, Gaita M, De Filippo C, Zorzano A, Putti R. High-lard and high-fish-oil diets differ in their effects on function and dynamic behaviour of rat hepatic mitochondria. PLoS One. 2014;9:e92753.
Reznick RM, Shulman GI. The role of AMP-activated protein kinase in mitochondrial biogenesis. J Physiol. 2006;574:33–9.
Rockl KS, Witczak CA, Goodyear LJ. Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life. 2008;60:145–53.
Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015;347:1253–6.
Lou PH, Hansen BS, Olsen PH, Tullin S, Murphy MP, Brand MD. Mitochondrial uncouplers with an extraordinary dynamic range. Biochem J. 2007;407:129–40.
Koch RA, Lee RC, Tainter ML. Dinitrophenol on liver function. Cal West Med. 1935;43:337–9.
Antonenko YN, Avetisyan AV, Cherepanov DA, Knorre DA, Korshunova GA, Markova OV, Ojovan SM, Perevoshchikova IV, Pustovidko AV, Rokitskaya TI, Severina II, Simonyan RA, Smirnova EA, Sobko AA, Sumbatyan NV, Severin FF, Skulachev VP. Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers. J Biol Chem. 2011;286:17831–40.
Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009;20:98–105.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–42.
Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100:328–41.
Biala A, Tauriainen E, Siltanen A, Shi J, Merasto S, Louhelainen M, Martonen E, Finckenberg P, Muller DN, Mervaala E. Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes. Blood Press. 2010;19:196–205.
Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289:2126–8.
Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390–2.
Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127:1109–22.
Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010;285:8340–51.
Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, Pearson K, de Cabo R, Pacher P, Zhang C, Ungvari Z. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. 2009;297:H13–20.
Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14:612–22.
Jackson JR, Ryan MJ, Alway SE. Long-term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in aged mice. J Gerontol A Biol Sci Med Sci. 2011;66:751–64.
Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res (New York, NY). 2012;32:537–41.
Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci. 2012;67:1307–12.
Yoshino J, Conte C, Fontana L, Mittendorfer B, Imai S, Schechtman KB, Gu C, Kunz I, Rossi Fanelli F, Patterson BW, Klein S. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 2012;16:658–64.
Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712–6.
Maguire JJ, Wilson DS, Packer L. Mitochondrial electron transport-linked tocopheroxyl radical reduction. J Biol Chem. 1989;264:21462–5.
Yi X, Maeda N. alpha-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E-deficient mice fed high-fat/low-cholesterol diet. Diabetes. 2006;55:2238–44.
Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem. 2001;276:4588–96.
Baksi A, Kraydashenko O, Zalevkaya A, Stets R, Elliott P, Haddad J, Hoffmann E, Vlasuk GP, Jacobson EW. A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes. Br J Clin Pharmacol. 2014;78:69–77.