Molecular Aspects of Obesity and Insulin Resistance in Metabolic Syndrome and Neurological Disorders

  • Akhlaq A. Farooqui


It is becoming increasingly evident that obesity is mediated by dysfunction of feeding centers in hypothalamus, imbalance in energy intake and expenditure, and genetic variations. Obesity is an essential component of the MetS, which is characterized by abnormalities in glucose and lipid metabolism, low-grade inflammation, hypertension, and insulin resistance. Obesity is mediated by a variety of mediators, such as leptin, insulin, and different adipocytokines. Leptin resistance is closely associated with obesity and diabetes. In contrast, adiponectin produces anti-inflammatory effects and reduces obesity by regulating food intake and therefore exerting a direct effect on energy balance and weight control. Other cytokines and chemokines contribute to low-grade inflammation and initial adipose macrophage infiltration, which promote impairment in adipocyte insulin signaling and induction of insulin resistance through the interference of insulin/insulin-like growth factor 1 receptor (IGF-IR) signaling pathways. Oxidative stress and low-grade inflammation are caused by an imbalance between increased production of ROS and/or reduced antioxidant activity and secretion of adipocytokines and cytokines, respectively. Collective evidence suggests that obesity is closely associated with changes in the serum levels of leptin, insulin, glucose, and corticosterone/cortisol.


Insulin Resistance Adipose Tissue Insulin Sensitivity Endoplasmic Reticulum Stress Alzheimer Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abizaid A, Horvath TL (2008) Brain circuits regulating energy homeostasis. Regul Pept 149:3–10CrossRefPubMedGoogle Scholar
  2. Adams JM II, Pratipanawatr T, Berria R, Wang E, DeFronzo RA, Sullards MC, Mandarino LJ (2004) Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53:25–31CrossRefPubMedGoogle Scholar
  3. Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, Hwang DH, Newman JW, Garvey WT (2009) Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr 139:1073–1081CrossRefPubMedGoogle Scholar
  4. Agouni A, Mody N, Owen C, Czopek A, Zimmer D, Bentires-Alj M, Bence KK, Delibegović M (2011) Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress. Biochem J 438:369–378CrossRefPubMedGoogle Scholar
  5. Ahima RS, Prabakaran D, Flier JS (2000) Leptin. Annu Rev Physiol 62:413–437CrossRefPubMedGoogle Scholar
  6. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801CrossRefPubMedGoogle Scholar
  7. Alam I, Ng TP, anf Larbi NA (2012) Does inflammation determine whether obesity is metabolically healthy or unhealthy? The aging perspective. Mediators Inflamm 2012:456456CrossRefPubMedGoogle Scholar
  8. Altintas MM, Rossetti MA, Nayer B, Puig A, Zagallo P, Ortega LM, Johnson KB, McNamara G, Reiser J, Mendez AJ, Nayer A (2011) Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long-standing diet-induced obese mice. Lipids Health Dis 10:198CrossRefPubMedGoogle Scholar
  9. Alzheimer Scotland (2011) Risk factors in dementia. Alzheimer Scotland, EdinburghGoogle Scholar
  10. Alzheimer’s Disease International (2010) World Alzheimer Report 2010. ADI, IllinoisGoogle Scholar
  11. Alzheimer’s disease, Senile dementia [Last cited on 2010 Jan 8]. http://www.Dementia/
  12. An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB (2004) Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 10:268–274CrossRefPubMedGoogle Scholar
  13. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW III, Kang L, Kabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Nufer PD (2009) Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119:573–581CrossRefPubMedGoogle Scholar
  14. Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR (2010) Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem 285:21590–21599CrossRefPubMedGoogle Scholar
  15. Arab L, Sadeghi R, Walker DG, Lue LF, Sabbagh MN (2011) Consequences of Aberrant Insulin Regulation in the Brain: Can Treating Diabetes be Effective for Alzheimer’s Disease. Curr Neuropharmacol 9:693–705CrossRefPubMedGoogle Scholar
  16. Archer ZA, Mercer JG (2007) Brain responses to obesogenic diets and diet-induced obesity. Proc Nutr Soc 66:124–130CrossRefPubMedGoogle Scholar
  17. Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E (2005) Free fatty acids repress the Glut4 gene expression in cardiac muscle via novel response elements. J Biol Chem 280:34786–34795CrossRefPubMedGoogle Scholar
  18. Atkinson LL, Fischer MA, Lopaschuk GD (2002) Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis. J Biol Chem 277:29424–29430CrossRefPubMedGoogle Scholar
  19. Avena NM, Rada P, Hoebel BG (2009) Sugar and fat bingeing have notable differences in addictive-like behavior. J Nutr 139:623–628CrossRefPubMedGoogle Scholar
  20. Avramoglu RK, Basciano H, Adeli K (2006) Lipid and lipoprotein dysregulation in insulin resistant states. Clin Chim Acta 368:1–19CrossRefPubMedGoogle Scholar
  21. Baile CA, Della-Fera MA, Martin RJ (2000) Regulation of metabolism and body fat mass by leptin. Annu Rev Nutr 20:105–127CrossRefPubMedGoogle Scholar
  22. Balakrishnan K, Verdile G, Mehta PD, Beilby J, Nolan D, Galvão DA, Newton R, Gandy SE, Martins RN (2005) Plasma Abeta42 correlates positively with increased body fat in healthy individuals. J Alzheimers Dis 8:269–282PubMedGoogle Scholar
  23. Banks AS, Davis SM, Bates SH, Myers MG Jr (2000) Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 275:14563–14572CrossRefPubMedGoogle Scholar
  24. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 17:4–12PubMedGoogle Scholar
  25. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421:856–859CrossRefPubMedGoogle Scholar
  26. Bates SH, Kulkarni RN, Seifert M, Myers MG Jr (2005) Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab 1:169–178CrossRefPubMedGoogle Scholar
  27. Bays H, Mandarino L, DeFronzo RA (2004) Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 89:463–478CrossRefPubMedGoogle Scholar
  28. Bays HE, Tighe AP, Sadovsky R, Davidson MH (2008a) Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther 6:391–409CrossRefPubMedGoogle Scholar
  29. Bays HE, Gonzalez-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, Rodbard HW, Henry RR (2008b) The pathogenic potential of adipose tissue and the metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther 6:343–368CrossRefPubMedGoogle Scholar
  30. Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB (2006) Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12:917–924CrossRefPubMedGoogle Scholar
  31. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953CrossRefPubMedGoogle Scholar
  32. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2002) ACRP30/adiponectin; adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13:84–89CrossRefPubMedGoogle Scholar
  33. Bergeron R, Russell RR III, Young LH, Ren JM, Marcucci M, Lee A, Shulman GI (1999) Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol 276:E938–E944PubMedGoogle Scholar
  34. Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, Hucking K, Ader M (2006) Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring) 14(Suppl 1):16S–19SCrossRefGoogle Scholar
  35. Bjorbaek C, Kahn BB (2004) Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 59:305–331CrossRefPubMedGoogle Scholar
  36. Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS (1999) The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 274:30059–30065CrossRefPubMedGoogle Scholar
  37. Bjørbæk C, Elmquist JK, Michl P, Ahima RS, van Bueren A, McCall AL, Flier JS (1998) Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139:3485–3491CrossRefPubMedGoogle Scholar
  38. Blouet C, Schwartz GJ (2010) Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 209:1–12CrossRefPubMedGoogle Scholar
  39. Boden G, Chen X (1995) Effects of fat on glucose uptake and utilization in patients with noninsulin-dependent diabetes. J Clin Invest 96:1261–1268CrossRefPubMedGoogle Scholar
  40. Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, Xiang X, Luo Z, Ruderman N (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver. Diabetes 54:3458–3465CrossRefPubMedGoogle Scholar
  41. Borst SE (2004) The role of TNF-alpha in insulin resistance. Endocrine 23:177–182CrossRefPubMedGoogle Scholar
  42. Bottner A, Kratzsch J, Muller G, Kapellen TM, Bluher S, Keller F, Bluher M, Kiess W (2004) Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metab 89:4053–4061CrossRefPubMedGoogle Scholar
  43. Boura-Halfon S, Zick Y (2009) Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 296:E581–E591CrossRefPubMedGoogle Scholar
  44. Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y (2004) Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA 101:2476–2481CrossRefPubMedGoogle Scholar
  45. Brown LA, Kerr CJ, Whiting P (2009) Oxidant stress in healthy normal-weight, overweight, and obese individuals. Obesity (Silver Spring) 17:460–466CrossRefGoogle Scholar
  46. Businaro R, Ippoliti F, Ricci S, Canitano N, Fuso A (2012) Alzheimer’s disease promotion by obesity: induced mechanisms-molecular links and perspectives. Curr Gerontol Geriatr Res 2012:986823PubMedGoogle Scholar
  47. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190CrossRefPubMedGoogle Scholar
  48. Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J (2010) Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab 11:213–219CrossRefPubMedGoogle Scholar
  49. Castro JP, El-Atat FA, McFarlane SI, Aneja A, Sowers JR (2003) Cardiometabolic syndrome: pathophysiology and treatment. Curr Hypertens Rep 5:393–401CrossRefPubMedGoogle Scholar
  50. Ceddia RB, Somwar R, Maida A, Fang X, Bikopoulos G, Sweeney G (2005) Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia 48:132–139CrossRefPubMedGoogle Scholar
  51. Chaudhuri K, Samarakoon SM, Chandola HM, Kumar R, Ravishankar B (2011) Evaluation of diet and life style in etiopathogenesis of senile dementia: a survey study. Ayu 32:171–176CrossRefPubMedGoogle Scholar
  52. Cheng ZJ, Vapaatalo H, Mervaala E (2005) Angiotensin II and vascular inflammation. Med Sci Monit 11:RA194–RA205PubMedGoogle Scholar
  53. Chiba T, Yamada M, Aiso S (2009) Targeting the JAK2/STAT3 axis in Alzheimer’s disease. Expert Opin Ther Targets 13:1155–1167CrossRefPubMedGoogle Scholar
  54. Chrysohoou C, Panagiotakos DB, Pitsavos C, Skoumas I, Papademetriou L, Economou M, Stefanadis C (2007) The implication of obesity on total antioxidant capacity apparently healthy men and women: the ATTICA study. Nutr Metab Cardiovasc Dis 17:590–597CrossRefPubMedGoogle Scholar
  55. Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci USA 105:1739–1744CrossRefPubMedGoogle Scholar
  56. Civitarese AE, Ukropcova B, Carling S, Hulver M, DeFronzo RA, Mandarino L, Ravussin E, Smith SR (2006) Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab 4:75–87CrossRefPubMedGoogle Scholar
  57. Colantuoni C, Schwenker J, McCarthy J, Rada P, Ladenheim B, Cadet JL, Schwartz GJ, Moran TH, Hoebel BG (2001) Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. Neuroreport 12:3549–3552CrossRefPubMedGoogle Scholar
  58. Coll AP, Farooqi IS, O’Rahilly S (2007) The hormonal control of food intake. Cell 129:251–262CrossRefPubMedGoogle Scholar
  59. Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, Russell RG, Lindemann D, Hartley A, Baker GR, Obici S, Deshaies Y, Ludgate M, Rossetti L, Scherer PE (2004) A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145:367–383CrossRefPubMedGoogle Scholar
  60. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295CrossRefPubMedGoogle Scholar
  61. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH (2008) The metabolic syndrome. Endocr Rev 29:777–822CrossRefPubMedGoogle Scholar
  62. Corton JM, Gillespie JG, Hardie DG (1994) Role of the AMP-activated protein kinase in the cellular stress response. Curr Biol 4:315–324CrossRefPubMedGoogle Scholar
  63. Craft S (2009) The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 66:300–305CrossRefPubMedGoogle Scholar
  64. Davis JF, Choi DL, Benoit SC (2010) Insulin, leptin and reward. Trends Endocrinol Metab 21:68–74CrossRefPubMedGoogle Scholar
  65. de la Monte SM (2012) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 9:35–66CrossRefPubMedGoogle Scholar
  66. de la Monte SM, Wands JR Jr (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2:1101–1113PubMedGoogle Scholar
  67. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199CrossRefPubMedGoogle Scholar
  68. De TB, Smith LH, Vaughan DE (2005) Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr Opin Pharmacol 5:149–154CrossRefGoogle Scholar
  69. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J, Zhu H, Ghiso J, Frangione B, Stern A, Schmidt AM, Armstrong DL, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic B (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9:907–913CrossRefPubMedGoogle Scholar
  70. del Aguila LF, Claffey KP, Kirwan JP (1999) TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol 276:E849–E855PubMedGoogle Scholar
  71. Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, Cho YR, Kim JK, Kahn BB, Neel BG, Bence KK (2009) Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress. Diabetes 58:590–599CrossRefPubMedGoogle Scholar
  72. Denke MA, Sempos CT, Grundy SM (1994) Excess body weight. An under-recognized contributor to dyslipidemia in white American women. Arch Intern Med 154:401–410CrossRefPubMedGoogle Scholar
  73. Dietrich M, Horvath T (2009) Feeding signals and brain circuitry. Eur J Neurosci 30:1688–1696CrossRefPubMedGoogle Scholar
  74. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M (2001) Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 108:1341–1348PubMedGoogle Scholar
  75. Duracková Z (2010) Some current insights into oxidative stress. Physiol Res 59:459–469PubMedGoogle Scholar
  76. Egger G, Dixon J (2011) Non-nutrient causes of low-grade, systemic inflammation: support for a “canary in the mineshaft” view of obesity in chronic disease. Obes Rev 12:339–345CrossRefPubMedGoogle Scholar
  77. El-Khairy L, Ueland PM, Refsum H, Graham IM, Vollset SE (2001) Plasma total cysteine as a risk factor for vascular disease: the European Concerted Action Project. Circulation 103:2544–2549CrossRefPubMedGoogle Scholar
  78. Elshorbagy AK, Refsum H, Smith AD, Graham IM (2009) The association of plasma cysteine and gamma-glutamyltransferase with BMI and obesity. Obesity (Silver Spring) 17:1435–1440Google Scholar
  79. Elshorbagy AK, Church C, Valdivia-Garcia M, Smith AD, Refsum H, Cox R (2012) Dietary cystine level affects metabolic rate and glycaemic control in adult mice. J Nutr Biochem 23:332–340CrossRefPubMedGoogle Scholar
  80. Esposito K, Ciotola M, Giugliano D (2006) Oxidative stress in the metabolic syndrome. J Endocrinol Invest 29:791–795PubMedGoogle Scholar
  81. Fang X, Palanivel R, Zhou X, Liu Y, Xu A, Wang Y, Sweeney G (2005) Hyperglycemia- and hyperinsulinemia-induced alteration of adiponectin receptor expression and adiponectin effects in L6 myoblasts. J Mol Endocrinol 35:465–476CrossRefPubMedGoogle Scholar
  82. Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM, Chen JX, Yan S (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24:1043–1055CrossRefPubMedGoogle Scholar
  83. Farooqui AA (2010) Neurochemical aspects of neurotraumatic and neurodegenerative diseases. Springer, New YorkCrossRefGoogle Scholar
  84. Farooqui AA, Horrocks LA (2007) Glycerophospholipids in the brain. Springer, New YorkCrossRefGoogle Scholar
  85. Farooqui AA, Farooqui T, Panza F, Frisardi V (2012) Metabolic syndrome as a risk factor for neurological disorders. Cell Mol Life Sci 69:741–762CrossRefPubMedGoogle Scholar
  86. Fernández-Galaz C, Fernández-Agulló T, Campoy F, Arribas C, Gallardo N, Andres A, Ros M, Carrascosa M (2001) Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats. J Endocrinol 171:23–32CrossRefPubMedGoogle Scholar
  87. Fernandez-Sanchez A, Madrigal-Santillan E, Bautista M, Esquivel-Soto J, Morales-Gonzalez A, Esquivel-Chirino C, Durante-Montiel I, Sanchez-Rivera G, Valadez-Vega C, Morales-Gonzalez JA (2011) Inflammation, oxidative stress, and obesity. Int J Mol Sci 12:3117–3132CrossRefPubMedGoogle Scholar
  88. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N (2004) Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J 18:1870–1878CrossRefPubMedGoogle Scholar
  89. Flegal KM, Graubard BI, Williamson DF, Gail MH (2007) Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 298:2028–2037CrossRefPubMedGoogle Scholar
  90. Fonseca V, Desouza C, Asnani S, Jialal I (2004) Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev 25:153–175CrossRefPubMedGoogle Scholar
  91. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB (2003) Years of life lost due to obesity. JAMA 289:187–193CrossRefPubMedGoogle Scholar
  92. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1:1311–1314CrossRefPubMedGoogle Scholar
  93. Freeman LR, Zhang L, Dasuri K, Fernandez-Kim SO, Bruce-Keller AJ, Keller JN (2012) Mutant amyloid precursor protein differentially alters adipose biology under obesogenic and non-obesogenic conditions. PLoS One 7:e43193CrossRefPubMedGoogle Scholar
  94. Fukuyama Y, Ohta K, Okoshi R, Suehara M, Kizaki H, Nakagawa K (2007) Hypoxia induces expression and activation of AMPK in rat dental pulp cells. J Dent Res 86:903–907CrossRefPubMedGoogle Scholar
  95. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomurai I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761PubMedGoogle Scholar
  96. Geiger BM, Behr GG, Frank LE, Caldera-Siu AD, Beinfeld MC, Kokkotou EG, Pothos EN (2008) Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats. FASEB J 22:2740–2746CrossRefPubMedGoogle Scholar
  97. Gesta S, Blüher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, Boucher J, Lewis C, Kahn CR (2006) Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci USA 103:6676–6681CrossRefPubMedGoogle Scholar
  98. Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131:242–256CrossRefPubMedGoogle Scholar
  99. Ghilardi N, Skoda RC (1997) The leptin receptor activates Janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol Endocrinol 11:393–399CrossRefPubMedGoogle Scholar
  100. Giral P, Jacob N, Dourmap C, Hansel B, Carrie A, Bruckert E (2008) Elevated gamma-glutamyltransferase activity and perturbed thiol profile are associated with features of metabolic syndrome. Arterioscler Thromb Vasc Biol 28:587–593CrossRefPubMedGoogle Scholar
  101. Girones X, Guimera A, Cruz-Sanchez CZ, Ortega A, Sasaki N, Makita Z, Lafuente JV, Kalaria R, Cruz-Sanchez FF (2004) N ε-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer’s disease. Free Radic Biol Med 36:1241–1247CrossRefPubMedGoogle Scholar
  102. Grundy SM (2003) Inflammation, hypertension and the metabolic syndrome. JAMA 290:3000–3002CrossRefPubMedGoogle Scholar
  103. Hajnal A, Smith GP, Norgren R (2004) Oral sucrose stimulation increases accumbens dopamine in the rat. Am J Physiol Regul Integr Comp Physiol 286:R31–R37CrossRefPubMedGoogle Scholar
  104. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658CrossRefPubMedGoogle Scholar
  105. Hamilton MT, Hamilton DG, Zderic TW (2007) The role of low energy expenditure and sitting on obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 56:2655–2667CrossRefPubMedGoogle Scholar
  106. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785CrossRefPubMedGoogle Scholar
  107. Hardie DG, Sakamoto K (2006) AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 21:48–60CrossRefGoogle Scholar
  108. Harding HP, Novoa I, Zhang H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108CrossRefPubMedGoogle Scholar
  109. Hartwich J, Góralska J, Siedlecka D, Gruca A, Trzos M, Dembinska-Kiec A (2007) Effect of supplementation with vitamin E and C on plasma hsCRP level and cobalt-albumin binding score as markers of plasma oxidative stress in obesity. Genes Nutr 2:151–154CrossRefPubMedGoogle Scholar
  110. Harvey J, McKay NG, Walker KS, Van der Kaay J, Downes CP, Ashford ML (2000) Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line. J Biol Chem 275:4660–4669CrossRefPubMedGoogle Scholar
  111. Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132:344–362CrossRefPubMedGoogle Scholar
  112. Herrara BM, Lindgren CM (2010) The genetics of obesity. Curr Diab Rep 10:498–505CrossRefGoogle Scholar
  113. Hirosumi J, Tuneman G, Chang L, Gorgun CZ, Uysal KT, Karin M, Hotamisligil S (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336CrossRefPubMedGoogle Scholar
  114. Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, Stocker R, Van Remmen H, Kraegen EW, Cooney GJ, Richardson AR, James DE (2009) Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci USA 106:17787–17792CrossRefPubMedGoogle Scholar
  115. Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K (2009) Serum leptin level and cognition in the elderly: findings from the Health ABC Study. Neurobiol Aging 30:1483–1489CrossRefPubMedGoogle Scholar
  116. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat- and obesity-induced insulin resistance. Cell Metab 5:167–179CrossRefPubMedGoogle Scholar
  117. Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM, Wade MR, Tenorio VM, Kuo MS, Brozinick JT, Zhang BB, Birnbaum MJ, Summers SA, Scherer PE (2011) Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17:55–63CrossRefPubMedGoogle Scholar
  118. Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, Tschöp MH (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA 107:14875–14880CrossRefPubMedGoogle Scholar
  119. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I (2007) Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:901–911CrossRefPubMedGoogle Scholar
  120. Hossain P, Kawar B, El Nahas M (2007) Obesity and diabetes in the developing world: a growing challenge. N Engl J Med 356:213–215CrossRefPubMedGoogle Scholar
  121. Hotamisligil GS (2003) Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord 27(Suppl 3):S53–S55CrossRefPubMedGoogle Scholar
  122. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867CrossRefPubMedGoogle Scholar
  123. Hotamisligil GS (2008) Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond) 32(Suppl 7):S52–S54CrossRefGoogle Scholar
  124. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y (2000) Plasma concentrations of a novel adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599CrossRefPubMedGoogle Scholar
  125. Hoyer S (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490:115–125CrossRefPubMedGoogle Scholar
  126. Hsu HT, Chang YC, Chiu YN, Liu CL, Chang KJ, Guo IC (2006) Leptin interferes with adrenocorticotropin/3′,5′-cyclic adenosine monophosphate (cAMP) signaling, possibly through a Janus kinase 2-phosphatidylinositol 3-kinase/Akt-phosphodiesterase 3-cAMP pathway, to down-regulate cholesterol side-chain cleavage cytochrome P450 enzyme in human adrenocortical NCI-H295 cell line. J Clin Endocrinol Metab 91:2761–2769CrossRefPubMedGoogle Scholar
  127. Huffman DM, Barzilai N (2009) Role of visceral adipose tissue in aging. Biochim Biophys Acta 1790:1117–1123CrossRefPubMedGoogle Scholar
  128. Hug C, Lodish HF (2005) The role of the adipocyte hormone adiponectin in cardiovascular disease. Curr Opin Pharmacol 5:129–134CrossRefPubMedGoogle Scholar
  129. Ibrahimi A, Bonen A, Blinn WD, Hajri T, Li X, Zhong K, Cameron R, Abumrad NA (1999) Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin. J Biol Chem 274:26761–26766CrossRefPubMedGoogle Scholar
  130. Ido Y, Carling D, Ruderman N (2002) Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 51:159–167CrossRefPubMedGoogle Scholar
  131. Ikonen E, Vainio S (2005) Lipid microdomains and insulin resistance: is there a connection? Sci STKE 2005:pe3PubMedGoogle Scholar
  132. Inokuchi J (2006) Insulin resistance as a membrane microdomain disorder. Biol Pharm Bull 29:1532–1537CrossRefPubMedGoogle Scholar
  133. Itani SI, Ruderman NB, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51:2005–2011CrossRefPubMedGoogle Scholar
  134. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T (2010) Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464:1313–1319CrossRefPubMedGoogle Scholar
  135. Jazet IM, Pijl H, Meinders AE (2003) Adipose tissue as an endocrine organ: impact on insulin resistance. Neth J Med 61:194–212PubMedGoogle Scholar
  136. Jellinger KA (2009) Recent advances in our understanding of neurodegeneration. J Neural Transm 116:1111–1162CrossRefPubMedGoogle Scholar
  137. Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB (2009) Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab 296:E955–E964CrossRefPubMedGoogle Scholar
  138. Jiao P, Chen Q, Shah S, Tao B, Tzameli I, Yan W, Xu H (2009) Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-κB and c-Jun NH2-terminal kinase pathways. Diabetes 58:104–115CrossRefPubMedGoogle Scholar
  139. Johansen D, Stocks T, Jonsson H, Lindkvist B, Bjorge T, Concin H, Almquist M, Haggstrom C, Engeland A, Ulmer H, Hallmans G, Selmer R, Nagel G, Tretli S, Stattin P, Manjer J (2010) Metabolic factors and the risk of pancreatic cancer: a prospective analysis of almost 580,000 men and women in the Metabolic Syndrome and Cancer Project. Cancer Epidemiol Biomarkers Prev 19:2307–2317CrossRefPubMedGoogle Scholar
  140. Johnson JA, Ynada Y, Flancbaum L, Albu J (2001) Cytokine release in deep subcutaneous, abdominal and visceral tissue depots. Diabetes 50:A88Google Scholar
  141. Juhan-Vague I, Alessi MC, Mavri A, Morange PE (2003) Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 1:1575–1579CrossRefPubMedGoogle Scholar
  142. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792CrossRefPubMedGoogle Scholar
  143. Kadowaki T, Yamauchi T, Kubota N (2008) The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett 582:74–80CrossRefPubMedGoogle Scholar
  144. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL (2005) Harrison’s principles of Internal medicine, 16th edn. McGraw-Hill Medical publishing division, New York, pp 2393–2399Google Scholar
  145. Kassi E, Pervanidou P, Kaltsas G, Chrousos G (2011) Metabolic syndrome: definitions and controversies. BMC Med 9:48CrossRefPubMedGoogle Scholar
  146. Kavanagh K, Jones KL, Sawyer J, Kelley K, Carr JJ, Wagner JD, Rudel LL (2007) Trans fat diet induces abdominal obesity and changes in insulin sensitivity in monkeys. Obesity (Silver Spring) 15:1675–1684CrossRefGoogle Scholar
  147. Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:2944–2950CrossRefPubMedGoogle Scholar
  148. Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S (2009) Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem Biophys Res Commun 384:311–315CrossRefPubMedGoogle Scholar
  149. 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 (2001) Tissue-specific overexpression of lipoprotein lipase causes tissue specific insulin resistance. Proc Natl Acad Sci USA 98:7522–7527CrossRefPubMedGoogle Scholar
  150. Kim JK, Fillman JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, Soos TJ, Cline GW, O’Brien WR, Littman DR, Shulman GI (2004) PKC-θ knockout mice are protected from fat-induced insulin resistance. J Clin Invest 114:823–827PubMedGoogle Scholar
  151. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM et al (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117:2621–2637CrossRefPubMedGoogle Scholar
  152. Kivipelto M, Solomon A (2008) Alzheimer’s disease—the ways of prevention. J Nutr Health Aging 12:89S–94SCrossRefPubMedGoogle Scholar
  153. Koistinen HA, Galuska D, Chibalin AV, Yang J, Zierath JR, Holman GD, Wallberg-Henriksson H (2003) 5-Amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes 52:1066–1072CrossRefPubMedGoogle Scholar
  154. Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM (2005) Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 280:33588–33598CrossRefPubMedGoogle Scholar
  155. Koves TR, Ussher JR, Noland RC, Sientz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45–56CrossRefPubMedGoogle Scholar
  156. Kraegen EW, Cooney GJ, Ye JM, Thompson AL, Furler SM (2001) The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity. Exp Clin Endocrinol Diabetes 109(Suppl 2):S189–S201CrossRefPubMedGoogle Scholar
  157. Krötz F, Sohn H-Y, Pohl U (2004) Reactive oxygen species: players in the platelet game. Arterioscler Thromb Vasc Biol 24:1988–1996CrossRefPubMedGoogle Scholar
  158. Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Matsumura T, Araki E (2006) Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55:120–127CrossRefPubMedGoogle Scholar
  159. Lam TT, Van De Werve G, Giacca A (2003) Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol Endocrinol Metab 284:E281–E290PubMedGoogle Scholar
  160. Leahey TM, Myers TA, Gunstad J, Glickman E, Spitznagel MB, Alexander T, Juvancic-Heltzel J (2007) Abeta40 is associated with cognitive function, body fat and physical fitness in healthy older adults. Nutr Neurosci 10:205–209CrossRefPubMedGoogle Scholar
  161. Lee YH, Tharp WG, Maple RL, Nair S, Permana PA et al (2008) Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity (Silver Spring) 16:1493–1500CrossRefGoogle Scholar
  162. Lelliott C, Vidal-Puig AJ (2004) Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int J Obes Relat Metab Disord 28(Suppl 4):S22–S28CrossRefPubMedGoogle Scholar
  163. Lenoir M, Serre F, Cantin L, Ahmed SH (2007) Intense sweetness surpasses cocaine reward. PLoS One 2:e698CrossRefPubMedGoogle Scholar
  164. Li WX (2008) Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol 18:545–551CrossRefPubMedGoogle Scholar
  165. Li X, Stark GR (2002) NFkappaB-dependent signaling pathways. Exp Hematol 30:285–296CrossRefPubMedGoogle Scholar
  166. Li M, Baumeister P, Roy B, Phan T, Foti D, Luo S, Lee AS (2000) ATF6 as a transcription activator of the endoplasmic reticulum stress element. Thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1. Mol Cell Biol 20:5096–5106CrossRefPubMedGoogle Scholar
  167. Li X, Han Y, Pang W, Li C, Xie X et al (2008) AMP-activated protein kinase promotes the differentiation of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 28:1789–1795CrossRefPubMedGoogle Scholar
  168. Li FY, Cheng KK, Lam KS, Vanhoutte PM, Xu A (2011) Cross-talk between adipose tissue and vasculature: role of adiponectin. Acta Physiol (Oxf) 203:167–180CrossRefGoogle Scholar
  169. Liang NC, Hajnal A, Norgren R (2006) Sham feeding corn oil increases accumbens dopamine in the rat. Am J Physiol Regul Integr Comp Physiol 291:R1236–R1239CrossRefPubMedGoogle Scholar
  170. Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S (2009) Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging. JAMA 302:2565–2572CrossRefPubMedGoogle Scholar
  171. Lillioja S, Nyomba BL, Saad MF, Ferraro R, Castillo C, Bennett PH (1991) Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab 73:866–876CrossRefPubMedGoogle Scholar
  172. Long YC, Zierath JR (2006) AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest 116:1776–1783CrossRefPubMedGoogle Scholar
  173. Loskutoff DJ, Samad F (1998) The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol 18:1–6CrossRefPubMedGoogle Scholar
  174. Lowell BB (1999) PPARγ: an essential regulator of adipogenesis and modulator of fat cell function. Cell 99:239–242CrossRefPubMedGoogle Scholar
  175. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23CrossRefPubMedGoogle Scholar
  176. Lund IV, Hu Y, Raol YH, Benham RS, Faris R, Russek SJ, Brooks-Kayal AR (2008) BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway. Sci Signal 1:ra9CrossRefPubMedGoogle Scholar
  177. Mahmoud GS, Grover LM (2006) Growth hormone enhances excitatory synaptic transmission in area CA1 of rat hippocampus. J Neurophysiol 95:2962–2974CrossRefPubMedGoogle Scholar
  178. Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731CrossRefPubMedGoogle Scholar
  179. Mao X, Hong JY, Dong LQ (2006) The adiponectin signaling pathway as a novel pharmacological target. Mini Rev Med Chem 6:1331–1340CrossRefPubMedGoogle Scholar
  180. Massiera F, Saint-Marc P, Seydoux J, Murata T, Kobayashi T, Narumiya S, Guesnet P, Amri EZ, Negrel R, Ailhaud G (2003) Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern? J Lipid Res 44:271–279CrossRefPubMedGoogle Scholar
  181. Matsubara M, Maruoka S, Katayose S (2002) Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 147:173–180CrossRefPubMedGoogle Scholar
  182. McCall AL (2005) Altered glycemia and brain-update and potential relevance to the aging brain. Neurobiol Aging 26:70–75CrossRefPubMedGoogle Scholar
  183. McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS (2004) Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53:1953–1958CrossRefPubMedGoogle Scholar
  184. Michels KB, Greenland S, Rosner BA (1998) Does body mass index adequately capture the relation of body composition and body size to health outcomes? Am J Epidemiol 147:167–172CrossRefPubMedGoogle Scholar
  185. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343CrossRefPubMedGoogle Scholar
  186. Mittra S, Bansal VS, Bhatnagar PK (2008) From a glucocentric to a lipocentric approach towards metabolic syndrome. Drug Discov Today 13:211–218CrossRefPubMedGoogle Scholar
  187. Mokdad AH, Ford ES, Bowman LA, Dietz WH, Vinicor E, Bales VS, Mark JS (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:76–79CrossRefPubMedGoogle Scholar
  188. Moller DE, Kaufman KD (2005) Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 56:45–62CrossRefPubMedGoogle Scholar
  189. Molnar A, Toth A, Bagi Z, Papp Z, Edes I, Vaszily M, Galajda Z, Papp JG, Varro A, Szuts V, Lacza Z, Gero D, Szabo C (2006) Activation of the poly(ADP-ribose) polymerase pathway in human heart failure. Mol Med 12:143–152CrossRefPubMedGoogle Scholar
  190. Moraes JC, Coope A, Morari J, Cintra DE, Roman EA, Pauli JR, Romanatto T, Carvalheira JB, Oliveira AL, Saad MJ, Velloso LA (2009) High-fat diet induces apoptosis of hypothalamic neurons. PLoS One 4:e5045CrossRefPubMedGoogle Scholar
  191. Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2):S9–S15CrossRefPubMedGoogle Scholar
  192. Morino K, Neschen S, Bilz S, Sono S, Tsirigotis D, Reznick RM, Moore I, Nagai Y, Samuel V, Sebastian D, White M, Philbrick W, Shulman GI (2008) Muscle-specific IRS-1 Ser → Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. Diabetes 57:2644–2651CrossRefPubMedGoogle Scholar
  193. Morley JE, Banks WA (2010) Lipids and cognition. J Alzheimers Dis 20:737–747PubMedGoogle Scholar
  194. Morrison CD, White CL, Wang Z, Lee SY, Lawence DS, Cefalu WT, Zhang ZY, Gettys TW (2007) Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology 148:433–440CrossRefPubMedGoogle Scholar
  195. Morrow VA, Foufelle F, Connell JMC, Petrie JR, Gould GW, Salt IP (2003) Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J Biol Chem 278:31629–31639CrossRefPubMedGoogle Scholar
  196. Morton GJ, Blevins JE, Kim F, Matsen M, Figlewicz DP (2009) The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling. Am J Physiol Endocrinol Metab 297:E202–E210CrossRefPubMedGoogle Scholar
  197. Mruthinti S, Schade RF, Harrell DU, Gulati NK, Swamy-Mruthinti S, Lee GP, Buccafusco JJ (2006) Autoimmunity in Alzheimer’s disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes. Curr Alzheimer Res 3:229–235CrossRefPubMedGoogle Scholar
  198. Muoio DM, Newguard CB (2005) Metabolism: A is for adipokine. Nature 436:337–338CrossRefPubMedGoogle Scholar
  199. Nakamura Y, Shimada K, Fukuda D, Shimada Y, Ehara S, Hirose M, Kataoka T, Kamimori K, Shimodozono S, Kobayashi Y, Yoshiyama M, Takeuchi K, Yoshikawa J (2004) Implications of plasma concentrations of adiponectin in patients with coronary artery disease. Heart 90:528–533CrossRefPubMedGoogle Scholar
  200. Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE (2006) Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 281:2654–2660CrossRefPubMedGoogle Scholar
  201. Ng DT, Spear ED, Walter P (2000) The unfolded protein response regulates multiple aspects of secretory and membrane protein biogenesis and endoplasmic reticulum quality control. J Cell Biol 150:77–88CrossRefPubMedGoogle Scholar
  202. Niswender KD, Baskin DG, Schwartz MW (2004) Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab 15:362–369PubMedGoogle Scholar
  203. Nogueira-Machado JA, Chaves MM (2008) From hyperglycemia to AGE-RAGE interaction on the cell surface: a dangerous metabolic route for diabetic patients. Expert Opin Ther Targets 12:871–882CrossRefPubMedGoogle Scholar
  204. Noland RC, Koves TR, Seiler SE, Lum H, Lust RM, Ilkayeva O, Stevens RD, Hegardt FG, Muoio DM (2009) Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J Biol Chem 284:22840–22852CrossRefPubMedGoogle Scholar
  205. O’Malley D, Irving AJ, Harvey J (2005) Leptin-induced dynamic changes in the actin cytoskeleton mediate the activation and synaptic clustering of BK channels. FASEB J 19:1917–1919PubMedGoogle Scholar
  206. Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275–297CrossRefPubMedGoogle Scholar
  207. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246CrossRefPubMedGoogle Scholar
  208. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, De Paoli AM, Reitman ML, Taylor SI, Gorden P, Garg A (2002) Leptin—replacement therapy for lipodystrophy. N Engl J Med 346:570–578CrossRefPubMedGoogle Scholar
  209. Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, Chan L, Goldstein BJ, Scalia R (2007) Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 117:1718–1761CrossRefPubMedGoogle Scholar
  210. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–461CrossRefPubMedGoogle Scholar
  211. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140CrossRefPubMedGoogle Scholar
  212. Pacher P, Szabo C (2008) Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. Am J Pathol 173:2–13CrossRefPubMedGoogle Scholar
  213. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424CrossRefPubMedGoogle Scholar
  214. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE (2003) Structure–function studies of the adipocyte-secreted hormonec Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 278:9073–9085CrossRefPubMedGoogle Scholar
  215. Peralta S, Carrascosa JM, Gallardo N, Ros M, Arribas C (2002) Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction. Biochem Biophys Res Commun 296:425–428CrossRefPubMedGoogle Scholar
  216. Power DA, Noel J, Collins R, O’Neill D (2001) Circulating leptin levels and weight loss in Alzheimer’s disease patients. Dement Geriatr Cogn Disord 12:167–170CrossRefPubMedGoogle Scholar
  217. Puig KL, Floden AM, Adhikari R, Golovko MY, Combs CK (2012) Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS One 7:e30378CrossRefPubMedGoogle Scholar
  218. Qaseem A, Snow V, Cross J Jr, Forciea MA, Hopkins R Jr, Shekelle P, Adelman A, Mehr D, Schellhase K, Campos-Outcalt D, Santaguida P, Owens DK, American College of Physicians/American Academy of Family Physicians Panel on Dementia (2008) Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 148:370–378CrossRefPubMedGoogle Scholar
  219. Qiu WQ, Folstein MF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging 27:190–198CrossRefPubMedGoogle Scholar
  220. Raffaitin C, Feart C, Le Goff M, Amieva H, Helmer C, Akbaraly TN, Tzourio C, Gin H, Barberger-Gateau P (2011) Metabolic syndrome and cognitive decline in French elders: the Three-City Study. Neurology 76:518–525CrossRefPubMedGoogle Scholar
  221. Reaven GM (1995) Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473–486PubMedGoogle Scholar
  222. Reaven G (2005) All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res 2:105–112CrossRefPubMedGoogle Scholar
  223. Reaven G (2008) Why a cluster is truly a cluster: insulin resistance and cardiovascular disease. Clin Chem 54:785–787CrossRefPubMedGoogle Scholar
  224. Riccardi G, Giacco R, Rivellese AA (2004) Dietary fat, insulin sensitivity and the metabolic syndrome. Clin Nutr 23:447–456CrossRefPubMedGoogle Scholar
  225. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM (2005) Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 8:247–268PubMedGoogle Scholar
  226. Robertson RP (2004) Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet β cells in diabetes. J Biol Chem 279:42351–42354CrossRefPubMedGoogle Scholar
  227. Roriz-Filho J, Sá-Roriz TM, Rosset I, Camozzato AL, Santos AC, Chaves ML, Moriguti JC, Roriz-Cruz M (2009) (Pre)diabetes, brain aging, and cognition. Biochim Biophys Acta 1792:432–443CrossRefGoogle Scholar
  228. Rothenbacher D, Brenner H, Marz W, Koenig W (2005) Adiponectin, risk of coronary heart disease and correlations with cardiovascular risk markers. Eur Heart J 26:1640–1646CrossRefPubMedGoogle Scholar
  229. Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447–455CrossRefPubMedGoogle Scholar
  230. Ruvolo PP (2003) Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol Res 47:383–392CrossRefPubMedGoogle Scholar
  231. Sader S, Nian M, Liu P (2003) Leptin: a novel link between obesity, diabetes, cardiovascular risk, and ventricular hypertrophy. Circulation 108:644–646CrossRefPubMedGoogle Scholar
  232. Sakamoto S, Ishikawa K, Senda S, Nakajima S, Matsuo H (1993) The effect of obesity on ventilator and anaerobic threshold during exercise. J Med Syst 17:227–231CrossRefPubMedGoogle Scholar
  233. Saltiel AR (2001) You are what you secrete. Nat Med 7:887–888CrossRefPubMedGoogle Scholar
  234. Sasaki T, Kitamura T (2010) Roles of FoxO1 and Sirt1 in the central regulation of food intake. Endocr J 57:939–946CrossRefPubMedGoogle Scholar
  235. Savage DB, Petersen KF, Shulman GI (2007) Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87:507–520CrossRefPubMedGoogle Scholar
  236. Scarpace PJ, Matheny M, Moore RL, Tümer N (2000) Impaired leptin responsiveness in aged rats. Diabetes 49:431–435CrossRefPubMedGoogle Scholar
  237. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671PubMedGoogle Scholar
  238. Shankar SS, Steinberg HO (2005) Obesity and endothelial dysfunction. Semin Vasc Med 5:56–64CrossRefPubMedGoogle Scholar
  239. Sharma AM, Engeli S (2006) The role of renin-angiotensin system blockade in the management of hypertension associated with the cardiometabolic syndrome. J Cardiometab Syndr 1:29–35CrossRefPubMedGoogle Scholar
  240. Shearer J, Fueger PT, Vorndick B, Bracy DP, Rottman JN, Clanton JA, Wasserman DH (2004) AMP kinase-induced skeletal muscle glucose but not long-chain fatty acid uptake is dependent on nitric oxide. Diabetes 53:1429–1435CrossRefPubMedGoogle Scholar
  241. Shi H, Clegg DJ (2009) Sex differences in the regulation of body weight. Physiol Behav 97:199–204CrossRefPubMedGoogle Scholar
  242. Shimada K, Miyazaki T, Daida H (2004) Adiponectin and atherosclerotic disease. Clin Chim Acta 344:1–12CrossRefPubMedGoogle Scholar
  243. Shoelson SE, Lee J, Yuan M (2003) Inflammation and the IKKβ/IκB/NF-κB axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 27:S49–S52CrossRefPubMedGoogle Scholar
  244. Sikaris K (2004) The clinical biochemistry of obesity. Clin Biochem Rev 25:165–181PubMedGoogle Scholar
  245. Sommer G, Kralisch S, Lipfert J, Weise S, Krause K, Jessnitzer B, Lössner U, Blüher M, Stumvoll M, Fasshauer M (2009) Amyloid precursor protein expression is induced by tumor necrosis factor alpha in 3 T3-L1 adipocytes. J Cell Biochem 108:1418–1422CrossRefPubMedGoogle Scholar
  246. Sonnen JA, Larson EB, Haneuse S, Woltjer R, Li G, Crane PK, Craft S, Montine TJ (2009) Neuropathology in the adult changes in thought study: a review. J Alzheimers Dis 18:703–711PubMedGoogle Scholar
  247. Spangler R, Wittkowski KM, Goddard NL, Avena NM, Hoebel BG, Leibowitz SF (2004) Opiate-like effects of sugar on gene expression in reward areas of the rat brain. Brain Res Mol Brain Res 124:134–142CrossRefPubMedGoogle Scholar
  248. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis 7:63–80PubMedGoogle Scholar
  249. Straub RH, Buttgereit F, Cutolo M (2011) Alterations of the hypothalamic-pituitary-adrenal axis in systemic immune diseases—a role for misguided energy regulation. Clin Exp Rheumatol 29(5 Suppl 68):S23–S31PubMedGoogle Scholar
  250. Stumvoll M, Goldstein BJ, van Haeften TW (2005) Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365:1333–1346CrossRefPubMedGoogle Scholar
  251. Summers SA, Garza L, Zhou H, Birnbaum MJ (1998) Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol Cell Biol 18:5457–5464PubMedGoogle Scholar
  252. Sun XJ, Liu F (2009) Phosphorylation of IRS proteins Yin-Yang regulation of insulin signaling. Vitam Horm 80:351–387CrossRefPubMedGoogle Scholar
  253. Szanto I, Kahn CR (2000) Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. Proc Natl Acad Sci USA 97:2355–2360CrossRefPubMedGoogle Scholar
  254. Taheri S, Lin L, Austin D, Young T, Mignot E (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 1:e62CrossRefPubMedGoogle Scholar
  255. Takeda S, Sato N, Rakugi H, Morishita R (2011) Molecular mechanisms linking diabetes mellitus and Alzheimer disease: beta-amyloid peptide, insulin signaling, and neuronal function. Mol Biosyst 7:1822–1827CrossRefPubMedGoogle Scholar
  256. Tanaka M, Suganami T, Sugita S, Shimoda Y, Kasahara M, Aoee SS, Takeya MM, Takeda SS, Kamei YY, Ogawa YY (2010) Role of central leptin signaling in renal macrophage infiltration. Endocr J 57:61–72CrossRefPubMedGoogle Scholar
  257. Tanaka M, Suganami T, Kim-Saijo M, Toda C, Tsuiji M, Ochi K, Kamei Y, Minokoshi Y, Ogawa Y (2011) Role of central leptin signaling in the starvation-induced alteration of B-cell development. J Neurosci 31:8373–8380CrossRefPubMedGoogle Scholar
  258. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriatry A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor OB-R. Cell 83:1263–1271CrossRefPubMedGoogle Scholar
  259. Thaler JP, Schwartz MW (2010) Minireview: inflammation and obesity pathogenesis: the hypothalamus heats up. Endocrinology 151:4109–4115CrossRefPubMedGoogle Scholar
  260. Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton GJ, Horvath TL, Baskin DG, Tschop MH, Schwartz MW (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153–162CrossRefPubMedGoogle Scholar
  261. Thomas DE, Elliott EJ, Baur L (2007) Low glycaemic index or low glycaemic load diets for overweight and obesity. Cochrane Database Syst Rev 2007, CD005105Google Scholar
  262. Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783CrossRefPubMedGoogle Scholar
  263. Tomas E, Tsao TS, Saha AK, Murray HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99:16309–16313CrossRefPubMedGoogle Scholar
  264. Toth C, Schmidt AM, Tuor UI, Francis G, Foniok T, Brussee V, Kaur J, Yan SF, Martinez JA, Barber PA, Buchan A, Zochodne DW (2006) Diabetes, leukoencephalopathy and rage. Neurobiol Dis 23:445–461CrossRefPubMedGoogle Scholar
  265. Unger RH (2003) Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol Metab 14:398–403CrossRefPubMedGoogle Scholar
  266. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666CrossRefPubMedGoogle Scholar
  267. Valassi E, Scacchi M, Cavagnini F (2008) Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis 18:158–168CrossRefPubMedGoogle Scholar
  268. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, Aviv A, Spector TD (2005) Obesity, cigarette smoking, and telomere length in women. Lancet 366:662–664CrossRefPubMedGoogle Scholar
  269. Vincent HK, Taylor AG (2006) Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes (Lond) 30:400–418CrossRefGoogle Scholar
  270. Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429CrossRefPubMedGoogle Scholar
  271. Virtanen JK, Voutilainen S, Rissanen TH, Happonen P, Mursu J, Laukkanen JA, Poulsen H, Lakka TA, Salonen JT (2006) High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutr Metab Cardiovasc Dis 16:113–120CrossRefPubMedGoogle Scholar
  272. Volkow ND, Wang GJ, Baler RD (2011) Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci 15:37–46CrossRefPubMedGoogle Scholar
  273. Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF (2002) Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 34:616–621CrossRefPubMedGoogle Scholar
  274. Wang Y, Beydom MA (2007) The obesity epidemic in the United States—gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev 29:6–28CrossRefPubMedGoogle Scholar
  275. Wang Q, Jin T (2009) The role of insulin signaling in the development of beta-cell dysfunction and diabetes. Islets 1:95–101CrossRefPubMedGoogle Scholar
  276. Wang Z, Zhou YT, Kakuma T, Lee Y, Kalra SP, Kalra PS, Pan W, Unger RH (2000) Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling. Biochem Biophys Res Commun 277:20–26CrossRefPubMedGoogle Scholar
  277. Watt MJ, Hevener A, Lancaster GI, Febbraio MA (2006) Ciliary neurotrophic factor prevents acute lipid-induced insulin resistance by attenuating ceramide accumulation and phosphorylation of JNK in peripheral tissues. Endocrinology 147:2077–2085CrossRefPubMedGoogle Scholar
  278. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K (2005) Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64:277–281CrossRefPubMedGoogle Scholar
  279. WHO (2011a) WHO calls for action to restrict marketing of unhealthy foods and drinks to children. BMJ 342:d503CrossRefGoogle Scholar
  280. WHO (World Health Organization) (2011b) Obesity and overweight. 2010.
  281. Williams KW, Scott MM, Elmquist JK (2011) Modulation of the central melanocortin system by leptin, insulin, and serotonin: co-ordinated actions in a dispersed neuronal network. Eur J Pharmacol 660:2–12CrossRefPubMedGoogle Scholar
  282. World Health Organization (2006) Neurological disorders: public health challenges. WHO, GenevaGoogle Scholar
  283. Xiao X, Su G, Brown SN, Chen L, Ren J, Zhao P (2010) Peroxisome proliferator-activated receptors gamma and alpha agonists stimulate cardiac glucose uptake via activation of AMP-activated protein kinase. J Nutr Biochem 21:621–626CrossRefPubMedGoogle Scholar
  284. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830PubMedGoogle Scholar
  285. Xu WL, Qiu CX, Wahlin A, Winblad B, Fratiglioni L (2004) Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6-year follow-up study. Neurology 63:1181–1186CrossRefPubMedGoogle Scholar
  286. Xu L, Rensing N, Yang XF, Zhang HX, Thio LL, Rothman SM, Weisenfeld AE, Wong M, Yamada KA (2008) Leptin inhibits 4-aminopyridine- and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents. J Clin Invest 118:272–280CrossRefPubMedGoogle Scholar
  287. Xydakis AM, Case CC, Jones PH, Hoogeveen RC, Liu MY, Smith EO, Nelson KW, Ballantyne CM (2004) Adiponectin, inflammation and the expression of the metabolic syndrome in obese individuals: the impact of rapid weight loss through caloric restriction. J Clin Endocrinol Metab 89:2697–2703CrossRefPubMedGoogle Scholar
  288. Yadav A, Kalita A, Dhillon S, Banerjee K (2005) JAK/STAT3 pathway is involved in survival of neurons in response to insulin-like growth factor and negatively regulated by suppressor of cytokine signaling-3. J Biol Chem 280:31830–31840CrossRefPubMedGoogle Scholar
  289. Yamauchi T, Kamon J (2002) Adiponectin stimulates glucose utilization and fatty acid oxidation by activating AMP-kinase. Nat Med 8:1288–1295CrossRefPubMedGoogle Scholar
  290. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946CrossRefPubMedGoogle Scholar
  291. Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K (2003) Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 278:2461–2468CrossRefPubMedGoogle Scholar
  292. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, Okada-Iwabu M, Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon J, Tsuchida A, Kumagai K, Kozono H, Hada Y, Ogata H, Tokuyama K, Tsunoda M, Ide T, Murakami K, Awazawa M, Takamoto I, Froguel P, Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13:332–339CrossRefPubMedGoogle Scholar
  293. Yan SD, Stern D, Schmidt AM (1997) What’s the RAGE? The receptor for advanced glycation end products (RAGE) and the dark side of glucose. Eur J Clin Invest 27:179–181CrossRefPubMedGoogle Scholar
  294. Yaqoob P (2009) The nutritional significance of lipid rafts. Annu Rev Nutr 29:257–282CrossRefPubMedGoogle Scholar
  295. Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB (2006) Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 55:2562–2570CrossRefPubMedGoogle Scholar
  296. 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 (2002) 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 277:50230–50236CrossRefPubMedGoogle Scholar
  297. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V (2000) Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148:209–214CrossRefPubMedGoogle Scholar
  298. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180–2191CrossRefPubMedGoogle Scholar
  299. Zeyda M, Stulnig TM (2007) Adipose tissue macrophages. Immunol Lett 112:61–67CrossRefPubMedGoogle Scholar
  300. Zeyda M, Stulnig TM (2009) Obesity, inflammation, and insulin resistance—a mini-review. Gerontology 55:379–386CrossRefPubMedGoogle Scholar
  301. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432CrossRefPubMedGoogle Scholar
  302. Zhao AZ, Huan JN, Gupta S, Pal R, Sahu A (2002) A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Nat Neurosci 5:727–728PubMedGoogle Scholar
  303. Zhou L, Deepa SS, Etzler JC, Ryu J, Mao X et al (2009) Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinase-dependent pathways. J Biol Chem 284:22426–22435CrossRefPubMedGoogle Scholar
  304. Ziegler O, Quilliot D, Guerci B, Drouin P (2001) Macronutrients, fat mass, fatty acid flux and insulin sensitivity. Diabetes Metab 27:261–270PubMedGoogle Scholar
  305. Zimmerman GA, Meistrell M III, Bloom O, Cockroft KM, Bianchi M, Risucci D, Broome J, Farmer P, Cerami A, Vlassara H, Tracey KJ (1995) Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci USA 92:3744–3748CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Akhlaq A. Farooqui
    • 1
  1. 1.Ohio State UniversityColumbusUSA

Personalised recommendations