Skip to main content

Advertisement

SpringerLink
Log in

Metabolic Factors Determining the Susceptibility to Weight Gain: Current Evidence

  • Metabolism (M Dalamaga, Section Editor)
  • Published:
Current Obesity Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

There is substantial inter-individual variability in body weight change, which is not fully accounted by differences in daily energy intake and physical activity levels. The metabolic responses to short-term perturbations in energy intake can explain part of this variability by quantifying the degree of metabolic “thriftiness” that confers more susceptibility to weight gain and more resistance to weight loss. It is unclear which metabolic factors and pathways determine this human “thrifty” phenotype. This review will investigate and summarize emerging research in the field of energy metabolism and highlight important metabolic mechanisms implicated in body weight regulation in humans.

Recent Findings

Dysfunctional adipose tissue lipolysis, reduced brown adipose tissue activity, blunted fibroblast growth factor 21 secretion in response to low-protein hypercaloric diets, and impaired sympathetic nervous system activity might constitute important metabolic factors characterizing “thriftiness” and favoring weight gain in humans.

Summary

The individual propensity to weight gain in the current obesogenic environment could be ascertained by measuring specific metabolic factors which might open up new pathways to prevent and treat human obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

24hEE:

24-h energy expenditure

BAT:

Brown adipose tissue

BMI:

Body mass index

FGF21:

Fibroblast growth factor 21

RQ:

Respiratory quotient

SNS:

Sympathetic nervous system

UCP1:

Uncoupling protein 1

WAT:

White adipose tissue

References

  1. Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016. Jama. 2018;319:1723–5.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Masters RK, Reither EN, Powers DA, Yang YC, Burger AE, Link BG. The impact of obesity on US mortality levels: the importance of age and cohort factors in population estimates. Am J Public Health. 2013;103:1895–901.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bray GA, Smith SR, de Jonge L, Xie H, Rood J, Martin CK, et al. Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: a randomized controlled trial. JAMA. 2012;307:47–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hollstein T, Ando T, Basolo A, Krakoff J, Votruba SB, Piaggi P. Metabolic response to fasting predicts weight gain during low-protein overfeeding in lean men: further evidence for spendthrift and thrifty metabolic phenotypes. Am J Clin Nutr. 2019.

  5. Norgan NG, Durnin JV. The effect of 6 weeks of overfeeding on the body weight, body composition, and energy metabolism of young men. Am J Clin Nutr. 1980;33:978–88.

    Article  PubMed  CAS  Google Scholar 

  6. Piaggi P. Metabolic determinants of weight gain in humans. Obesity (Silver Spring). 2019;27:691–9.

    Article  Google Scholar 

  7. Marlatt KL, Ravussin E. Brown adipose tissue: an update on recent findings. Curr Obes Rep. 2017;6:389–96.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Fernández-Verdejo R, Marlatt KL, Ravussin E, Galgani JE. Contribution of brown adipose tissue to human energy metabolism. Mol Asp Med. 2019;68:82–9.

    Article  CAS  Google Scholar 

  9. Müller MJ, Enderle J, Bosy-Westphal A. Changes in energy expenditure with weight gain and weight loss in humans. Curr Obes Rep. 2016;5:413–23.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dulloo AG, Schutz Y. Adaptive thermogenesis in resistance to obesity therapies: issues in quantifying thrifty energy expenditure phenotypes in humans. Curr Obes Rep. 2015;4:230–40.

    Article  PubMed  Google Scholar 

  11. Galgani J, Ravussin E. Energy metabolism, fuel selection and body weight regulation. Int J Obes. 2008;32:S109–19.

    Article  CAS  Google Scholar 

  12. Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet. 1962;14:353.

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35:595–601.

    Article  PubMed  CAS  Google Scholar 

  14. Weyer C, Vozarova B, Ravussin E, Tataranni PA. Changes in energy metabolism in response to 48 h of overfeeding and fasting in Caucasians and Pima Indians. Int J Obes Relat Metab Disord. 2001;25:593–600.

    Article  PubMed  CAS  Google Scholar 

  15. Reinhardt M, Thearle MS, Ibrahim M, Hohenadel MG, Bogardus C, Krakoff J, et al. A human thrifty phenotype associated with less weight loss during caloric restriction. Diabetes. 2015;64:2859–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Schlogl M, Piaggi P, Pannacciuli N, Bonfiglio SM, Krakoff J, Thearle MS. Energy expenditure responses to fasting and overfeeding identify phenotypes associated with weight change. Diabetes. 2015;64:3680–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Piaggi P, Vinales KL, Basolo A, Santini F, Krakoff J. Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms. J Endocrinol Investig. 2018;41:83–9.

    Article  CAS  Google Scholar 

  18. Dulloo AG, Jacquet J. Low-protein overfeeding: a tool to unmask susceptibility to obesity in humans. Int J Obes Relat Metab Disord. 1999;23:1118–21.

    Article  PubMed  CAS  Google Scholar 

  19. Stock MJ. Gluttony and thermogenesis revisited. Int J Obes Relat Metab Disord. 1999;23:1105–17.

    Article  PubMed  CAS  Google Scholar 

  20. Begaye B, Vinales KL, Hollstein T, Ando T, Walter M, Bogardus C, et al. Impaired metabolic flexibility to high-fat overfeeding predicts future weight gain in healthy adults. Diabetes. 2019.

  21. Rynders CA, Pereira RI, Bergouignan A, Kealey EH, Bessesen DH. Associations among dietary fat oxidation responses to overfeeding and weight gain in obesity-prone and resistant adults. Obesity. 2018;26:1758–66.

    Article  PubMed  CAS  Google Scholar 

  22. Frankl J, Piaggi P, Foley JE, Krakoff J, Votruba SB. In vitro lipolysis is associated with whole-body lipid oxidation and weight gain in humans. Obesity. 2017;25:207–14.

    Article  PubMed  CAS  Google Scholar 

  23. Arner P, Andersson DP, Backdahl J, Dahlman I, Ryden M. Weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell lipolysis. Cell Metab. 2018;28:45–54.e43.

    Article  PubMed  CAS  Google Scholar 

  24. Schlögl M, Piaggi P, Thiyyagura P, Reiman EM, Chen K, Lutrin C, et al. Overfeeding over 24 hours does not activate brown adipose tissue in humans. J Clin Endocrinol Metab. 2013;98:E1956–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Begaye B, Piaggi P, Thearle MS, Haskie K, Walter M, Schlogl M, et al. Norepinephrine and T4 are predictors of fat mass gain in humans with cold-induced brown adipose tissue activation. J Clin Endocrinol Metab. 2018;103:2689–97.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Vinales KL, Begaye B, Bogardus C, Walter M, Krakoff J, Piaggi P. FGF21 is a hormonal mediator of the human “thrifty” metabolic phenotype. Diabetes. 2018.

  27. Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension. 2003;42:474–80.

    Article  PubMed  CAS  Google Scholar 

  28. Gudmundsdottir H, Strand A, Kjeldsen S, Hoieggen A, Os I. Arterial noradrenaline predicts rise in body mass index in a 20-year follow-up of lean normotensive and hypertensive men. In: Journal of hypertension. LIPPINCOTT WILLIAMS & WILKINS 530 WALNUT ST, PHILADELPHIA, PA 19106–3621 USA. p. S347-S347.

  29. Flaa A, Sandvik L, Kjeldsen SE, Eide IK, Rostrup M. Does sympathoadrenal activity predict changes in body fat? An 18-y follow-up study. Am J Clin Nutr. 2008;87:1596–601.

    Article  PubMed  CAS  Google Scholar 

  30. Tataranni PA, Young JB, Bogardus C, Ravussin E. A low sympathoadrenal activity is associated with body weight gain and development of central adiposity in Pima Indian men. Obes Res. 1997;5:341–7.

    Article  PubMed  CAS  Google Scholar 

  31. Johannsen DL, Marlatt KL, Conley KE, Smith SR, Ravussin E. Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery. Am J Clin Nutr. 2019;110:805.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Astrup A. The relevance of increased fat oxidation for body-weight management: metabolic inflexibility in the predisposition to weight gain. Obes Rev. 2011;12:859–65.

    Article  PubMed  CAS  Google Scholar 

  33. Galgani JE, Heilbronn LK, Azuma K, Kelley DE, Albu JB, Pi-Sunyer X, et al. Metabolic flexibility in response to glucose is not impaired in people with type 2 diabetes after controlling for glucose disposal rate. Diabetes. 2008;57:841–5.

    Article  PubMed  CAS  Google Scholar 

  34. Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000;49:677–83.

    Article  PubMed  CAS  Google Scholar 

  35. Schmidt SL, Kealey EH, Horton TJ, VonKaenel S, Bessesen DH. The effects of short-term overfeeding on energy expenditure and nutrient oxidation in obesity-prone and obesity-resistant individuals. Int J Obes. 2013;37:1192.

    Article  CAS  Google Scholar 

  36. Eckel J. Chapter 2 - Adipose tissue: a major secretory organ. In: Eckel J, editor. The Cellular Secretome and Organ Crosstalk. Cambridge: Academic Press; 2018. p. 9–63.

    Chapter  Google Scholar 

  37. Karastergiou K, Smith SR, Greenberg AS, Fried SK. Sex differences in human adipose tissues–the biology of pear shape. Biol Sex Differ. 2012;3:13.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Laforest S, Labrecque J, Michaud A, Cianflone K, Tchernof A. Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction. Crit Rev Clin Lab Sci. 2015;52:301–13.

    Article  PubMed  CAS  Google Scholar 

  39. Knittle J, Timmers K, Ginsberg-Fellner F, Brown R, Katz D. The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest. 1979;63:239–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. McLaughlin T, Lamendola C, Coghlan N, Liu T, Lerner K, Sherman A, et al. Subcutaneous adipose cell size and distribution: relationship to insulin resistance and body fat. Obesity. 2014;22:673–80.

    Article  PubMed  CAS  Google Scholar 

  41. Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, et al. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci. 2019;20:2358.

    Article  PubMed Central  CAS  Google Scholar 

  42. Gurr MI, Jung RT, Robinson MP, James W. Adipose tissue cellularity in man: the relationship between fat cell size and number, the mass and distribution of body fat and the history of weight gain and loss. Int J Obes. 1982;6:419–36.

    PubMed  CAS  Google Scholar 

  43. Imbeault P, Tremblay A, Després J, Mauriège P: Beta-adrenoceptor-stimulated lipolysis of subcutaneous abdominal adipocytes as a determinant of fat oxidation in obese men. Eur J Clin Investig 2000;30:290–296.

    Article  PubMed  CAS  Google Scholar 

  44. Begaye B, Vinales KL, Hollstein T, Ando T, Walter M, Bogardus C, et al. Impaired metabolic flexibility to high-fat overfeeding predicts future weight gain. SSRN Electron J. 2019.

  45. Rydén M, Andersson DP, Bernard S, Spalding K, Arner P. Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects. J Lipid Res. 2013;54:2909–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Arner P, Bernard S, Appelsved L, Fu KY, Andersson DP, Salehpour M, et al. Adipose lipid turnover and long-term changes in body weight. Nat Med. 2019;25:1385–9.

    Article  PubMed  CAS  Google Scholar 

  47. Arner P. Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab. 2005;19:471–82.

    Article  PubMed  CAS  Google Scholar 

  48. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr. 2007;27:79–101.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. de Oliveira LV, Mafra D. Adipokines in obesity. Clin Chim Acta. 2013;419:87–94.

    Article  CAS  Google Scholar 

  50. Funcke J-B, Scherer PE. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res. 2019:jlr. R094060.

  51. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Brit J Nutr. 2004;92:347–55.

    Article  PubMed  CAS  Google Scholar 

  52. Lehr S, Hartwig S, Lamers D, Famulla S, Müller S, Hanisch F-G, et al. Identification and validation of novel adipokines released from primary human adipocytes. Mol Cell Proteomics. 2012;11:M111. 010504.

    Article  PubMed  CAS  Google Scholar 

  53. Rosenbaum M, Leibel RL. 20 years of leptin: role of leptin in energy homeostasis in humans. J Endocrinol. 2014;223:T83–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Vong L, Ye C, Yang Z, Choi B, Chua S Jr, Lowell BB. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron. 2011;71:142–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–9.

    Article  PubMed  CAS  Google Scholar 

  56. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480.

    Article  CAS  PubMed  Google Scholar 

  57. Pandit R, Beerens S, Adan RAH. Role of leptin in energy expenditure: the hypothalamic perspective. Am J Physiol Regul Integr Comp Physiol. 2017;312:R938–47.

    Article  PubMed  CAS  Google Scholar 

  58. Fischer AW, Cannon B, Nedergaard J: Leptin – is it thermogenic? Endocrine reviews 2019;

    Google Scholar 

  59. Rosenbaum M. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Investig. 2005;115:3579–86.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Bi X, Loo YT, Henry CJ. Does circulating leptin play a role in energy expenditure? Nutrition. 2019;60:6–10.

    Article  PubMed  CAS  Google Scholar 

  61. Flier JS. What’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab. 1998;83:1407–13.

    PubMed  CAS  Google Scholar 

  62. Farooqi IS, Bullmore E, Keogh J, Gillard J, O'Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behavior. Science. 2007;317:1355–1355.

    Article  CAS  Google Scholar 

  63. Ravussin E, Pratley RE, Maffei M, Wang H, Friedman JM, Bennett PH, et al. Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat Med. 1997;3:238.

    Article  PubMed  CAS  Google Scholar 

  64. Haffner S, Mykkänen L, Gonzalez C, Stern M. Leptin concentrations do not predict weight gain: the Mexico City Diabetes Study. Int J Obes. 1998;22:695.

    Article  CAS  Google Scholar 

  65. Langenberg C, Bergstrom J, Laughlin GA, Barrett-Connor E. Ghrelin, adiponectin, and leptin do not predict long-term changes in weight and body mass index in older adults: longitudinal analysis of the Rancho Bernardo cohort. Am J Epidemiol. 2005;162:1189–97.

    Article  PubMed  Google Scholar 

  66. Chu N, Spiegelman D, Yu J, Rifai N, Hotamisligil G, Rimm E. Plasma leptin concentrations and four-year weight gain among US men. Int J Obes. 2001;25:346.

    Article  CAS  Google Scholar 

  67. Lissner L, Karlsson C, Lindroos AK, Sjöström L, Carlsson B, Carlsson L, et al. Birth weight, adulthood BMI, and subsequent weight gain in relation to leptin levels in Swedish women. Obes Res. 1999;7:150–4.

    Article  PubMed  CAS  Google Scholar 

  68. Farr OM, Gavrieli A, Mantzoros CS. Leptin applications in 2015. Curr Opin Endocrinol Diabetes Obes. 2015;22:353–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Gruzdeva O, Borodkina D, Uchasova E, Dyleva Y, Barbarash O. Leptin resistance: underlying mechanisms and diagnosis. Diabetes, Metab Syndr Obesity: Targets Ther. 2019;12:191–8.

    Article  CAS  Google Scholar 

  70. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. Jama. 1999;282:1568–75.

    Article  PubMed  CAS  Google Scholar 

  71. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995;270:26746–9.

    Article  PubMed  CAS  Google Scholar 

  72. Yadav A, Kataria MA, Saini V, Yadav A. Role of leptin and adiponectin in insulin resistance. Clin Chim Acta. 2013;417:80–4.

    Article  PubMed  CAS  Google Scholar 

  73. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway. Circulation. 2000;102:1296–301.

    Article  PubMed  CAS  Google Scholar 

  74. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation. 2001;103:1057–63.

    Article  PubMed  CAS  Google Scholar 

  75. Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, et al. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Metabolism. 2003;52:1274–8.

    Article  PubMed  CAS  Google Scholar 

  76. Nigro E, Scudiero O, Monaco ML, Palmieri A, Mazzarella G, Costagliola C, et al. New insight into adiponectin role in obesity and obesity-related diseases. Biomed Res Int. 2014;2014.

  77. Loos RJ, Ruchat S, Rankinen T, Tremblay A, Pérusse L, Bouchard C. Adiponectin and adiponectin receptor gene variants in relation to resting metabolic rate, respiratory quotient, and adiposity-related phenotypes in the Quebec Family Study. Am J Clin Nutr. 2007;85:26–34.

    Article  PubMed  CAS  Google Scholar 

  78. Vozarova B, Stefan N, Lindsay RS, Krakoff J, Knowler WC, Funahashi T, et al. Low plasma adiponectin concentrations do not predict weight gain in humans. Diabetes. 2002;51:2964–7.

    Article  PubMed  CAS  Google Scholar 

  79. Hivert MF, Sun Q, Shrader P, Mantzoros CS, Meigs JB, Hu FB. Higher adiponectin levels predict greater weight gain in healthy women in the Nurses’ Health Study. Obesity. 2011;19:409–15.

    Article  PubMed  CAS  Google Scholar 

  80. Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Ravussin E, Weyer C, et al. Plasma adiponectin levels are not associated with fat oxidation in humans. Obes Res. 2002;10:1016–20.

    Article  PubMed  CAS  Google Scholar 

  81. Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012;122:545–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Bakker LE, Boon MR, van der Linden RA, Arias-Bouda LP, van Klinken JB, Smit F, et al. Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study. Lancet Diabetes Endocrinol. 2014;2:210–7.

    Article  PubMed  Google Scholar 

  83. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Chen KY, Cypess AM, Laughlin MR, Haft CR, Hu HH, Bredella MA, et al. Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): recommendations for standardized FDG-PET/CT experiments in humans. Cell Metab. 2016;24:210–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue: functional relevance and implications in obesity and type 2 diabetes. Diabetes. 2013;62:1783–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500–8.

    Article  PubMed  Google Scholar 

  87. Chen KY, Brychta RJ, Linderman JD, Smith S, Courville A, Dieckmann W, et al. Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J Clin Endocrinol Metab. 2013;98:E1218–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Cypess AM, Chen Y-C, Sze C, Wang K, English J, Chan O, et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci. 2012;109:10001–5.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Vosselman MJ, Brans B, van der Lans AA, Wierts R, van Baak MA, Mottaghy FM, et al. Brown adipose tissue activity after a high-calorie meal in humans. Am J Clin Nutr. 2013;98:57–64.

    Article  PubMed  CAS  Google Scholar 

  90. Din MU, Saari T, Raiko J, Kudomi N, Maurer SF, Lahesmaa M, et al. Postprandial oxidative metabolism of human brown fat indicates thermogenesis. Cell Metab. 2018;28:207–216. e203.

    Google Scholar 

  91. Peterson CM, Orooji M, Johnson DN, Naraghi-Pour M, Ravussin E. Brown adipose tissue does not seem to mediate metabolic adaptation to overfeeding in men. Obesity. 2017;25:502–5.

    Article  PubMed  Google Scholar 

  92. Cypess AM, Weiner LS, Roberts-Toler C, Elía EF, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015;21:33–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Loh RK, Formosa MF, La Gerche A, Reutens AT, Kingwell BA, Carey AL. Acute metabolic and cardiovascular effects of mirabegron in healthy individuals. Diabetes Obes Metab. 2019;21:276–84.

    Article  PubMed  CAS  Google Scholar 

  94. Baskin AS, Linderman JD, Brychta RJ, McGehee S, Anflick-Chames E, Cero C, et al. Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a β3-adrenergic receptor agonist. Diabetes. 2018;67:2113–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. O'Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, et al. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Investig. 2020.

  96. Almind K, Manieri M, Sivitz WI, Cinti S, Kahn CR. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc Natl Acad Sci. 2007;104:2366–71.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Lowell BB, Vedrana S, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB, et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature. 1993;366:740.

    Article  PubMed  CAS  Google Scholar 

  98. Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 2009;9:203–9.

    Article  PubMed  CAS  Google Scholar 

  99. Enerbäck S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper M-E, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997;387:90.

    Article  PubMed  Google Scholar 

  100. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252.

    Article  PubMed  CAS  Google Scholar 

  101. Piaggi P, Thearle MS, Bogardus C, Krakoff J. Lower energy expenditure predicts long-term increases in weight and fat mass. J Clin Endocrinol Metab. 2013;98:E703–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Tataranni PA, Harper IT, Snitker S, Del Parigi A, Vozarova B, Bunt J, et al. Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure. Int J Obes Relat Metab Disord. 2003;27:1578–83.

    Article  PubMed  CAS  Google Scholar 

  103. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WG, et al. Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med. 1988;318:467–72.

    Article  PubMed  CAS  Google Scholar 

  104. Buscemi S, Verga S, Caimi G, Cerasola G. Low relative resting metabolic rate and body weight gain in adult Caucasian Italians. Int J Obes. 2005;29:287.

    Article  CAS  Google Scholar 

  105. Seidell J, Muller D, Sorkin J, Andres R. Fasting respiratory exchange ratio and resting metabolic rate as predictors of weight gain: the Baltimore Longitudinal Study on Aging. International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity. 1992;16:667–74.

    CAS  Google Scholar 

  106. Weinsier RL, Nelson KM, Hensrud DD, Darnell BE, Hunter GR, Schutz Y: Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-obese and never-obese women. J Clin Invest 1995;95:980–985.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Anthanont P, Jensen MD. Does basal metabolic rate predict weight gain? Am J Clin Nutr. 2016;104:959–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Luke A, Durazo-Arvizu R, Cao G, Adeyemo A, Tayo B, Cooper R. Positive association between resting energy expenditure and weight gain in a lean adult population. Am J Clin Nutr. 2006;83:1076–81.

    Article  PubMed  CAS  Google Scholar 

  109. Dulloo AG, Jacquet J, Miles-Chan JL, Schutz Y. Passive and active roles of fat-free mass in the control of energy intake and body composition regulation. Eur J Clin Nutr. 2017;71:353–7.

    Article  PubMed  CAS  Google Scholar 

  110. Li Y, Schnabl K, Gabler S-M, Willershäuser M, Reber J, Karlas A, et al. Secretin-activated brown fat mediates prandial thermogenesis to induce satiation. Cell. 2018;175:1561–1574. e1512.

    Google Scholar 

  111. Sanchez-Delgado G, Acosta FM, Martinez-Tellez B, Finlayson G, Gibbons C, Labayen I, et al. Brown adipose tissue volume and 18F-fluorodeoxyglucose uptake are not associated with energy intake in young human adults. Am J Clin Nutr. 2019:nqz300.

  112. Wang Z, Ying Z, Bosy-Westphal A, Zhang J, Schautz B, Later W, et al. Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr. 2010;92:1369–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Jung TW, Yoo HJ, Choi KM. Implication of hepatokines in metabolic disorders and cardiovascular diseases. 2016;5:108–13.

  114. Stefan N, Häring H-U. The role of hepatokines in metabolism. Nat Rev Endocrinol. 2013;9:144–52.

    Article  PubMed  CAS  Google Scholar 

  115. Staiger H, Keuper M, Berti L, Hrabě De Angelis M, Häring H-U: Fibroblast growth factor 21—metabolic role in mice and men. Endocr Rev 2017;38:468–488.

    Article  PubMed  Google Scholar 

  116. Lewis JE, Ebling FJP, Samms RJ, Tsintzas K. Going back to the biology of FGF21: new insights. Trends Endocrinol Metab. 2019.

  117. Xu J, Stanislaus S, Chinookoswong N, Lau YY, Hager T, Patel J, et al. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects. Am J Physiol-Endocrinol Metab. 2009;297:E1105–14.

    Article  PubMed  CAS  Google Scholar 

  118. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149:6018–27.

    Article  PubMed  CAS  Google Scholar 

  119. Talukdar S, Bryn, Song P, Hernandez G, Zhang Y, Zhou Y, et al. FGF21 regulates sweet and alcohol preference. Cell Metab. 2016;23:344–9.

    Article  PubMed  CAS  Google Scholar 

  120. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19:302–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  121. Søberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL, Von Holstein-Rathlou S, et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab. 2017;25:1045–1053.e1046.

    Article  CAS  Google Scholar 

  122. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1 and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26:271–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Murielle, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. 2015;21:731–8.

  124. Ricardo, Dennis, Christine, Patrick, James, Kharitonenkov A, et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. 2015;11:991–9.

  125. BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga SO, Acevedo MR, et al. FGF21 regulates metabolism through adipose-dependent and-independent mechanisms. Cell Metab. 2017;25:935–944. e934.

    Article  CAS  Google Scholar 

  126. Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL, Rahmouni K, et al. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab. 2014;20:670–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Zhang X, Yeung DCY, Karpisek M, Stejskal D, Zhou ZG, Liu F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. 2008;57:1246–53.

  128. Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 2010;59:2781–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Markan KR. Defining “FGF21 resistance” during obesity: controversy, criteria and unresolved questions. F1000Res. 2018;7:289.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Lundsgaard A-M, Fritzen AM, Sjøberg KA, Myrmel LS, Madsen L, Wojtaszewski JFP, et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol Metab. 2017;6:22–9.

    Article  PubMed  CAS  Google Scholar 

  131. Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. 2015;4:51–7.

  132. Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, et al. FGF21 is an endocrine signal of protein restriction. J Clin Invest. 2014;124:3913–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Samms RJ, Lewis JE, Norton L, Stephens FB, Gaffney CJ, Butterfield T, et al. FGF21 is an insulin-dependent postprandial hormone in adult humans. J Clin Endocrinol Metab. 2017;102:3806–13.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–25.

    Article  PubMed  CAS  Google Scholar 

  135. Gaich G, Jenny, Fu H, Leonard, Mark, William, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18:333–40.

    Article  PubMed  CAS  Google Scholar 

  136. Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016;23:427–40.

    Article  PubMed  CAS  Google Scholar 

  137. Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS, et al. Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity. 2019;27:41–9.

    Article  PubMed  CAS  Google Scholar 

  138. Trepanowski JF, Mey J, Varady KA. Fetuin-A: a novel link between obesity and related complications. Int J Obes. 2015;39:734–41.

    Article  CAS  Google Scholar 

  139. Ix JH, Chertow GM, Shlipak MG, Brandenburg VM, Ketteler M, Whooley MA. Association of fetuin-A with mitral annular calcification and aortic stenosis among persons with coronary heart disease: data from the heart and soul study. 2007;115:2533–9.

  140. Ix JH. Fetuin-A and incident diabetes mellitus in older persons. JAMA. 2008;300:182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Krober SM, et al. 2-Heremans-Schmid glycoprotein/ fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care. 2006;29:853–7.

    Article  PubMed  CAS  Google Scholar 

  142. Laughlin GA, Barrett-Connor E, Cummins KM, Daniels LB, Wassel CL, Ix JH. Sex-specific association of fetuin-A with type 2 diabetes in older community-dwelling adults: the Rancho Bernardo Study. Diabetes Care. 2013;36:1994–2000.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Guo VY, Cao B, Cai C, Cheng KK-Y, Cheung BMY. Fetuin-A levels and risk of type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol. 2018;55:87–98.

    Article  PubMed  CAS  Google Scholar 

  144. Vörös K, Gráf L Jr, Prohászka Z, Gráf L, Szenthe P, Kaszás E, et al. Serum fetuin-A in metabolic and inflammatory pathways in patients with myocardial infarction. Eur J Clin Investig. 2011;41:703–9.

    Article  CAS  Google Scholar 

  145. Mathews ST, Singh GP, Ranalletta M, Cintron VJ, Qiang X, Goustin AS, et al. Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes. 2002;51:2450–8.

    Article  PubMed  CAS  Google Scholar 

  146. Thakkinstian A, Chailurkit L, Warodomwichit D, Ratanachaiwong W, Yamwong S, Chanprasertyothin S, et al. Causal relationship between body mass index and fetuin-A level in the asian population: a bidirectional mendelian randomization study. Clin Endocrinol. 2014;81:197–203.

    Article  CAS  Google Scholar 

  147. Ix JH, Wassel CL, Chertow GM, Koster A, Johnson KC, Tylavsky FA, et al. Fetuin-A and change in body composition in older persons. 2009;94:4492–8.

  148. Wang Q, Zhang M, Ning G, Gu W, Su T, Xu M, et al. Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS One. 2011;6:e21006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Tank AW, Lee Wong D. Peripheral and central effects of circulating catecholamines. Compr Physiol. 2015;5:1–15.

    PubMed  Google Scholar 

  150. Palkovits M. Sympathoadrenal system: neural arm of the stress response. In: Encyclopedia of Neuroscience: Elsevier Ltd; 2010. p. 679–84.

    Chapter  Google Scholar 

  151. Landsberg L. Feast or famine: the sympathetic nervous system response to nutrient intake. Cell Mol Neurobiol. 2006;26:495–506.

    Article  CAS  Google Scholar 

  152. Wijers SL, Saris WH, van Marken Lichtenbelt WD. Individual thermogenic responses to mild cold and overfeeding are closely related. J Clin Endocrinol Metab. 2007;92:4299–305.

    Article  PubMed  CAS  Google Scholar 

  153. Mansell P, Fellows I, Macdonald I. Enhanced thermogenic response to epinephrine after 48-h starvation in humans. Am J Phys Regul Integr Comp Phys. 1990;258:R87–93.

    CAS  Google Scholar 

  154. Saad MF, Alger SA, Zurlo F, Young JB, Bogardus C, Ravussin E. Ethnic differences in sympathetic nervous system-mediated energy expenditure. Am J Phys. 1991;261:E789–94.

    CAS  Google Scholar 

  155. Zauner C, Schneeweiss B, Kranz A, Madl C, Ratheiser K, Kramer L, et al. Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine. Am J Clin Nutr. 2000;71:1511–5.

    Article  PubMed  CAS  Google Scholar 

  156. Spraul M, Ravussin E, Fontvieille AM, Rising R, Larson DE, Anderson EA. Reduced sympathetic nervous activity. A potential mechanism predisposing to body weight gain. J Clin Invest. 1993;92:1730–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Landsberg L, Young JB. The role of the sympathoadrenal system in modulating energy expenditure. Clin Endocrinol Metab. 1984;13:475–99.

    Article  PubMed  CAS  Google Scholar 

  158. Webber J, Macdonald I. Metabolic actions of catecholamines in man. Baillieres Clin Endocrinol Metab. 1993;7:393–413.

    Article  PubMed  CAS  Google Scholar 

  159. Macdonald I, Bennett T, Fellows I. Catecholamines and the control of metabolism in man. Clin Sci. 1985;68:613–9.

    Article  CAS  Google Scholar 

  160. Macdonald I, Stock M. Influence of norepinephrine and fasting on the oxygen consumption of genetically-obese mice. Ann Nutr Metab. 1979;23:250–5.

    Article  CAS  Google Scholar 

  161. Bray G. Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. Int J Obes. 2000;24:S8.

    Article  CAS  Google Scholar 

  162. Arner P. Catecholamine-induced lipolysis in obesity. Int J Obes. 1999;23:S10.

    Article  Google Scholar 

  163. Troisi RJ, Weiss ST, Parker DR, Sparrow D, Young JB, Landsberg L. Relation of obesity and diet to sympathetic nervous system activity. Hypertension. 1991;17:669–77.

    Article  PubMed  CAS  Google Scholar 

  164. Ward KD, Sparrow D, Landsberg L, Young JB, Vokonas PS, Weiss ST. The relationship of epinephrine excretion to serum lipid levels: the normative aging study. Metabolism. 1994;43:509–13.

    Article  PubMed  CAS  Google Scholar 

  165. Lee ZS, Critchley JA, Tomlinson B, Young RP, Thomas GN, Cockram CS, et al. Urinary epinephrine and norepinephrine interrelations with obesity, insulin, and the metabolic syndrome in Hong Kong Chinese. Metab-Clin Exp. 2001;50:135–43.

    Article  PubMed  CAS  Google Scholar 

  166. Bougnères P, Stunff C, Pecqueur C, Pinglier E, Adnot P, Ricquier D. In vivo resistance of lipolysis to epinephrine. A new feature of childhood onset obesity. J Clin Invest. 1997;99:2568–73.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Thorp AA, Schlaich MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res. 2015;2015.

    Article  CAS  Google Scholar 

  168. Schlaich M, Straznicky N, Lambert E, Lambert G. Metabolic syndrome: a sympathetic disease? Lancet Diabetes Endocrinol. 2015;3:148–57.

    Article  PubMed  Google Scholar 

  169. Landsberg L. Diet, obesity and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. Citeseer. 1986.

  170. O'Hare JA, Minaker KL, Meneilly GS, Rowe JW, Pallotta JA, Young JB. Effect of insulin on plasma norepinephrine and 3, 4-dihydroxyphenylalanine in obese men. Metabolism. 1989;38:322–9.

    Article  PubMed  CAS  Google Scholar 

  171. Landsberg L. Insulin resistance, energy balance and sympathetic nervous system activity. Clin Exp Hypertens Part A: Theory Pract. 1990;12:817–30.

    CAS  Google Scholar 

  172. Rothwell N, Stock M. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin Sci. 1983;64:19–23.

    Article  CAS  Google Scholar 

  173. Gentile CL, Orr JS, Davy BM, Davy KP. Modest weight gain is associated with sympathetic neural activation in nonobese humans. Am J Phys Regul Integr Comp Phys. 2007;292:R1834–8.

    CAS  Google Scholar 

  174. O'Dea K, Esler M, Leonard P, Stockigt J, Nestel P. Noradrenaline turnover during under-and over-eating in normal weight subjects. Metabolism. 1982;31:896–9.

    Article  PubMed  CAS  Google Scholar 

  175. Katzeff HL, O'Connell M, Horton ES, Danforth E Jr, Young JB, Landsberg L. Metabolic studies in human obesity during overnutrition and undernutrition: thermogenic and hormonal responses to norepinephrine. Metabolism. 1986;35:166–75.

    Article  PubMed  CAS  Google Scholar 

  176. WELLE S, CAMPBELL R. Effect of overeating on plasma and urinary concentrations of norepinephrine. J Clin Endocrinol Metab. 1984;59:531–4.

    Article  PubMed  CAS  Google Scholar 

  177. Julius S, Nesbitt S. Sympathetic overactivity in hypertension: a moving target. Am J Hypertens. 1996;9:113S–20S.

    Article  PubMed  CAS  Google Scholar 

  178. Komai AM, Musovic S, Peris E, Alrifaiy A, El Hachmane MF, Johansson M, et al. White adipocyte adiponectin exocytosis is stimulated via β3-adrenergic signaling and activation of Epac1: catecholamine resistance in obesity and type 2 diabetes. Diabetes. 2016;65:3301–13.

    Article  PubMed  CAS  Google Scholar 

  179. Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off the signal: desensitization of beta-adrenergic receptor function. FASEB J. 1990;4:2881–9.

    Article  PubMed  CAS  Google Scholar 

  180. Mowers J, Uhm M, Reilly SM, Simon J, Leto D, Chiang S-H, et al. Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1. Elife. 2013;2:e01119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Reynisdottir S, Wahrenberg H, Carlström K, Rössner S, Arner P. Catecholamine resistance in fat cells of women with upper-body obesity due to decreased expression of beta 2-adrenoceptors. Diabetologia. 1994;37:428–35.

    Article  PubMed  CAS  Google Scholar 

  182. Arner P. Genetic variance and lipolysis regulation: implications for obesity. Ann Med. 2001;33:542–6.

    Article  PubMed  CAS  Google Scholar 

  183. Masuo K, Katsuya T, Kawaguchi H, Fu Y, Rakugi H, Ogihara T, et al. Rebound weight gain as associated with high plasma norepinephrine levels that are mediated through polymorphisms in the β2-adrenoceptor. Am J Hypertens. 2005;18:1508–16.

    Article  PubMed  CAS  Google Scholar 

  184. Simonsen L, Bülow J, Madsen J, Christensen NJ. Thermogenic response to epinephrine in the forearm and abdominal subcutaneous adipose tissue. Am J Phys. 1992;263:E850–5.

    CAS  Google Scholar 

  185. Galster AD, Clutter WE, Cryer PE, Collins JA, Bier DM. Epinephrine plasma thresholds for lipolytic effects in man: measurements of fatty acid transport with [l-13C]palmitic acid. 1981;67:1729–38.

  186. Lafontan M, Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res. 1993;34:1057–91.

    PubMed  CAS  Google Scholar 

  187. Reimann M, Qin N, Gruber M, Bornstein S, Kirschbaum C, Ziemssen T, et al. Adrenal medullary dysfunction as a feature of obesity. Int J Obes. 2017;41:714.

    Article  CAS  Google Scholar 

  188. Vinales KL, Schlogl M, Piaggi P, Hohenadel M, Graham A, Bonfiglio S, et al. The consistency in macronutrient oxidation and the role for epinephrine in the response to fasting and overfeeding. J Clin Endocrinol Metab. 2017;102:279–89.

    Article  PubMed  Google Scholar 

  189. Hollstein T, Basolo A, Ando T, Votruba SB, Walter M, Krakoff J, et al. Recharacterizing the Metabolic State of Energy Balance in Thrifty and Spendthrift Phenotypes. J Clin Endocrinol Metab. 2020;105(5). https://doi.org/10.1210/clinem/dgaa098.

    Article  Google Scholar 

  190. Khatib N, Gaidhane S, Gaidhane AM, Khatib M, Simkhada P, Gode D, et al. Ghrelin: ghrelin as a regulatory peptide in growth hormone secretion. J Clin Diagn Res. 2014;8:MC13.

    PubMed  PubMed Central  Google Scholar 

  191. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714–9.

    Article  PubMed  CAS  Google Scholar 

  192. Cummings DE, Foster-Schubert KE, Overduin J. Ghrelin and energy balance: focus on current controversies. Curr Drug Targets. 2005;6:153–69.

    Article  PubMed  CAS  Google Scholar 

  193. Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908–13.

    Article  PubMed  Google Scholar 

  194. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194–8.

    Article  PubMed  CAS  Google Scholar 

  195. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86:5992–5992.

    Article  Google Scholar 

  196. Druce MR, Neary NM, Small CJ, Milton J, Monteiro M, Patterson M, et al. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int J Obes. 2006;30:293–6.

    Article  CAS  Google Scholar 

  197. Zakhari JS, Zorrilla EP, Zhou B, Mayorov AV, Janda KD. Oligoclonal antibody targeting ghrelin increases energy expenditure and reduces food intake in fasted mice. Mol Pharm. 2012;9:281–9.

    Article  PubMed  CAS  Google Scholar 

  198. Marzullo P, Verti B, Savia G, Walker GE, Guzzaloni G, Tagliaferri M, et al. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. J Clin Endocrinol Metab. 2004;89:936–9.

    Article  PubMed  CAS  Google Scholar 

  199. St-Pierre DH, Karelis AD, Cianflone K, Conus F, Mignault D, Rabasa-Lhoret R, St-Onge M, Tremblay-Lebeau Aa, Poehlman ET: Relationship between ghrelin and energy expenditure in healthy young women. J Clin Endocrinol Metab 2004;89:5993–5997.

    Article  CAS  Google Scholar 

  200. Yasuda T, Masaki T, Kakuma T, Yoshimatsu H. Centrally administered ghrelin suppresses sympathetic nerve activity in brown adipose tissue of rats. Neurosci Lett. 2003;349:75–8.

    Article  PubMed  CAS  Google Scholar 

  201. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. 2001;50:707–9.

  202. Le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. 2005;90:1068–71.

  203. Spiegel K. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. 2004;141:846.

  204. Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Schmid SM, Hallschmid M, Jauch-Chara K, Born J, Schultes B. A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J Sleep Res. 2008;17:331–4.

    Article  PubMed  Google Scholar 

  206. Morselli L, Leproult R, Balbo M, Spiegel K. Role of sleep duration in the regulation of glucose metabolism and appetite. Best Pract Res Clin Endocrinol Metab. 2010;24:687–702.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Rihm JS, Menz MM, Schultz H, Bruder L, Schilbach L, Schmid SM, et al. Sleep deprivation selectively upregulates an amygdala–hypothalamic circuit involved in food reward. J Neurosci. 2019;39:888–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Broussard JL, Kilkus JM, Delebecque F, Abraham V, Day A, Whitmore HR, et al. Elevated ghrelin predicts food intake during experimental sleep restriction. Obesity. 2016;24:132–8.

    Article  PubMed  CAS  Google Scholar 

  209. Crujeiras AB, Goyenechea E, Abete I, Lage M, Carreira MC, Martínez JA, et al. Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels. 2010;95:5037–44.

  210. Chao AM, Jastreboff AM, White MA, Grilo CM, Sinha R. Stress, cortisol, and other appetite-related hormones: prospective prediction of 6-month changes in food cravings and weight. Obesity. 2017;25:713–20.

    Article  PubMed  CAS  Google Scholar 

  211. Chaput J-P, St-Onge M-P. Increased food intake by insufficient sleep in humans: are we jumping the gun on the hormonal explanation? Front Endocrinol. 2014;5.

Download references

Funding

P.P. was supported by the program “Rita Levi Montalcini for young researchers” from the Italian Minister of Education and Research.

Author information

Authors and Affiliations

  1. Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA

    Tim Hollstein & Paolo Piaggi

  2. Department of Information Engineering, University of Pisa, Pisa, Italy

    Paolo Piaggi

Authors
  1. Tim Hollstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paolo Piaggi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Piaggi.

Ethics declarations

Conflict of Interest

The authors have nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Metabolism

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hollstein, T., Piaggi, P. Metabolic Factors Determining the Susceptibility to Weight Gain: Current Evidence. Curr Obes Rep 9, 121–135 (2020). https://doi.org/10.1007/s13679-020-00371-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13679-020-00371-4

Keywords

Search

Navigation