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Narrative Review

Vol. 11 No. 2 (2008)

Could there be a fine-tuning role for brain-derived adipokines in the regulation of bodyweight and prevention of obesity?

  • Russell E. Brown
November 7, 2020


Obesity is one of the most prevalent medical conditions, often associated with several negative stereotypes. Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years. Further, the body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function. When RNA interference (RNAi) was used to specifically silence adipokine gene expression in various in vitro models, this led to increases in cell death, modification of the expression of key signaling genes (i.e. suppressor of cytokine signaling-3; SOCS-3), and modulation of the activation of cellular energy sensors (i.e. adenosine monophosphate-activated protein kinase; AMPK). Subsequently, when RNAi was used to inhibit the expression of brain-derived leptin in adult rats this resulted in minor increases in weight gain in addition to modifying the expression of other adipokine genes (eg. resistin). In summary, although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain.


  1. Keith SW, Redden DT, et al. Putative contributors to the secular increase in obesity: Exploring the roads less traveled. Int J Obes 2006;30:1585-1594.
  2. Bray GA. Good calories, bad calories by gary taubes; new york: Aa knopf. Obes Rev 2008
  3. Katzmarzyk PT. The Canadian obesity epidemic, 1985-1998. CMAJ. 2002;166:1039-1040.
  4. Prentice AM. The emerging epidemic of obesity in developing countries. Int J Epidemiol 2006;35:93-99.
  5. Trifiletti LB, Shields W, Bishai D, McDonald E, Reynaud F, Gielen A. Tipping the scales: Obese children and child safety seats. Pediatrics 2006;117:1197-1202.
  6. Olshansky SJ, Passaro DJ,et al. A potential decline in life expectancy in the united states in the 21st century. N Engl J Med 2005;352:1138-1145.
  7. Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 2005;146:693-700.
  8. Katzmarzyk PT, Janssen I. The economic costs associated with physical inactivity and obesity in canada. An update. Can J Appl Physiol 2004;29:90-115.
  9. Jeffery RW, Drewnowski A, Epstein LH, Stunkard AJ, Wilson GT, Wing RR, Hill DR. Long-term maintenance of weight loss: Current status. Health Psychol 2000;19:5-16.
  10. Friedman JM, Leibel RL. Tackling a weighty problem. Cell 1992;69:217-220.
  11. Blundell JE. Appetite disturbance and the problems of overweight. Drugs 1990;39 Suppl 3:119.
  12. Stoger R. The thrifty epigenotype: An acquired and heritable predisposition for obesity and diabetes? Bioessays 2008;30:156- 166.
  13. Neel JV. Diabetes mellitus: A "Thrifty" Genotype rendered detrimental by "Progress"? Am J Hum Genet 1962;14:353-362.
  14. Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and thev environment: Where do we go from here? Science 2003;299:853-855.
  15. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976;295:349-353.
  16. Kramer FM, Jeffery RW, Forster JL, Snell MK. Long-term follow-up of behavioral treatment for obesity: Patterns of weight regain among men and women. Int J Obes 1989;13:123-136.
  17. Levin BE, Dunn-Meynell AA. Defense of body weight against chronic caloric restriction in obesity-prone and -resistant rats. Am J Physiol Regul Integr Comp Physiol 2000;278:R231-237.
  18. Levin BE, Keesey RE. Defense of differing body weight set points in diet-induced obese and resistant rats. Am J Physiol 1998;274:R412-419.
  19. Sims EA, Horton ES. Endocrine and metabolic adaptation to obesity and starvation. Am J Clin Nutr 1968;21:1455-1470.
  20. Schwartz MW, Woods SC, Seeley RJ, Barsh GS, Baskin DG, Leibel RL. Is the energy homeostasis system inherently biased toward weight gain? Diabetes 2003;52:232-238.
  21. Bernard C. Leçons de physiologie experimentale appliqués á là medecine. Paris, Baillere et Fils, 1854.
  22. Feldberg W, Pyke D, Stubbs WA. Hyperglycaemia: Imitating claude bernard's piqure with drugs. J Auton Nerv Syst 1985;14:213-228.
  23. Donhoffer C, MacLeod JJR. Studies in the nervous control of carbohydrate metabolism. I.--the position of the centre. Proc R Soc Lond B Biol Sci 1932;110:125-141.
  24. Pizzi WJ, Barnhart JE. Effects of monosodium glutamate on somatic development, obesity and activity in the mouse. Pharmacol Biochem Behav 1976;5:551-557.
  25. Cameron DP, Poon TK, Smith GC. Effects of monosodium glutamate administration in the neonatal period on the diabetic syndrome in kk mice. Diabetologia 1976;12:621-626.
  26. Schwartz MW, Porte D, Jr.. Diabetes, obesity, and the brain. Science 2005;307:375-379.
  27. Lee M, Korner J. Review of physiology, clinical manifestations, and management of hypothalamic obesity in humans. Pituitary 2008
  28. Hervey GR. Regulation of energy balance. Nature 1969;222:629-631.
  29. Harris RB. Role of set-point theory in regulation of body weight. Faseb J 1990;4:3310-3318.
  30. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci 1953;140:578-596.
  31. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432.
  32. Badman MK, Flier JS. The gut and energy balance: Visceral allies in the obesity wars. Science 2005;307:1909-1914.
  33. Fry M, Hoyda TD, Ferguson AV. Making sense of it: Roles of the sensory circumventricular organs in feeding and regulation of energy homeostasis. Exp Biol Med (Maywood) 2007;232:14-26.
  34. Montague CT, Farooqi IS, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-908.
  35. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weightreducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-546.
  36. Trayhurn P, Bing C, Wood IS. Adipose tissue and adipokines--energy regulation from the human perspective. J Nutr 2006;136:1935S-1939S.
  37. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR,Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001;409:307-312.
  38. 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;270:26746-26749.
  39. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, Wahli W. Characterization of the fasting-induced adipose factor fiaf, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem 2000;275:28488-28493.
  40. Fukuhara A, Matsuda M, et al. Visfatin. A protein secreted by visceral fat that mimics the effects of insulin. Science 2005;307:426-430.
  41. Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS. Visceral adipose tissue-derived serine protease inhibitor: A unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci U S A 2005;102.10610-10615.
  42. Bullo M, Peeraully MR, Trayhurn P: Stimulation of ngf expression and secretion in 3t3-l1 adipocytes by prostaglandins pgd2, pgj2, and delta12-pgj2. Am J Physiol Endocrinol Metab 2005;289.E62-67.
  43. Kratchmarova I, Kalume DE, Blagoev B, Scherer PE, Podtelejnikov AV, Molina H, Bickel PE, Andersen JS, Fernandez MM, Bunkenborg J, Roepstorff P, Kristiansen K, Lodish HF, Mann M, Pandey A. A proteomic approach for identification of secreted proteins during the differentiation of 3t3-l1 preadipocytes to adipocytes. Mol Cell Proteomics 2002;1:213-222.
  44. Yang YS, Song HD, Li RY, Zhou LB, Zhu ZD, Hu RM, Han ZG, Chen JL. The gene expression profiling of human visceral adipose tissue and its secretory functions. Biochem Biophys Res Commun 2003;300:839-846.
  45. Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring) 2006;14 Suppl 5:242S-249S.
  46. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 2008;22:1023-1031.
  47. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D, Jr.. Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans. Nat Med 1996;2:589-593.
  48. Becker DJ, Ongemba LN, Brichard V, Henquin JC, Brichard SM. Diet- and diabetes-induced changes of ob gene expression in rat adipose tissue. FEBS Lett 1995;371:324-328.
  49. 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;269:546-549.
  50. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptindeficient adults. Proc Natl Acad Sci U S A 2004;101:4531-4536.
  51. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nat Med 1995;1:1311-1314.
  52. Jackson MB, Ahima RS. Neuroendocrine and metabolic effects of adipocyte-derived hormones. Clin Sci (Lond) 2006;110:143-152.
  53. Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS. The role of socs-3 in leptin signaling and leptin resistance. J Biol Chem 1999;274:30059-30065.
  54. Munzberg H, Myers MG, Jr.. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 2005;8:566-570.
  55. Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 2003;285:E10-15.
  56. Wilkinson M, Brown R, Imran SA, Ur E: Adipokine gene expression in brain and pituitary gland. Neuroendocrinology 2007;86:191-209.
  57. Morash B, Li A, Murphy PR, Wilkinson M, Ur E. Leptin gene expression in the brain and pituitary gland. Endocrinology 1999;140:5995-5998.
  58. Wiesner G, Morash BA, Ur E, Wilkinson M. Food restriction regulates adipose-specific cytokines in pituitary gland but not in hypothalamus. J Endocrinol 2004;180:R1-6.
  59. Morash BA, Wilkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett 2002;526:26-30.
  60. Brown R, Imran SA, Belsham DD, Ur E, Wilkinson M. Adipokine gene expression in a novel hypothalamic neuronal cell line: Resistin-dependent regulation of fasting-induced adipose factor and socs-3. Neuroendocrinology 2007;85:232-241.
  61. Wiesner G, Brown RE, Robertson GS, Imran SA, Ur E, Wilkinson M. Increased expression of the adipokine genes resistin and fasting-induced adipose factor in hypoxic/ischaemic mouse brain. Neuroreport 2006;17:1195-1198.
  62. Steppan CM, Lazar MA: The current biology of resistin. J Intern Med 2004;255:439-447.
  63. Sahu A. Leptin signaling in the hypothalamus: Emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol 2003;24:225-253.
  64. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mrna isoforms in the rat brain. J Comp Neurol 1998;395:535-547.
  65. Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci 1998;18:559-572.
  66. Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, Lambert G, Wilkinson D, Esler M. Leptin is released from the human brain: Influence of adiposity and gender. J Clin Endocrinol Metab 1999;84:2270-2274.
  67. Eikelis N, Esler M, Barton D, Dawood T, Wiesner G, Lambert G. Reduced brain leptin in patients with major depressive disorder and in suicide victims. Mol Psychiatry 2006;11:800-801.
  68. Thakker DR, Hoyer D, Cryan JF. Interfering with the brain: Use of rna interference for understanding the pathophysiology of psychiatric and neurological disorders. Pharmacol Ther 2006;109:413-438.
  69. Gan L, Anton KE, Masterson BA, Vincent VA, Ye S, GonzalezZulueta M. Specific interference with gene expression and gene function mediated by long dsrna in neural cells. J Neurosci Methods 2002;121:151-157.
  70. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded rna in caenorhabditis elegans. Nature 1998;391:806-811.
  71. Steppan CM, Swick AG. A role for leptin in brain development. Biochem Biophys Res Commun 1999;256:600-602.
  72. Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108-110.
  73. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, Friedman JM, Horvath TL. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 2004;304:110-115.
  74. Morash B, Wilkinson D, Murphy P, Ur E, Wilkinson M. Developmental regulation of leptin gene expression in rat brain and pituitary. Mol Cell Endocrinol 2001;185:151-159.
  75. Brown R, Thompson HJ, Imran SA, Ur E, Wilkinson M. Traumatic brain injury induces adipokine gene expression in rat brain. Neurosci Lett 2008;432:73-78.
  76. Morash B, Johnstone J, Leopold C, Li A, Murphy P, Ur E, Wilkinson M. The regulation of leptin gene expression in the c6 glioblastoma cell line. Mol Cell Endocrinol 2000;165:97-105.
  77. Brown R, Morash B, Ur E, Wilkinson M. Rnai-mediated silencing of leptin gene expression increases cell death in c6 glioblastoma cells. Brain Res Mol Brain Res 2005;139:357-360.
  78. Russo VC, Metaxas S, Kobayashi K, Harris M, Werther GA. Antiapoptotic effects of leptin in human neuroblastoma cells. Endocrinology 2004;145:4103-4112.
  79. Belsham DD, Cai F, Cui H, Smukler SR, Salapatek AM, Shkreta L. Generation of a phenotypic array of hypothalamic neuronal cell models to study complex neuroendocrine disorders. Endocrinology 2004;145:393-400.
  80. Brown R, Wilkinson P, Imran SA, Ur E, Wilkinson M. Resistin activates amp-activated protein kinase in a novel hypothalamic neuronal cell line: Implications for central energy metabolism. Endocrine abstracts 2008
  81. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. Amp-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004;428:569- 574.
  82. McCrimmon RJ, Fan X, Cheng H, McNay E, Chan O, Shaw M, Ding Y, Zhu W, Sherwin RS. Activation of amp-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 2006;55:1755-1760.
  83. Kahn BB, Alquier T, Carling D, Hardie DG. Amp-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005;1:15-25.
  84. Baker-Herman TL, Fuller DD, Bavis RW, Zabka AG, Golder FJ, Doperalski NJ, Johnson RA, Watters JJ, Mitchell GS. Bdnf is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 2004;7:48-55.
  85. Ahima RS. Central actions of adipocyte hormones. Trends Endocrinol Metab 2005;16:307-313.
  86. Ahima RS, Qi Y, Singhal NS. Adipokines that link obesity and diabetes to the hypothalamus. Prog Brain Res 2006;153:155-174.


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