Human Leptin: An Adipocyte Hormone with Weight-Regulatory and Endocrine Functions

ABSTRACT

Leptin is synthesized and secreted primarily by adipocytes, and is present in serum in direct proportion to the amount of adipose tissue. The primary role of leptin is to provide to the central nervous system a signal of energy intake and energy stores in the body so that the hypothalamus can efficiently maintain a stable body weight. The receptor for leptin in the hypothalamus signals by activation of an associated janus kinase which phosphorylates signal transducer and activator of transcription (STAT) proteins that regulate neuronal gene expression. Genetic mutations in leptin and its receptor can result in obesity in both rodents and humans, supporting a central role for leptin in the regulation of body weight. Leptin has also been implicated in a variety of physiological processes other than body weight homeostasis. Many of these functions are mediated through the central nervous system; however, the presence of leptin receptors in tissues throughout the body suggests that leptin can also have direct effects on cells and tissues. Serum leptin levels have been associated with cardiovascular risk factors after correction for adiposity. Leptin can promote platelet aggregation, which requires expression of functional leptin receptors on the platelet. Leptin-induced increases in sympathetic nerve activity have been suggested to contribute to hypertension, and leptin has been observed to increase oxidative stress in cultured endothelial cells. Many of these pathophysiologic effects of leptin on the vasculature are most likely of importance when leptin levels are elevated in obese subjects due to resistance to the weight-reducing effects of the hormone. An improved understanding of the effects of leptin on the vasculature will provide valuable insight into the relationship between obesity and cardiovascular disease.

KEYWORDS

Obesity - hyperleptinemia - hypertension - angiogenesis - thrombosis - oxidative stress

REFERENCES

• 1 Kenchaiah S, Evans J C, Levy D et al.. Obesity and the risk of heart failure.  N Engl J Med. 2002;  347 305-313
• 2 Sowers J R. Obesity as a cardiovascular risk factor.  Am J Med. 2003;  115 37S-41S
• 3 Reaven G, Abbasi F, McLaughlin T. Obesity, insulin resistance and cardiovascular disease.  Recent Prog Horm Res. 2004;  59 207-223
• 4 Lyon C J, Law R E, Hseuh W A. Minireview: adiposity, inflammation and atherogenesis.  Endocrinology. 2003;  144 2195-2200
• 5 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
• 6 Cohen S L, Halaas J L, Friedman J M, Chait B T. Human leptin characterization.  Nature. 1996;  382 589
• 7 Considine R V. Regulation of leptin production.  Rev Endocr Metab Disord. 2001;  2 357-363
• 8 Tartaglia L A. The leptin receptor.  J Biol Chem. 1997;  272 6093-6096
• 9 Vaisse C, Halaas J L, Horvath C M, Darnell Jr J E, Stoffel M, Friedman J M. Leptin activation of STAT3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.  Nat Genet. 1996;  14 95-97
• 10 Niswender K D, Morton G J, Stearns W H, Rhodes C J, Myers Jr M G, Schwartz M W. Intracellular signalling. Key enzyme in leptin-induced anorexia.  Nature. 2001;  413 794-795
• 11 Zhao A Z, Huan J N, Gupta S, Pal R, Sahu A. A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding.  Nat Neurosci. 2002;  5 727-728
• 12 Lee G H, Proenca R, Montez J M et al.. Abnormal splicing of the leptin receptor in diabetic mice.  Nature. 1996;  379 632-635
• 13 Wang M -Y, Zhou Y T, Newgard C B, Unger R H. A novel leptin receptor isoform in rat.  FEBS Lett. 1996;  392 87-90
• 14 Bjorbaek C, Uotani S, da Silva B, Flier J S. Divergent signaling capacities of the long and short isoforms of the leptin receptor.  J Biol Chem. 1997;  272 32686-32695
• 15 Tartaglia L A, Dembski M, Weng X et al.. Identification and expression cloning of the a leptin receptor, OB-R.  Cell. 1995;  83 1263-1271
• 16 Banks W A, Kastin A J, Huang W, Jaspan J B, Maness L M. Leptin enters the brain by a saturable system independent of insulin.  Peptides. 1996;  17 305-311
• 17 Golden P L, Maccagnan T J, Pardridge W M. Human blood-brain barrier leptin receptor.  J Clin Invest. 1997;  99 14-18
• 18 Sinha M K, Opentanova I, Ohannesian J P et al.. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting.  J Clin Invest. 1996;  98 1277-1282
• 19 Houseknecht K L, Mantzoros C S, Kuliawat R, Hadro E, Flier J S, Kahn B B. Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity.  Diabetes. 1996;  45 1638-1643
• 20 Huang L, Wang Z, Li C. Modulation of circulating leptin levels by its soluble receptor.  J Biol Chem. 2001;  276 6343-6349
• 21 Moon B C, Friedman J M. The molecular basis of the obese mutation in ob^2j mice.  Genomics. 1997;  42 152-156
• 22 Chen H, Charlat O, Tartaglia L A et al.. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice.  Cell. 1996;  84 491-495
• 23 Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim M H, Skoda R C. Defective STAT signaling by the leptin receptor in diabetic mice.  Proc Natl Acad Sci U S A. 1996;  93 6231-6235
• 24 Friedman J M. Leptin, leptin receptors, and the control of body weight.  Nutr Rev. 1998;  56 S38-S48
• 25 Phillips M S, Liu Q, Hammond H A et al.. Leptin receptor missense mutation in the fatty Zucker rat.  Nat Genet. 1996;  13 18-19
• 26 Chua Jr S C, White D W, Wu-Peng S et al.. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (lepr).  Diabetes. 1996;  45 1141-1143
• 27 White D W, Wang D W, Chua Jr S C, Morgenstern J P, Leibel R L. Constitutive and impaired signaling of leptin receptors containing the Gln-Pro extracellular domain mutation.  Proc Natl Acad Sci USA. 1997;  94 10657-10662
• 28 Takaya K, Ogawa Y, Hiraoka J et al.. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat.  Nat Genet. 1996;  14 130-131
• 29 Wu-Peng S, Chua Jr S C, Okada N, Lui S M, Nicolson M, Leibel R L. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma to CSF transport of leptin in both the Zucker and Koletsky obese rat.  Diabetes. 1997;  46 513-518
• 30 Caro J F, Considine R V. Leptin: From laboratory to clinic. in GA Bray, C Bouchard Handbook of Obesity, Clinical Applications, 2nd ed. New York; Marcel Dekker 2004: 275-295
• 31 Zigman J M, Elmquist J K. Minireview: From anorexia to obesity-the yin and yang of body weight control.  Endocrinology. 2003;  144 3749-3756
• 32 Hickey M S, Israel R G, Gardiner S N et al.. Gender differences in serum leptin levels in humans.  Biochem Mol Med. 1996;  59 1-6
• 33 Rosenbaum M, Leibel R L. Clinical Review 107. Role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin.  J Clin Endocrinol Metab. 1999;  84 1784-1789
• 34 Montague C T, Prins J B, Sanders L, Digby J, Orahilly S. Depot and sex specific differences in human leptin mRNA expression.  Diabetes. 1997;  46 342-347
• 35 Lefebvre A M, Laville M, Vega N et al.. Depot-specific differences in adipose tissue gene expression in lean and obese subjects.  Diabetes. 1998;  47 98-103
• 36 Van Harmelen V, Reynisdotir S, Eriksson P et al.. Leptin secretion from subcutaneous and visceral adipose tissue of women.  Diabetes. 1998;  47 913-917
• 37 Fried S K, Kral J G. Sex differences in regional distribution of fat cell size and lipoprotein lipase activity in morbidly obese patients.  Int J Obes. 1987;  11 129-140
• 38 Fried S K, Russell C D, Grauso N L, Brolin R E. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men.  J Clin Invest. 1993;  92 2191-2198
• 39 Sih R, Morley J E, Kaiser F E, Perry 3rd H M, Patrick P, Ross C. Testosterone replacement in older hypogondal men: a 12-month randomized controlled trial.  J Clin Endocrinol Metab. 1997;  82 1661-1667
• 40 Jockenhovel F, Blum W F, Vogel E et al.. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men.  J Clin Endocrinol Metab. 1997;  82 2510-2513
• 41 Mantzoros C S, Flier J S, Rogol A D. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty.  J Clin Endocrinol Metab. 1997;  82 1066-1070
• 42 Elbers J M, Asscheman H, Seidell J C, Frolich M, Meinders A E, Gooren L J. Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals.  J Clin Endocrinol Metab. 1997;  82 3267-3270
• 43 Casabiell X, Pineiro V, Peino R et al.. Gender differences in both spontaneous and stimulated leptin secretion by human omental adipose tissue in vitro: dexamethasone and estradiol stimulate leptin release in women, but not in men.  J Clin Endocrinol Metab. 1998;  83 2149-2155
• 44 Pineiro V, Casabiell X, Peino R et al.. Dihydrotestosterone, stanozol, androstenedione and dehydroepiandrosterone sulphate inhibit leptin secretion in female but not male samples of omental adipose tissue in vitro: lack of effect of testosterone.  J Endocrinol. 1999;  160 425-432
• 45 Caro J F, Sinha M K, Kolaczynski J W, Zhang P L, Considine R V. Leptin: the tale of an obesity gene.  Diabetes. 1996;  45 1455-1462
• 46 Sinha M, Ohannesian J P, Heiman M L, Kriauciunas A, Stephens T W, Magosin S, Marco C, Caro J F. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects.  J Clin Invest. 1996;  97 1344-1347
• 47 Kolaczynski J W, Considine R V, Ohannesian J et al.. Responses of leptin to short-term fasting and refeeding in humans: A link with ketogenesis but not ketones themselves.  Diabetes. 1996;  45 1511-1515
• 48 Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects.  J Clin Endocrinol Metab. 1996;  81 3419-3423
• 49 Wisse B E, Campfield L A, Marliss E B, Morais J A, Tenenbaum R, Gougeon R. Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women.  Am J Clin Nutr. 1999;  70 321-330
• 50 Schoeller D A, Cella L K, Sinha M K, Caro J F. Entrainment of the diurnal rhythm of plasma leptin to meal timing.  J Clin Invest. 1997;  100 1882-1887
• 51 Havel P J, Townsend R, Chaump L, Teff K. High fat meals reduce 24 h circulating leptin concentrations in women.  Diabetes. 1999;  48 334-341
• 52 Teff K L, Elliott S S, Tschop M et al.. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women.  J Clin Endocrinol Metab. 2004;  89 2963-2972
• 53 Saad M F, Khan A, Sharma A, Michael R, Road-Gabriel M G, Boyadjian R, Jinagouda S D, Steil G M, Kamdar V. Physiological insulinemia acutely modulates plasma leptin.  Diabetes. 1998;  47 544-549
• 54 Utriainen T, Malmstrom R, Makimattila S, Yki-Jarvinen H. Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects.  Diabetes. 1996;  45 1364-1366
• 55 Mueller W M, Gregoire F M, Stanhope K L et al.. Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes.  Endocrinology. 1998;  139 551-558
• 56 Rossetti L. Perspective: hexosamines and nutrient sensing.  Endocrinology. 2000;  141 1922-1925
• 57 McClain D A, Alexander T, Cooksey R C, Considine R V. Hexosamines stimulate leptin production in transgenic mice.  Endocrinology. 2000;  141 1999-2002
• 58 Considine R V, Cooksey R C, Williams L B et al.. Hexosamines regulate leptin production in human subcutaneous adipocytes.  J Clin Endocrinol Metab. 2000;  85 3551-3556
• 59 Donahoo W T, Jensen D R, Yost T J, Eckel R H. Isoproterenol and somatostatin decrease plasma leptin in humans: a novel mechanism regulating leptin secretion.  J Clin Endocrinol Metab. 1997;  82 4139-4143
• 60 Pinkney J H, Coppack S W, Mohamed Ali V. Effect of isoproterenol on plasma leptin and lipolysis in humans.  Clin Endocrinol (Oxf). 1998;  48 407-411
• 61 Stumvoll M, Fritsche A, Tschritter O et al.. Leptin levels in humans are acutely suppressed by isoproterenol despite Acipomox-induced inhibition of lipolysis, but not by free fatty acids.  Metabolism. 2000;  49 335-339
• 62 Slieker L J, Sloop K W, Surface P L et al.. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP.  J Biol Chem. 1996;  271 5301-5304
• 63 Kosaki A, Yamada K, Kuzuya H. Reduced expression of the leptin gene (ob) by catecholamine through a Gs protein-coupled pathway in 3T3-L1 adipocytes.  Diabetes. 1996;  45 1744-1749
• 64 Ricci M R, Fried S K. Isoproterenol decreases leptin expression in adipose tissue of obese humans.  Obes Res. 1999;  7 233-240
• 65 Flier J S. Clinical Review 94. What’s in a name? In search of leptin’s physiologic role.  J Clin Endocrinol Metab. 1998;  83 1407-1413
• 66 Ahima R S, Prabakaran D, Mantzoros C et al.. Role of leptin in the neuroendocrine response to fasting.  Nature. 1996;  382 250-252
• 67 Chan J L, Heist K, DePaoli A M, Veldhuis J D, Mantzoros C S. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.  J Clin Invest. 2003;  111 1409-1421
• 68 Van Heek M, Compton D S, France C F et al.. Diet-induced obese mice develop peripheral, but not central, resistance to leptin.  J Clin Invest. 1997;  99 385-390
• 69 El-Haschimi K, Pierroz D D, Hileman S M, Bjorbaek C, Flier J S. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.  J Clin Invest. 2000;  105 1827-1832
• 70 Bjorbaek C, Elmquist J K, Frantz J D, Shoelson S E, Flier J S. Identification of SOCS-3 as a potential mediator of central leptin resistance.  Mol Cell. 1998;  1 619-625
• 71 Montague C T, Farooqi I S, Whitehead J P et al.. Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 1997;  387 903-908
• 72 Rau H, Reaves B J, O'Rahilly S, Whitehead J P. Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport.  Endocrinology. 1999;  140 1718-1723
• 73 Farooqi I S, O'Rahilly S. Monogenic human obesity syndromes.  Recent Prog Horm Res. 2004;  59 409-424
• 74 Strobel A, Issad T, Camoin L, Ozata M, Strosberg A D. A leptin missense mutation associated with hypogonadism and morbid obesity.  Nat Genet. 1998;  18 213-215
• 75 Clement K, Vaisse C, Lahlou N et al.. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.  Nature. 1998;  392 398-401
• 76 Lahlou N, Clement K, Carel J C et al.. Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass.  Diabetes. 2000;  49 1347-1352
• 77 Farooqi I S, Matarese G, Lord G M et al.. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency.  J Clin Invest. 2002;  110 1093-1103
• 78 Heymsfield S B, Greenberg A S, Fujioka K et al.. Recombinant leptin for weight Loss in obese and lean adults.  JAMA. 1999;  282 1568-1575
• 79 Pelleymounter M A, Cullen M J, Baker M B et al.. Effects of the obese gene product on body weight regulation in ob/ob mice.  Science. 1995;  269 540-543
• 80 Schwartz M W, Baskin D G, Bukowski T R et al.. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.  Diabetes. 1996;  45 531-535
• 81 Sivitz W I, Walsh S A, Morgan D A, Thomas M J, Haynes W G. Effects of leptin on insulin sensitivity in normal rats.  Endocrinology. 1997;  138 3395-3401
• 82 Kamohara S, Burcelin R, Halaas J L, Friedman J M, Charron M J. Acute stimulation of glucose metabolism in mice by leptin treatment.  Nature. 1997;  389 374-377
• 83 Shimomura I, Hammer R E, Ikemoto S, Brown M S, Goldstein J L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.  Nature. 1999;  401 73-76
• 84 Ebihara K, Ogawa Y, Masuzaki H et al.. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipatrophic diabetes.  Diabetes. 2001;  50 1440-1448
• 85 Berti L, Kellerer M, Capp E, Haring H U. Leptin stimulates glucose transport and glycogen synthesis in C₂C₁₂ myotubes: evidence for a PI3-kinase mediated effect.  Diabetologia. 1997;  40 606-609
• 86 Kim Y-B, Uotani S, Pierroz D D, Flier J S, Kahn B B. In vivo administration of leptin activates signal transduction directly in insulin-sensitive tissues: overlapping but distinct pathways from insulin.  Endocrinology. 2000;  141 2328-2339
• 87 Fruhbeck G. Peripheral actions of leptin and its involvement in disease.  Nutr Rev. 2002;  60 S47-S55
• 88 Orci L, Cook W S, Ravazzola M et al.. Rapid transformation of white adipocytes into fat-oxidizing machines.  Proc Natl Acad Sci USA. 2004;  101 2058-2063
• 89 Henson MC, Castracane VD Leptin and Reproduction. Kluwer Academic New York; 2003
• 90 Lord G. Role of leptin in immunology.  Nutr Rev. 2002;  60 S35-S38
• 91 Rahmouni K, Haynes W G. Leptin and the cardiovascular system.  Recent Prog Horm Res. 2004;  59 225-244
• 92 Mark A L, Correia M L, Rahmouni K, Haynes W G. Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications.  J Hypertens. 2002;  20 1245-1250
• 93 Nakata M, Yada T, Soejima N, Maruyama I. Leptin promotes aggregation of human platelets via the long form of its receptor.  Diabetes. 1999;  48 426-429
• 94 Konstantinides S, Schafer K, Koschnick S, Loskutoff D J. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity.  J Clin Invest. 2001;  108 1533-1540
• 95 Soderberg S, Olsson T, Eliasson M, Johnson O, Ahren B. Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women.  J Intern Med. 1999;  245 533-543
• 96 Collins S, Kuhn C M, Petro A E, Swick A G, Chrunyk B A, Surwit R S. Role of leptin in fat regulation.  Nature. 1996;  380 677
• 97 Haynes W G, Morgan D A, Walsh S A, Mark A L, Sivitz W I. Receptor-mediated regional sympathetic nerve activation by leptin.  J Clin Invest. 1997;  100 270-278
• 98 Dunbar J C, Hu Y, Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats.  Diabetes. 1997;  46 2040-2043
• 99 Lembo G, Vecchione C, Fratta L et al.. Leptin induces direct vasodilation through distinct endothelial mechanisms.  Diabetes. 2000;  49 293-297
• 100 Vecchione C, Maffei A, Colella S et al.. Leptin effect on endothelial nitric oxide is mediated through Akt-endothelial nitric oxide synthase phosphorylation pathway.  Diabetes. 2002;  51 168-173
• 101 Fruhbeck G. Pivotal role of nitric oxide in the control of blood pressure after leptin administration.  Diabetes. 1999;  48 903-908
• 102 Gardiner S M, Kemp P A, March J E, Bennett T. Regional haemodynamic effects of recombinant murine or human leptin in conscious rats.  Br J Pharmacol. 2000;  130 805-810
• 103 Mitchell J L, Morgan D A, Correia M L, Mark A L, Sivitz W I, Haynes W G. Does leptin stimulate nitric oxide to oppose the effects of sympathetic activation?.  Hypertension. 2001;  38 1081-1086
• 104 Quehenberger P, Exner M, Sunder-Plassmann R et al.. Leptin induces endothelin-1 in endothelial cells in vitro.  Circ Res. 2002;  90 711-718
• 105 Singhal A, Farooqi I S, Cole T J et al.. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease?.  Circulation. 2002;  106 1919-1924
• 106 Sierra-Honigmann M R, Nath A K, Murakami C et al.. Biological action of leptin as an angiogenic factor.  Science. 1998;  281 1683-1686
• 107 Bouloumie A, Drexler H C, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis.  Circ Res. 1998;  83 1059-1066
• 108 Schafer K, Halle M, Goeschen C et al.. Leptin promotes vascular remodeling and neointimal growth in mice.  Arterioscler Thromb Vasc Biol. 2004;  24 112-117
• 109 Harrison D, Griendling K K, Landmesser U, Hornig B, Drexler H. Role of oxidative stress in atherosclerosis.  Am J Cardiol. 2003;  91 7A-11A
• 110 Bouloumie A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells.  FASEB J. 1999;  13 1231-1238
• 111 Yamagishi S I, Edelstein D, Du X L, Kaneda Y, Guzman M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A.  J Biol Chem. 2001;  276 25096-25100