Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-26T09:13:16.126Z Has data issue: false hasContentIssue false
  • English
  • Français

Role of adipose tissue in body-weight regulation: mechanisms regulating leptin production and energy balance

Published online by Cambridge University Press:  28 February 2007

Peter J. Havel
Peter J. Havel
Affiliation:
Department of Nutrition, University of California, Davis, CA 95616, USA
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor α, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24 h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity.

Keywords

LeptinAdipose tissueObesityFood intakeEnergy expenditureGlucose metabolism
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 59 , Issue 3 , August 2000 , pp. 359 - 371
Copyright
Copyright © The Nutrition Society 2000

References

Ahima, RS, Prabakaran, D, Mantzoros, C, Qu, D, Lowell, B, Maratos-Flier, E & Flier, JS (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.CrossRefGoogle ScholarPubMed
Ahren, B (1999) Plasma leptin and insulin in C57BI/6J mice on a high-fat diet: relation to subsequent changes in body weight. Acta Physiologica Scandinavica 165, 233–240.CrossRefGoogle ScholarPubMed
Ahren, B & Havel, PJ (1999a) Leptin increases circulating glucose, insulin and glucagon via sympathetic neural activation in fasted mice. International Journal of Obesity and Related Metabolic Disorders 23, 660–665.CrossRefGoogle ScholarPubMed
Ahren, B & Havel, PJ (1999b) Leptin inhibits insulin secretion induced by cellular cAMP in INS-1 cells. American Journal of Physiology 277, R959–R966.Google ScholarPubMed
Ahren, B, Mansson, S, Gingerich, RL & Havel, PJ (1997) Regulation of plasma leptin in mice: Influence of age, high-fat diet and fasting. American Journal of Physiology 273, R113–R120.Google ScholarPubMed
Barash, IA, Cheung, CC, Weigle, DS, Ren, H, Kabigting, EB, Kuijper, JL, Clifton, DK & Steiner, RA (1996) Leptin is a metabolic signal to the reproductive system. Endocrinology 137, 3144–3147.CrossRefGoogle Scholar
Barzilai, N, Wang, J, Massilon, D, Vuguin, P, Hawkins, M & Rossetti, L (1997) Leptin selectively decreases visceral adiposity and enhances insulin action. Journal of Clinical Investigation 100, 3105–3110.CrossRefGoogle ScholarPubMed
Blevins, JE, Havel, PJ & Gietzen, DW (1999) Injections of leptin into the anterior piriform cortex inhibit food intake in rats. Nutritional Neuroscience 2, 357–367.CrossRefGoogle ScholarPubMed
Boden, G, Chen, X, Mozzoli, M & Ryan, I (1996) Effect of fasting on serum leptin in normal human subjects. Journal of Clinical Endocrinology and Metabolism 81, 3419–3423.Google ScholarPubMed
Bornstein, SR, Uhlmann, K, Haidan, A, Ehrhart-Bornstein, M & Scherbaum, WA (1997) Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 46, 1235–1238.CrossRefGoogle Scholar
Bouloumie, A, Drexler, HC, Lafontan, M & Busse, R (1998) Leptin, the product of Ob gene, promotes angiogenesis. Circulation Research 83, 1059–1066.CrossRefGoogle Scholar
Bray, GA & Popkin, BM (1998) Dietary fat intake does affect obesity! American Journal of Clinical Nutrition 68, 1157–1173.CrossRefGoogle ScholarPubMed
Campfield, LA, Smith, FJ, Guisez, Y, Devos, R & Burn, P (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549.CrossRefGoogle ScholarPubMed
Cao, GY, Considine, RV & Lynn, RB (1997) Leptin receptors in the adrenal medulla of the rat. American Journal of Physiology 273, E448–E452.Google ScholarPubMed
Caro, JF, Kolaczynski, JW, Nyce, MR, Ohannesian, JP, Opentanova, I, Goldman, WH, Lynn, RB, Zhang, PL, Sinha, MK & Considine, RV (1996a) Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161.CrossRefGoogle ScholarPubMed
Caro, JR, Sinha, MK, Kolaczynski, JW, Zhang, PL & Considine, RV (1996b) Leptin: the tale of an obesity gene. Diabetes 45, 1455–1461.CrossRefGoogle ScholarPubMed
Chehab, FF, Lim, ME & Lu, R (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics 12, 318–320.CrossRefGoogle ScholarPubMed
Chehab, FF, Mounzih, K, Lu, R & Lim, ME (1997) Early onset of reproductive function in normal female mice treated with leptin. Science 275, 88–90.CrossRefGoogle ScholarPubMed
Chen, H, Charlat, O, Tartaglia, LA, Woolf, EA, Weng, X, Ellis, SJ, Lakey, ND, Culpepper, J, Moore, KJ, Breitbart, RE, Duyk, GM, Tepper, RI & Morgenstern, JP (1996a) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495.CrossRefGoogle ScholarPubMed
Chen, G, Koyama, K, Yuan, X, Lee, Y, Zhou, YT, O'Doherty, R, Newgard, CB & Unger, RH (1996b) Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proceedings of the National Academy of Sciences 93, 14795–14799.CrossRefGoogle ScholarPubMed
Chessler, SD, Fujimoto, WY, Shofer, JB, Boyko, EJ & Weigle, DS (1998) Increased plasma leptin levels are associated with fat accumulation in Japanese Americans. Diabetes 47, 239–243.CrossRefGoogle ScholarPubMed
Cheung, CC, Thornton, JE, Kuijper, JL, Weigle, DS, Clifton, DK & Steiner, RA (1997) Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 138, 855–858.CrossRefGoogle ScholarPubMed
Cianflone, K, Maslowska, M & Sniderman, AD (1999) Acylation stimulating protein (ASP), an adipocyte autocrine: new directions. Seminars in Cell and Development Biology 10, 31–41.CrossRefGoogle ScholarPubMed
Clement, K, Vaisse, C, Lahlou, N, Cabrol, S, Pelloux, V, Cassuto, D, Gourmelen, M, Dina, C, Chambaz, J, Lacorte, JM, Basdevant, A, Bougneres, P, Lebouc, Y, Froguel, P & Guy-Grand, B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401.CrossRefGoogle ScholarPubMed
Coleman, DL (1973) Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298.CrossRefGoogle ScholarPubMed
Coleman, DL & Hummel, KP (1969) Effects of parabiosis of normal with genetically diabetic mice. American Journal of Physiology 217, 1298–1304.CrossRefGoogle ScholarPubMed
Considine, RV, Considine, EL, Williams, CJ, Hyde, TM & Caro, JF (1996a) The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations. Diabetes 45, 992–994.CrossRefGoogle ScholarPubMed
Considine, RV, Sinha, MK, Heiman, ML, Kríauciunas, A, Stephens, TW, Nyce, MR, Ohannesian, JP, Marco, CC, McKee, LJ, Bauer, TL & Caro, JF (1996b) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine 334, 292–295.CrossRefGoogle ScholarPubMed
Cunningham, MJ, Clifton, DK & Steiner, RA (1999) Leptin's actions on the reproductive axis: perspectives and mechanisms. Biology of Reproduction 60, 216–222.CrossRefGoogle ScholarPubMed
Cusin, I, Sainsbury, A, Doyle, P, Rohner-Jeanrenaud, F & Jeanrenaud, B (1995) The ob gene and insulin: a relationship leading to clues to the understanding of obesity. Diabetes 44, 1467–1470.CrossRefGoogle Scholar
Dagogo-Jack, S, Fanelli, C, Paramore, D, Brothers, J & Landt, M (1996) Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes 45, 695–698.CrossRefGoogle ScholarPubMed
Doring, H, Schwarzer, K, Nuesslein-Hildesheim, B & Schmidt, I (1998) Leptin selectively increases energy expenditure of food-restricted lean mice. International Journal of Obesity and Related Metabolic Disorders 22, 83–88.CrossRefGoogle ScholarPubMed
Dubuc, GR, Phinney, SD, Stern, JS & Havel, PJ (1998) Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women. Metabolism 47, 429–434.CrossRefGoogle ScholarPubMed
Echwald, SM, Sorensen, TD, Sorensen, TI, Tybjaerg-Hansen, A, Andersen, T, Chung, WK, Leibel, RL & Pedersen, O (1997) Amino acid variants in the human leptin receptor: lack of association to juvenile onset obesity. Biochemical and Biophysical Research Communications 233, 248–252.CrossRefGoogle ScholarPubMed
Emilsson, V, Liu, YL, Cawthorne, MA, Morton, NM & Davenport, M (1997) Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 46, 313–316.CrossRefGoogle ScholarPubMed
Emond, M, Schwartz, GJ, Ladenheim, EE & Moran, TH (1999) Central leptin modulates behavioral and neural responsivity to CCK. American Journal of Physiology 276, R1545-R1549.Google ScholarPubMed
Farooqi, IS, Jebb, SA, Langmack, G, Lawrence, E, Cheetham, CH, Prentice, AM, Hughes, IA, McCamish, MA & O'Rahilly, S (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 341, 879–884.CrossRefGoogle Scholar
Fujioka, K, Patane, J, Lubina, J & Lau, D (1999) CSF leptin levels after exogenous administration of recombinant methionyl human leptin. Journal of the American Medical Association 282, 1517–1518.CrossRefGoogle ScholarPubMed
Funahashi, T, Nakamura, T, Shimomura, I, Maeda, K, Kuriyama, H, Takahashi, M, Arita, Y, Kihara, S & Matsuzawa, Y (1999) Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Internal Medicine 38, 202–206.CrossRefGoogle ScholarPubMed
Gainsford, T, Willson, TA, Metcalf, D, Handman, E, McFarlane, C, Ng, A, Nicola, NA, Alexander, WS & Hilton, DJ (1996) Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proceedings of the National Academy of Sciences 93, 14564–14568.CrossRefGoogle ScholarPubMed
Greenberg, AS, Fujioka, K, Heymsfield, S, Lau, D, Lubina, J, Patane, J & McCamish, M (1999) Clinical effects of leptin in obesity. Proceedings of the 81st Annual Meeting of the Endocrine Society, San Diego, CA, pp 53–54, S54–S63 Abstr (http://www.abstracts-on-line.com/abstracts/endo-society/).Google Scholar
Grinspoon, SK, Askari, H, Landt, ML, Nathan, DM, Schoenfeld, DA, Hayden, DL, Laposata, M, Hubbard, J & Klibanski, A (1997) Effects of fasting and glucose infusion on basal and overnight leptin concentrations in normal-weight women. American Journal of Clinical Nutrition 6, 1352–1356.CrossRefGoogle Scholar
Haffner, SM, Mykkanen, LA, Gonzalez, CC & Stern, MP (1998) Leptin concentrations do not predict weight gain: the Mexico City Diabetes Study. International Journal of Obesity and Related Metabolic Disorders 22, 695–699.CrossRefGoogle ScholarPubMed
Halaas, JL, Boozer, C, Blair-West, J, Fidahusein, N, Denton, DA & Friedman, JM (1997) Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proceedings of the National Academy of Sciences 94, 8878–8883.CrossRefGoogle ScholarPubMed
Halaas, JL, Gajiwala, KS, Maffei, M, Cohen, SL, Chait, BT, Rabinowitz, D, Lallone, RL, Burley, SK & Friedman, JM (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546.CrossRefGoogle ScholarPubMed
Hardie, LJ, Guilhot, N & Trayhurn, P (1996a) Regulation of leptin production in cultured mature white adipocytes. Hormone and Metabolic Research 28, 685–689.CrossRefGoogle ScholarPubMed
Hardie, LJ, Rayner, DV, Holmes, S & Trayhurn, P (1996b) Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. Biochemical and Biophysical Research Communications 223, 660–665.CrossRefGoogle Scholar
Harris, RB & Martin, RJ (1984) Specific depletion of body fat in parabiotic partners of tube-fed obese rats. American Journal of Physiology 247, R380-R386.Google ScholarPubMed
Havel, PJ (1997) Glucose infusion increases circulating leptin in proportion to adipose stores in rhesus monkeys. Journal of Experimental Endocrinology and Diabetes 105, 37–38.CrossRefGoogle Scholar
Havel, PJ (1998) Leptin production and action: relevance to energy balance in humans. American Journal of Clinical Nutrition 67, 355–356.CrossRefGoogle ScholarPubMed
Havel, PJ (1999) Mechanisms regulating leptin production: implications for the control of energy balance. American Journal of Clinical Nutrition 70, 305–306.CrossRefGoogle ScholarPubMed
Havel, PJ, Busch, BL, Curry, DL, Johnson, PR, Dallman, MF & Stern, JS (1996a) Predominately glucocorticoid agonist actions of RU-486 in young specific-pathogen-free Zucker rats. American Journal of Physiology 271, R710-R717.Google ScholarPubMed
Havel, PJ, Kasim-Karakas, S, Dubuc, GR, Mueller, WM & Phinney, SD (1996b) Gender differences in plasma leptin concentrations. Nature Medicine 2, 949–950.CrossRefGoogle ScholarPubMed
Havel, PJ, Kasim-Karakas, S, Mueller, W, Johnson, PR, Gingerich, RL & Stern, JS (1996c) Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: Effects of dietary fat content and sustained weight loss. Journal of Clinical Endocrinology and Metabolism 81, 4406–4413.Google ScholarPubMed
Havel, PJ, Larsen, PJ & Cameron, JL (2000) Control of food intake. In Neuroendocrinology in Physiology and Medicine, pp. 335–352 [Conn, PM and Freeman, ME, editors]. Totowa, NJ: Humana Press.CrossRefGoogle Scholar
Havel, PJ & Pelleymounter, M (1997) Acute adrenergically-mediated increases of circulating glucose and lactate after leptin administration in rhesus monkeys. Obesity Research 5, Suppl. 1, 17S.Google Scholar
Havel, PJ, Townsend, R, Chaump, L & Teff, K (1999) High fat meals reduce 24 h circulating leptin concentrations in women. Diabetes 48, 334–341.CrossRefGoogle ScholarPubMed
Havel, PJ, Uriu-Hare, JY, Liu, T, Stanhope, KL, Stern, JS, Keen, CL & Ahren, B (1998) Rapid and marked decreases of circulating leptin in streptozotocin diabetic rats: Reversal by insulin. American Journal of Physiology 274, R1482-R1491.Google ScholarPubMed
Haynes, WG, Morgan, DA, Walsh, SA, Mark, AL & Sivitz, WI (1997) Receptor-mediated regional sympathetic nerve activation by leptin. Journal of Clinical Investigation 100, 270–278.CrossRefGoogle ScholarPubMed
Heymsfield, SB, Greenberg, AS, Fujioka, K, Dixon, RM, Kushner, R, Hunt, T, Lubina, JA, Patane Self, B, Hunt, P & Mc, Camish (1999) Recombinant leptin for weight loss in lean and obese adults: a randomized, controlled, dose-escalation trial. Journal of the American Medical Association 282, 1568–1575.CrossRefGoogle ScholarPubMed
Hill, JO, Lin, D, Yakubu, F & Peters, JC (1992) Development of dietary obesity in rats: influence of amount and composition of dietary fat. International Journal of Obesity 16, 321–333.Google ScholarPubMed
Horton, TJ, Drougas, H, Brachey, A, Reed, GW, Peters, JC & Hill, JO (1995) Fat and carbohydrate overfeeding: different effects on energy storage. American Journal of Clinical Nutrition 62, 19–29.CrossRefGoogle ScholarPubMed
Hotamisligil, GS (1999) The role of TNFalpha and TNF receptors in obesity and insulin resistance.Journal of Internal Medicine 245, 621–625.CrossRefGoogle ScholarPubMed
Jacob, RJ, Dziura, J, Medwick, MB, Leone, P, Caprio, S, During, M, Shulman, GI & Sherwin, RS (1997) The effect of leptin is enhanced by microinjection into the ventromedial hypothalamus. Diabetes 46, 150–152.CrossRefGoogle ScholarPubMed
Keim, NL, Stern, JS & Havel, PJ (1998) Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women. American Journal of Clinical Nutrition 68, 794–801.CrossRefGoogle ScholarPubMed
Kennedy, AG (1953) The role of the fat depot in the hypothalamic control of food intake in the rat. Proceedings of the Royal Society of London 140, 578–592.Google ScholarPubMed
Kieffer, TJ, Heller, RS, Leech, CA, Holz, GG & Habener, JF (1997) Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Diabetes 46, 1087–1093.CrossRefGoogle ScholarPubMed
Kolaczynski, JW, Considine, RV, Ohannesian, J, Marco, C, Opentanova, I, Nyce, MR, Myint, M & Caro, JF (1996a) Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes 45, 1511–1515.CrossRefGoogle Scholar
Kolaczynski, JW, Nyce, MR, Considine, RV, Boden, G, Nolan, JJ, Henry, R, Mudaliar, SR, Olefsky, J & Caro, JF (1996b) Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes 45, 699–701.CrossRefGoogle ScholarPubMed
Kolaczynski, JW, Ohannesian, JP, Considine, RV, Marco, CC & Caro, JF (1996c) Response of leptin to short-term and prolonged overfeeding in humans. Journal of Clinical Endocrinology and Metabolism 81, 4162–4165Google ScholarPubMed
Kopp, W, Blum, WF, Ziegler, A, Mathiak, K, Lubbert, H, Herpertz, S, Deter, HC & Hebebrand, J (1998) Serum leptin and body weight in females with anorexia and bulimia nervosa. Hormone and Metabolic Research 30, 5272–5275.CrossRefGoogle ScholarPubMed
Landt, M, Gingerich, RL, Havel, PJ, Mueller, WM, Schoner, B, Hale, JE & Heiman, ML (1998) Radioimmunoassay of rat leptin: sexual dimorphism reversed from humans. Clinical Chemistry 44, 565–570.CrossRefGoogle ScholarPubMed
Laughlin, GA & Yen, SSC (1997) Hypoleptinemia in women athletes: absence of diurnal rhythm with amenorrhea. Journal of Clinical Endocrinology and Metabolism 82, 318–321.CrossRefGoogle ScholarPubMed
Leroy, P, Dessolin, S, Villageois, P, Moon, BC, Friedman, JM, Ailhaud, G & Dani, C (1996) Expression of ob gene in adipose cells: regulation by insulin. Journal of Biological Chemistry 271, 2365–2368.CrossRefGoogle Scholar
Levin, N, Nelson, C, Gurney, A, Vandlen, R & de Sauvage, F (1996) Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proceedings of the National Academy of Sciences 93, 1726–1730.CrossRefGoogle Scholar
Loffreda, S, Yang, SQ, Lin, HZ, Karp, CL, Brengman, ML, Wang, DJ, Klein, AS, Bulkley, GB, Bao, C, Noble, PW, Lane, MD & Diehl, AM (1998) Leptin regulates proinflammatory immune responses. FASEB Journal 12, 57–65.CrossRefGoogle ScholarPubMed
Lord, GM, Matarese, G, Howard, JK, Baker, RJ, Bloom, SR & Lechler, RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897–901.CrossRefGoogle ScholarPubMed
Maffei, M, Halaas, J, Ravussin, E, Pratley, RE, Lee, GH, Zhang, Y, Fei, H, Lallone, R, Ranganathan, S, Kern, PA & Friedman, JM (1995) Leptin levels in human and rodents: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine 1, 1155–1161.CrossRefGoogle ScholarPubMed
Malmstrom, R, Taskinen, MR, Karonen, SL & Yki-Harvinen, H (1996) Insulin increases plasma leptin concentrations in normal subjects and in patients with NIDDM. Diabetologia 39, 993–996.CrossRefGoogle ScholarPubMed
Matkovic, V, Ilich, JZ, Badenhop, NE, Skugor, M, Clairmont, A, Klisovic, D & Landoll, JD (1997) Gain in body fat is inversely related to the nocturnal rise in serum leptin level in young females. Journal of Clinical Endocrinology and Metabolism 82, 1368–1372.Google Scholar
Matson, CA, Wiater, MF, Kuijper, JL & Weigle, DS (1997) Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides 18, 1275–1278.CrossRefGoogle ScholarPubMed
Matsuoka, N, Ogawa, Y, Hosoda, K, Matsuda, J, Masuzaki, H, Miyawaki, T, Azuma, N, Natsui, K, Nishimura, H, Yoshimasa, Y, Nishi, S, Thompson, DB & Nakao, K (1997) Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity. Diabetologia 40, 1204–1210.CrossRefGoogle ScholarPubMed
Medina, EA, Stanhope, KL, Mizuno, TM, Mobbs, CV, Gregoire, F, Hubbard, NE, Erickson, KL & Havel, PJ (1999) Effects of tumour necrosis factor alpha (TNFα) on leptin secretion and gene expression: relationship to changes of glucose metabolism in isolated rat adipocytes. International Journal of Obesity and Related Metabolic Disorders 23, 896–903.CrossRefGoogle ScholarPubMed
Mohamed-Ali, V, Pinkney, JH & Coppack, SW (1998) Adipose tissue as an endocrine and paracrine organ. International Journal of Obesity and Related Metabolic Disorders 22, 1145–1158.CrossRefGoogle ScholarPubMed
Montague, CT, Farooqi, IS, Whitehead, JP, Soos, MA, Rau, H, Wareham, NJ, Sewter, CP, Digby, JE, Mohammed, SN, Hurst, JA, Cheetham, CH, Earley, AR, Barnett, AH, Prins, JB & O'Rahilly, S (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908.CrossRefGoogle ScholarPubMed
Mueller, WM, Gregoire, FM, Stanhope, KL, Mobbs, CV, Mizuno, TM, Warden, CH, Stern, JS & Havel, PJ (1998) Evidence that glucose metabolism regulates leptin secretion from cultured adipocytes. Endocrinology 139, 551–558.CrossRefGoogle Scholar
O'Donnell, CP, Schaub, CD, Haines, AS, Berkowitz, DE, Tankersley, CG, Schwartz, AR & Smith, PL (1999) Leptin prevents respiratory depression in obesity. American Journal of Respiratory and Critical Care Medicine 159, 1477–1484.CrossRefGoogle ScholarPubMed
Pelleymounter, MA, Cullen, MJ, Baker, MB, Hecht, R, Winters, D, Boone, T & Collins, F (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543.CrossRefGoogle ScholarPubMed
Ravussin, E, Pratley, RE, Maffei, M, Wang, H, Friedman, JM, Bennett, PH & Bogardus, C (1996) Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nature Medicine 2, 238–240.Google Scholar
Rebrin, K, Steil, GM, Getty, L & Bergman, RN (1995) Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 44, 1038–1045.CrossRefGoogle ScholarPubMed
Rentsch, J & Chiesi, M (1996) Regulation of ob gene mRNA levels in cultured adipocytes. FEBS Letters 379, 55–59.CrossRefGoogle Scholar
Rosenbaum, M, Nicolson, M, Hirsch, J, Heymsfield, SB, Gallagher, D, Chu, F & Leibel, RL (1996) Effects of gender, body composition, and menopause on plasma concentrations of leptin. Journal of Clinical Endocrinology and Metabolism 81, 3424–3427.Google ScholarPubMed
Rossetti, L, Massillon, D, Barzilai, N, Vuguin, P, Chen, W, Hawkins, M, Wu, J & Wang, J (1997) Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. Journal of Biological Chemistry 272, 27758–27763.CrossRefGoogle ScholarPubMed
Saad, MF, Khan, A, Sharma, A, Michael, R, Riad-Gabriel, MG, Boyadjian, R, Jinagouda, SD, Steil, GM & Kamdar, V (1998a) Physiological insulinemia acutely modulates plasma leptin. Diabetes 47, 544–549.CrossRefGoogle ScholarPubMed
Saad, MF, Riad-Gabriel, MG, Khan, A, Sharma, A, Michael, R, Jinagouda, SD, Boyadjian, R & Steil, GM (1998b) Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. Journal of Clinical Endocrinology and Metabolism 83, 2453–2459.Google ScholarPubMed
Saladin, R, De Vos, P, Guerre-Millo, M, Leturque, A, Girard, J, Staels, B & Auwerx, J (1995) Transient increase in obese gene expression after food intake or insulin administration. Nature 377, 527–529.CrossRefGoogle ScholarPubMed
Satoh, N, Ogawa, Y, Katsuura, G, Hayase, M, Tsuji, T, Imagawa, K, Yoshimasa, Y, Nishi, S, Hosoda, K & Nakao, K (1997) The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neuroscience Letters 224, 149–152.CrossRefGoogle ScholarPubMed
Scarpace, PJ & Matheny, M (1998) Leptin induction of UCP1 gene expression is dependent on sympathetic innervation. American Journal of Physiology 275, E259-E264.Google ScholarPubMed
Scarpace, PJ, Matheny, M, Pollock, BH & Tumer, N (1997) Leptin increases uncoupling protein expression and energy expenditure. American Journal of Physiology 273, E226-E230.Google ScholarPubMed
Schoeller, DA, Cella, LK, Sinha, MK & Caro, JF (1997) Entrainment of the diurnal rhythm of plasma leptin to meal timing. Journal of Clinical Investigation 100, 1882–1887.CrossRefGoogle ScholarPubMed
Schwartz, MW, Baskin, DG, Kaiyala, KJ & Woods, SC (1999) Model for the regulation of energy balance and adiposity by the central nervous system. American Journal of Clinical Nutrition 69, 584–596.CrossRefGoogle ScholarPubMed
Schwartz, MW, Figlewicz, DP, Baskin, DG, Woods, SC & Porte, D (1994) Insulin and the central regulation of energy balance. In Monographs 2; The Endocrine Pancreas, Insulin Action, and Diabetes. Endocrine Reviews, pp. 81–113 [Negro Vilar, A and Underwood, LE, editors]. Bethesda, MD: The Endocrine Society.Google Scholar
Schwartz, MW, Peskind, E, Raskind, M, Boyko, EJ & Porte, D Jr (1996a) Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nature Medicine 2, 589–593.CrossRefGoogle ScholarPubMed
Schwartz, MW, Seeley, RJ, Campfield, LA, Burn, P & Baskin, DG (1996b) Identification of targets of leptin action in rat hypothalamus. Journal of Clinical Investigation 98, 1101–1106.CrossRefGoogle ScholarPubMed
Sierra-Honigmann, MR, Nath, AK, Murakami, C, Garcia-Cardena, G, Papapetropoulos, A, Sessa, WC, Madge, LA, Schechner, JS, Schwabb, MB, Polverini, PJ & Flores-Riveros, JR (1998) Biological action of leptin as an angiogenic factor. Science 281, 1683–1686.CrossRefGoogle ScholarPubMed
Sindelar, DK, Chu, CA, Rohlie, M, Neal, DW, Swift, LL & Cherrington, AD (1997) The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. Diabetes 46, 187–196.CrossRefGoogle ScholarPubMed
Sindelar, DK, Havel, PJ, Seeley, RJ, Wilkinson, CW, Woods, SC & Schwartz, MW (1999) Low plasma leptin levels contribute to diabetic hyperphagia in rats. Diabetes 48, 1275–1280.CrossRefGoogle ScholarPubMed
Sinha, MK, Ohannesian, JP, Heiman, ML, Kriauciunas, A, Stephens, TW, Magosin, S, Marco, C & Caro, JF (1996) Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. Journal of Clinical Investigation 97, 1344–1347.CrossRefGoogle ScholarPubMed
Sivitz, WI, Walsh, S, Morgan, D, Donohue, P, Haynes, W & Leibel, RL (1998) Plasma leptin in diabetic and insulin-treated diabetic and normal rats. Metabolism 47, 584–591.CrossRefGoogle ScholarPubMed
Sonnenberg, GE, Krakower, GR, Hoffmann, RG, Maas, DL, Hennes, MMI & Kissebah, AH (1996) Plasma leptin concentrations: Effects of extended fasting and stepwise increases in glucose infusions. Obesity Research 4, 13S Abstr.Google Scholar
Strobel, A, Issad, T, Camoin, L, Ozata, M & Strosberg, AD (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genetics 18, 213–215.CrossRefGoogle ScholarPubMed
Surwit, RS, Petro, AE, Parekhand, P & Collins, S (1997) Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice. Diabetes 46, 1516–1520.CrossRefGoogle ScholarPubMed
Tang-Christensen, M, Havel, PJ, Jacobs, RR, Larsen, PJ & Cameron, JL (1999a) Central administration of leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques. Journal of Clinical Endocrinology and Metabolism 84, 711–717.Google ScholarPubMed
Tang-Christensen, M, Holst, JJ, Hartmann, B & Vrang, N (1999b) The arcuate nucleus is pivotal in mediating the anorectic effects of centrally administered leptin. NeuroReport 10, 1183–1187.CrossRefGoogle ScholarPubMed
Tartaglia, LA (1997) The leptin receptor. Journal of Biological Chemistry 272, 6093–6096.CrossRefGoogle ScholarPubMed
Tartaglia, LA, Dembski, M, Weng, X, Deng, N, Culpepper, J, Devos, R, Richards, GJ, Campfield, LA, Clark, FT & Deeds, J (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271.CrossRefGoogle ScholarPubMed
Tataranni, PA & Ravussin, E (1997) Effect of fat intake on energy balance. Annals of the New York Academy of Sciences 819, 37–43.CrossRefGoogle ScholarPubMed
Trayhurn, P, Duncan, JS, Hoggard, N & Rayner, DV (1998) Regulation of leptin production: a dominant role for the sympathetic nervous system? Proceedings of the Nutrition Society 57, 413–419.CrossRefGoogle ScholarPubMed
Tremblay, A, Plourde, G, Despres, JP & Bouchard, C (1998) Impact of dietary fat content and fat oxidation on energy intake in humans. American Journal of Clinical Nutrition 49, 799–805.CrossRefGoogle Scholar
Utriainen, R, Malmstrom, R, Makimattila, S & Yki-Jarvinen, H (1996) Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes 45, 1364–1366.CrossRefGoogle Scholar
Van Heek, M, Compton, DS, France, CF, Tedesco, RP, Fawzi, AB, Graziano, MP, Sybertz, EJ, Strader, CD & Davis, HR Jr (1997) Diet-induced obese mice develop peripheral, but not central, resistance to leptin. Journal of Clinical Investigation 99, 385–390.CrossRefGoogle Scholar
Wabitsch, M, Jensen, PB, Blum, WF, Christoffersen, CT, Englaro, P, Heinze, E, Rascher, W, Teller, W, Tornqvist, H & Hauner, H (1996) Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 45, 1435–1438.CrossRefGoogle ScholarPubMed
Wang, J, Liu, R, Hawkins, M, Barzilai, N & Rossetti, L (1998) A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393, 684–688.CrossRefGoogle ScholarPubMed
Weigle, DS, Duell, PB, Connor, WE, Steiner, RA, Soules, MR & Kuijper, JL (1997) Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. Journal of Clinical Endocrinology and Metabolism 82, 561–565.Google ScholarPubMed
Weigle, DS, Hutson, AM, Kramer, JM, Fallon, MG, Lehner, JM, Lok, S & Kuijper, JL (1998a) Leptin does not fully account for the satiety activity of adipose tissue-conditioned medium. American Journal of Physiology 275, R976-R985.Google Scholar
Weigle, DS, Selfridge, LE, Schwartz, MW, Seeley, RJ, Cummings, DE, Havel, PJ, Kuijper, JL & Beltran del Rio, H (1998b) Elevated free fatty acids induce uncoupling protein 3 expression in muscle: a potential explanation for the effect of fasting. Diabetes 147, 298–302.CrossRefGoogle Scholar
West, DB, Fey, D & Woods, SC (1984) Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. American Journal of Physiology 246, R776-R787.Google Scholar
Widdowson, PS, Upton, R, Buckingham, R, Arch, J & Williams, G (1997) Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity. Diabetes 46, 1782–1785.CrossRefGoogle ScholarPubMed
Wilson, BE, Meyer, GE, Cleveland JC, Jr & Weigle, DS (1990) Identification of candidate genes for a factor regulating body weight in primates. American Journal of Physiology 259, R1148-R1155.Google ScholarPubMed
Wiman, B & Hamsten, A (1990) The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Seminars in Thrombosis and Hemostasis 16, 207–216.CrossRefGoogle ScholarPubMed
Wisse, BE, Campfield, LA, Marliss, EB, Morais, JA, Tenenbaum, R & Gougeon, R (1999) Effects of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women. American Journal of Clinical Nutrition 70, 321–330.CrossRefGoogle ScholarPubMed
Woods, SC, Chavez, M, Park, CR, Riedy, C, Kaiyala, K, Richardson, RD, Figlewicz, DP, Schwartz, MW, Porte, D & Seeley, RJ (1996) The evaluation of insulin as a metabolic signal influencing behavior via the brain. Neuroscience and Biobehavior Reviews 20, 139–144.CrossRefGoogle ScholarPubMed
Woods, SC, Seeley, RJ, Porte, D Jr & Schwartz, MW (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383.CrossRefGoogle ScholarPubMed
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, 425–432.CrossRefGoogle ScholarPubMed