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Department of Nutrition (W.M.M., K.L.S., J.S.S., P.J.H.), and Department of Pediatrics (F.M.G., C.H.W.), School of Medicine, University of California, Davis, California 95616; and Neurobiology of Aging Laboratories, Mount Sinai School of Medicine (C.V.M., T.M.M.), New York, New York 10021
Address all correspondence and requests for reprints to: Peter J. Havel, D.V.M., Ph.D., Department of Nutrition, University of California, Davis, California 95616. E-mail: pjhavel{at}ucdavis.edu
Circulating leptin secreted from adipocytes is correlated with fat mass and plasma insulin concentrations in humans and rodents. Plasma leptin, insulin, and glucose decrease during fasting and increase after refeeding; however, the underlying mechanisms regulating the changes of leptin secretion are not known. To investigate the role of insulin-stimulated glucose metabolism in the regulation of leptin secretion, we examined the effects of insulin and inhibitors of glucose transport and metabolism on leptin secretion from rat adipocytes in primary culture. Insulin (0.16–16 nM) increased leptin secretion over 96 h; however, the increase in leptin was more closely related to the amount of glucose taken up by the adipocytes (r = 0.64; P < 0.0001) than to the insulin concentration per se (r = 0.20; P < 0.28), suggesting a role for glucose transport and/or metabolism in regulating leptin secretion.
2-Deoxy-D-glucose (2-DG), a competitive inhibitor of glucose transport and phosphorylation, caused a concentration-dependent (2–50 mg/dl) inhibition of leptin release in the presence of 1.6 nM insulin. The inhibitory effect of 2-DG was reversed by high concentrations of glucose. Two other inhibitors of glucose transport, phloretin (0.05–0.25 mM) and cytochalasin-B (0.5–50 µM), also inhibited leptin secretion. Inhibition of leptin secretion by these agents was proportional to the inhibition of glucose uptake (r = 0.60 to 0.86; all P < 0.01). Two inhibitors of glycolysis, iodoacetate (0.005–1.0 mM) and sodium fluoride (0.1–5 mM), produced concentration-dependent inhibition of leptin secretion in the presence of 1.6 nM insulin. In addition, both 2-DG and sodium fluoride markedly decreased the leptin (ob) messenger RNA content of cultured adipocytes, but did not affect 18S ribosomal RNA content.
We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. Thus, in vivo, decreased adipose glucose metabolism may be one mechanism by which fasting decreases circulating leptin, whereas increased adipose glucose metabolism would increase leptin after refeeding.
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S. K. Fried, M. R. Ricci, C. D. Russell, and B. Laferrere Regulation of Leptin Production in Humans J. Nutr., December 1, 2000; 130 (12): 3127S - 3131S. [Abstract] [Full Text] [PDF]
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J. R. Levy, J. Lesko, R. J. Krieg Jr., R. A. Adler, and W. Stevens Leptin responses to glucose infusions in obesity-prone rats Am J Physiol Endocrinol Metab, November 1, 2000; 279(5): E1088 - E1096. [Abstract] [Full Text] [PDF]
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R. V. Considine, R. C. Cooksey, L. B. Williams, R. L. Fawcett, P. Zhang, W. T. Ambrosius, R. M. Whitfield, R. Jones, M. Inman, J. Huse, et al. Hexosamines Regulate Leptin Production in Human Subcutaneous Adipocytes J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3551 - 3556. [Abstract] [Full Text]
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B. Lonnerdal and P. J Havel Serum leptin concentrations in infants: effects of diet, sex, and adiposity Am. J. Clinical Nutrition, August 1, 2000; 72(2): 484 - 489. [Abstract] [Full Text] [PDF]
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L. B. Williams, R. L. Fawcett, A. S. Waechter, P. Zhang, B. E. Kogon, R. Jones, M. Inman, J. Huse, and R. V. Considine Leptin Production in Adipocytes from Morbidly Obese Subjects: Stimulation by Dexamethasone, Inhibition with Troglitazone, and Influence of Gender J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2678 - 2684. [Abstract] [Full Text]
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J. R. Levy, J. Gyarmati, J. M. Lesko, R. A. Adler, and W. Stevens Dual regulation of leptin secretion: intracellular energy and calcium dependence of regulated pathway Am J Physiol Endocrinol Metab, May 1, 2000; 278(5): E892 - E901. [Abstract] [Full Text] [PDF]
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A. Suga, T. Hirano, H. Kageyama, T. Osaka, Y. Namba, M. Tsuji, M. Miura, M. Adachi, and S. Inoue Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats Am J Physiol Endocrinol Metab, April 1, 2000; 278(4): E677 - E683. [Abstract] [Full Text] [PDF]
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I. Murray, P. J. Havel, A. D. Sniderman, and K. Cianflone Reduced Body Weight, Adipose Tissue, and Leptin Levels Despite Increased Energy Intake in Female Mice Lacking Acylation-Stimulating Protein Endocrinology, March 1, 2000; 141(3): 1041 - 1049. [Abstract] [Full Text] [PDF]
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D. A Ainslie, J. Proietto, B. C Fam, and A. W Thorburn Short-term, high-fat diets lower circulating leptin concentrations in rats1 Am. J. Clinical Nutrition, February 1, 2000; 71(2): 438 - 442. [Abstract] [Full Text] [PDF]
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R. L. Fawcett, A. S. Waechter, L. B. Williams, P. Zhang, R. Louie, R. Jones, M. Inman, J. Huse, and R. V. Considine Tumor Necrosis Factor-{alpha} Inhibits Leptin Production in Subcutaneous and Omental Adipocytes from Morbidly Obese Humans J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 530 - 535. [Abstract] [Full Text]
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S. Klein, J. F. Horowitz, M. Landt, S. J. Goodrick, V. Mohamed-Ali, and S. W. Coppack Leptin production during early starvation in lean and obese women Am J Physiol Endocrinol Metab, February 1, 2000; 278(2): E280 - E284. [Abstract] [Full Text] [PDF]
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T. J. Kieffer and J. F. Habener The adipoinsular axis: effects of leptin on pancreatic beta -cells Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E1 - E14. [Abstract] [Full Text] [PDF]
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L. K. Hilton and A. B. Loucks Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin in healthy young women Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E43 - E49. [Abstract] [Full Text] [PDF]
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M. Romon, P. Lebel, C. Velly, N. Marecaux, J. C. Fruchart, and J. Dallongeville Leptin response to carbohydrate or fat meal and association with subsequent satiety and energy intake Am J Physiol Endocrinol Metab, November 1, 1999; 277(5): E855 - E861. [Abstract] [Full Text] [PDF]
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M. M. Hagan, P. J. Havel, R. J. Seeley, S. C. Woods, N. N. Ekhator, D. G. Baker, K. K. Hill, M. D. Wortman, A. H. Miller, R. L. Gingerich, et al. Cerebrospinal Fluid and Plasma Leptin Measurements: Covariability with Dopamine and Cortisol in Fasting Humans J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3579 - 3585. [Abstract] [Full Text] [PDF]
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T. M. Mizuno, H. Makimura, J. Silverstein, J. L. Roberts, T. Lopingco, and C. V. Mobbs Fasting Regulates Hypothalamic Neuropeptide Y, Agouti-Related Peptide, and Proopiomelanocortin in Diabetic Mice Independent of Changes in Leptin or Insulin Endocrinology, October 1, 1999; 140(10): 4551 - 4557. [Abstract] [Full Text]
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B. Ahren and P. J. Havel Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells) Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1999; 277(4): R959 - R966. [Abstract] [Full Text] [PDF]
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P. J Havel Mechanisms regulating leptin production: implications for control of energy balance Am. J. Clinical Nutrition, September 1, 1999; 70(3): 305 - 306. [Full Text] [PDF]
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B. E Wisse, L A. Campfield, E. B Marliss, J. A Morais, R. Tenenbaum, and R. Gougeon Effect of prolonged moderate and severe energy restriction and refeeding on plasma leptin concentrations in obese women Am. J. Clinical Nutrition, September 1, 1999; 70(3): 321 - 330. [Abstract] [Full Text] [PDF]
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 L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]
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M. J. Toth, C. K. Sites, and E. T. Poehlman Hormonal and Physiological Correlates of Energy Expenditure and Substrate Oxidation in Middle-Aged, Premenopausal Women J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2771 - 2775. [Abstract] [Full Text]
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M. W Schwartz, D. G Baskin, K. J Kaiyala, and S. C Woods Model for the regulation of energy balance and adiposity by the central nervous system Am. J. Clinical Nutrition, April 1, 1999; 69(4): 584 - 596. [Abstract] [Full Text] [PDF]
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B. Gutin, L. Ramsey, P. Barbeau, W. Cannady, M. Ferguson, M. Litaker, and S. Owens Plasma leptin concentrations in obese children: changes during 4-mo periods with and without physical training Am. J. Clinical Nutrition, March 1, 1999; 69(3): 388 - 394. [Abstract] [Full Text] [PDF]
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M. Tang-Christensen, P. J. Havel, R. R. Jacobs, P. J. Larsen, and J. L. Cameron Central Administration of Leptin Inhibits Food Intake and Activates the Sympathetic Nervous System in Rhesus Macaques J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 711 - 717. [Abstract] [Full Text]
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 E. LeGall-Salmon, W. D. Stevens, and J. R. Levy Total Parenteral Nutrition Increases Serum Leptin Concentration in Hospitalized, Undernourished Patients JPEN J Parenter Enteral Nutr, January 1, 1999; 23(1): 38 - 42. [Abstract] [PDF]
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J. Licinio, A. B. Negrão, C. Mantzoros, V. Kaklamani, M.-L. Wong, P. B. Bongiorno, P. P. Negro, A. Mulla, J. D. Veldhuis, L. Cearnal, et al. Sex Differences in Circulating Human Leptin Pulse Amplitude: Clinical Implications J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 4140 - 4147. [Abstract] [Full Text]
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 S. C. Woods, R. J. Seeley, D. Porte Jr., and M. W. Schwartz Signals That Regulate Food Intake and Energy Homeostasis Science, May 29, 1998; 280(5368): 1378 - 1383. [Abstract] [Full Text]
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P. J. Havel, J. Y. Uriu-Hare, T. Liu, K. L. Stanhope, J. S. Stern, C. L. Keen, and B. Ahren Marked and rapid decreases of circulating leptin in streptozotocin diabetic rats: reversal by insulin Am J Physiol Regulatory Integrative Comp Physiol, May 1, 1998; 274(5): R1482 - R1491. [Abstract] [Full Text] [PDF]
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