Leptin Regulation
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Body fat accounts for approximately 50-60% of the variability of Leptin levels. Leptin secretion increases with increasing adipocyte cell size, and hence plasma Leptin levels are directly proportional to fat mass. Obese individuals thus have higher Leptin mRNA and Leptin protein levels. When obese individuals lost 10% of their initial body weights, the serum Leptin level decreased by 55% on average. Age, gender, diurnal variation, hormones as insulin and cytokine levels also regulate Leptin to varying degrees. Inter-individual variability in plasma Leptin concentration is only partly explained by the degree of body fatness. Women have higher Leptin concentrations than men for any given degree of fat mass, J Clin Endocrinol Metab. 1997 Feb;82(2):579-84 with levels increasing during the luteal phase of the menstrual cycle. Metabolism. 2000 Oct;49(10):1278-84. Although this might suggest a role for female sex hormones in the regulation of Leptin secretion, women had higher levels than men even pre-pubertally J Clin Endocrinol Metab. 1997 Sep;82(9):2904-10 and post menopausally, J Clin Endocrinol Metab. 1996 Sep;81(9):3424-7 suggesting that testosterone in men may be the major determining factor for this sex based difference in Leptin levels. In keeping with this, estrogen or progesterone treatment as OCP or HRT does not alter Leptin levels. Fertil Steril. 1998 Sep;70(3):472-7. Leptin is increased by insulin, glucocorticoids, J Biol Chem. 1996 Mar 8;271(10):5301-4 TNF-alpha, estrogens, and decreased by sympathetic activity, (beta adrenergic) androgens, free fatty acids, growth hormone and peroxisome proliferator activated receptor gamma agonists. Int J Obes Relat Metab Disord. 2002 Nov;26(11):1407-33
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Fasting decreases plasma Leptin levels in rats as well as in humans. Diabetes. 1996 Nov;45(11):1511-5. In rats, re-feeding increases ob mRNA within 4 hours to levels of fed animals. Nature. 1995 Oct 12;377(6549):527-9 While normal feeding produces no significant rise in Leptin in humans, Clin Endocrinol (Oxf). 1997 Jun;46(6):751-7 acute massive overfeeding in humans results in a rise in circulating levels of Leptin by ~40%, with chronic overfeeding producing a three fold rise in Leptin levels. J Clin Endocrinol Metab. 1996 Nov;81(11):4162-5. Calorie intake in the form of dietary carbohydrate rather than fat alone is crucial to increase Leptin concentrations. A soluble Leptin receptor (sOBR) is positively correlated with energy intake as carbohydrates and negatively correlated with energy intake from dietary fat. J Clin Endocrinol Metab. 2003 Apr;88(4):1730-6. Leptin secretion exhibits a circadian rhythm with a nocturnal rise, which is independent of meal intake. Leptin levels are low at mid day and rise towards evening 3 pm, with maximal levels at night. J Clin Invest. 1996 Mar 1;97(5):1344-7. A pulsatile pattern of Leptin secretion with up to 30 pulses a day has also been described. Although glucocorticoids can influence Leptin levels, the early morning rise of Leptin occurs before the cortisol surge and is unlikely to be regulated by cortisol. While growth hormone deficiency with resultant adiposity increases Leptin levels, treatment with growth hormone does not seem to reverse this despite improvement of fat mass even at one year. Metabolism. 1997 Jul;46(7):812-7. Although thyroxine treatment decreases Leptin in rodents, Endocrinology. 1997 Oct;138(10):4485-8. it does not seem to alter Leptin levels in humans J Clin Endocrinol Metab. 1997 Feb;82(2):497-9. The increased cytokines of septic states (TNF-alpha, J Exp Med. 1997 Jan 6;185(1):171-5 IL-1 Am J Physiol. 1998 Jan;274(1 Pt 2):R204-8 ) increase Leptin contributing thus to the anorexia and cachexia. Anorexia nervosa patients have a low level of Leptin in keeping with their lower body fat mass, but their CSF to plasma Leptin ratio is increased during re-feeding, suggesting that this rise could contribute to their pathological perception of body fatness. Table of Leptin Regulators
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