Leptin’s Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals
Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as meta- bolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mel- litus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin’s contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes. (Endocrine Reviews 34: 377– 412, 2013)
Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as meta- bolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mel- litus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin’s contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes. (Endocrine Reviews 34: 377– 412, 2013)
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257. Zelissen PM, Stenlof K, Lean ME, et al. Effect of three
treatment schedules of recombinant methionyl human leptin
on body weight in obese adults: a randomized, placebocontrolled
trial. Diabetes Obes Metab. 2005;7:755–761.
258. Sumithran P, Prendergast LA, Delbridge E, et al. Longterm
persistence of hormonal adaptations to weight loss.
N Engl J Med. 2011;1597–1604.
259. Rosenbaum M, Goldsmith R, Bloomfield D, et al. Low
dose leptin reverses skeletal muscle, autonomic, and neuroendocrine
adaptations to maintenance of reduced
weight. J Clin Invest. 2005;115:3579–3586.
260. Ahima R, Prabakaran D, Mantzoros C, et al. Role of leptin
in the neuroendocrine response to fasting. Nature. 1996;
382:250–252.
261. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros
CS. 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.
262. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews
DE, Leibel RL. Low dose leptin administration reverses
effects of sustained weight-reduction on energy expenditure
and circulating concentrations of thyroid hormones.
J Clin Endocrinol Metab. 2002;87:2391–2394.
263. Aronis KN, Diakopoulos KN, Fiorenza CG, Chamberland
JP, Mantzoros CS. Leptin administered in physiological or
pharmacological doses does not regulate circulating angiogenesis
factors in humans. Diabetologia. 2011;54:
2358–2367.
264. Roth JD, Roland BL, Cole RL, et al. Leptin responsiveness
restored by amylin agonism in diet-induced obesity: evidence
from nonclinical and clinical studies. Proc Natl Acad
Sci U S A. 2008;105:7257–7262.
265. Kiess W, Anil M, Blum WF, et al. Serum leptin levels in
children and adolescents with insulin-dependent diabetes
mellitus in relation to metabolic control and body mass
index. Eur J Endocrinol. 1998;138:501–509.
266. Havel PJ, Uriu-Hare JY, Liu T, et al. Marked and rapid
decreases of circulating leptin in streptozotocin diabetic
rats: reversal by insulin. Am J Physiol. 1998;274:1482–
1491.
267. Chinookoswong N, Wang JL, Shi ZQ. Leptin restores euglycemia
and normalizes glucose turnover in insulin-deficient
diabetes in the rat. Diabetes. 1999;48:1487–1492.
268. Chan JL, Mietus JE, Raciti PM, Goldberger AL, Mantzoros
CS. Short-term fasting-induced autonomic activation
and changes in catecholamine levels are not mediated by
changes in leptin levels in healthy humans. Clin Endocrinol
(Oxf). 2007;66:49–57.
269. Lin CY, Higginbotham DA, Judd RL, White BD. Central
leptin increases insulin sensitivity in streptozotocin-induced
diabetic rats. Am J Physiol Endocrinol Metab. 2002;282:
1084–1091.
270. Hidaka S, Yoshimatsu H, Kondou S, et al. Chronic central
leptin infusion restores hyperglycemia independent of food
intake and insulin level in streptozotocin-induced diabetic
rats. FASEB J. 2002;16:509–518.
271. German JP, Thaler JP, Wisse BE, et al. Leptin activates a
novel CNS mechanism for insulin-independent normalization
of severe diabetic hyperglycemia. Endocrinology.
2011;152:394–404.
272. Denroche HC, Levi J, Wideman RD, et al. Leptin therapy
reverses hyperglycemia in mice with streptozotocin-induced
diabetes, independent of hepatic leptin signaling. Diabetes.
2011;60:1414–1423.
273. German JP, Wisse BE, Thaler JP, et al. Leptin deficiency
causes insulin resistance induced by uncontrolled diabetes.
Diabetes. 2010;59:1626–1634.
274. Naito M, Fujikura J, Ebihara K, et al. Therapeutic impact
of leptin on diabetes, diabetic complications, and longevity
in insulin-deficient diabetic mice. Diabetes. 2011;60:
2265–2273.
275. Saryusz-Wolska M, Szymanska-Garbacz E, Jablkowski
M, et al. Rosiglitazone treatment in nondiabetic subjects
with nonalcoholic fatty liver disease. Pol Arch Med Wewn.
2011;121:61–66.
276. Park JY, Chong AY, Cochran EK, et al. Type 1 diabetes
associated with acquired generalized lipodystrophy and
insulin resistance: the effect of long-term leptin therapy.
J Clin Endocrinol Metab. 2008;93:26–31.
277. Oral EA. Leptin for type 1 diabetes: coming onto stage to
be (or not?). Pediatr Diabetes. 2011;13:68–73.
278. Toyoshima Y, Gavrilova O, Yakar S, et al. Leptin improves
insulin resistance and hyperglycemia in a mouse model of
type 2 diabetes. Endocrinology. 2005;146:4024–4035.
279. Kusakabe T, Tanioka H, Ebihara K, et al. Beneficial effects
of leptin on glycaemic and lipid control in a mouse model
of type 2 diabetes with increased adiposity induced by
streptozotocin and a high-fat diet. Diabetologia. 2009;52:
675–683.
280. Banks WA. Leptin transport across the blood-brain barrier:
implications for the cause and treatment of obesity.
Curr Pharm Design. 2001;7:125–133.
281. Mittendorfer B, Horowitz JF, DePaoli AM, McCamish
MA, Patterson BW, Klein S. Recombinant human leptin
treatment does not improve insulin action in obese subjects
with type 2 diabetes. Diabetes. 2011;60:1474–1477.
282. Trevaskis JL, Lei C, Koda JE, Weyer C, Parkes DG, Roth
JD. Interaction of leptin and amylin in the long-term maintenance
of weight loss in diet-induced obese rats. Obesity.
2010;18:21–26.
283. Ravussin E, Smith SR, Mitchell JA, et al. Enhanced weight
loss with pramlintide/metreleptin: an integrated neurohormonal
approach to obesity pharmacotherapy.Obesity (Silver
Spring). 2009;17:1736–1743.
284. Hwang JJ, Chan JL, Ntali G, Malkova D, Mantzoros CS.
Leptin does not directly regulate the pancreatic hormones
amylin and pancreatic polypeptide: interventional studies
in humans. Diabetes Care. 2008;31:945–951.
285. Bates SH, Stearns WH, Dundon TA, et al. STAT3 signalling
is required for leptin regulation of energy balance but
not reproduction. Nature. 2003;421:856–859.
286. Morton GJ, Gelling RW, Niswender KD, Morrison CD,
Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity
via phosphatidylinositol-3-OH kinase signaling in
mediobasal hypothalamic neurons. Cell Metab. 2005;2:
411–420.
287. Vernon G, Baranova A, Younossi Z.Systematic review: the
epidemiology and natural history of non-alcoholic fatty
liver disease and non-alcoholic steatohepatitis in adults.
Aliment Pharmacol Ther. 2011;34:274–285.
288. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis:
natural history of non-alcoholic fatty liver disease
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