Acute Hyperleptinemia Does Not Modify Insulin Sensitivity<i>in vivo</i>in the Rat

Widdowson, Peter; Upton, R; Pickavance, Lucy; Buckingham, Robin E.; Tadayyon, M.; Arch, Jonathan R.S.; Williams, Gregory V.

doi:10.1055/s-2007-978879

Cited by 17 publications

(8 citation statements)

References 20 publications

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“…Additionally, circadian peaks of leptin are positively correlated with insulin resistance in humans (5), and leptin concentrations are higher in insulin-resistant than insulin-sensitive men, regardless of adiposity (53). In other studies, no effects of leptin on insulin sensitivity were observed (60,63).…”

Section: Discussionmentioning

confidence: 99%

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Paz-Filho

Esposito

Hurwitz³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m 2 ; female, 42 yr old, BMI 25.1 kg/m 2 ; female, 46 yr old, BMI 31.7 kg/m 2 ) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 Ϯ 3.27 vs. 8.16 Ϯ 2.77 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) ϭ 0.57 and P ϭ 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity. recombinant methionyl human leptin; euglycemic hyperinsulinemic clamp; homeostatic model assessment LEPTIN DEFICIENCY was the first described monogenic nonpleiotropic form of obesity. To date, 10 children (23,25,40,44,58) and three adults (46, 58) have been reported as leptin deficient in five families from Pakistan, one from Egypt, and one from Turkey. Leptin replacement decreases weight, fat mass, food intake, hyperinsulinemia, and serum lipid levels (22,23,25,46). We previously described a significant reduction in food intake (32-34, 61), resulting in substantial weight and fat loss, an increase in physical activity, and the resolution of hypogonadism and type 2 diabetes mellitus in leptin-treated adults (32). Moreover, leptin replacement altered the patients' brain structure and their response to food cues (2, 38).Although leptin and insulin have key metabolic roles, the interplay between both hormones is poorly understood. A majority of the studies suggest that leptin decreases insulin synthesis and secretion by pancreatic ␤-cells (9,12,29,54). It is speculated that the adipoinsular axis includes a leptinmediated inhibitory feedback loop on insulin secretion to decrease adipogenesi...

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Section: Discussionmentioning

confidence: 99%

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Paz-Filho

Esposito

Hurwitz³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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“…Schwartz et al (234) calculated that 42% of leptin's hypoglycemic action was independent of weight reduction. In contrast, the effects of leptin on whole body glucose metabolism in nonobese, nondiabetic animals remain inconsistent, but in general, short-term administration of leptin does not affect glucose metabolism (100,227,275). Similarly, the effects of leptin administration in animal models of diet-induced obesity, a model that provides important insights into understanding the effects of leptin on glucose metabolism in obese humans, also reveal largely null data (27,283).…”

Section: Physiological Role Of Leptin In the Regulation Of Insulin Sementioning

confidence: 99%

Leptin in human physiology and pathophysiology

Mantzoros

Magkos

Brinkoetter

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

510

322

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Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIVrelated lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics. adipokines; adipose tissue; leptin resistance; leptin deficiency; hypoleptinemia STUDIES OF GENETICALLY OBESE MICE serendipitously found in the Jackson Laboratories revealed that their phenotypes derive from homozygous mutations of either the obese (ob) or diabetic (db) genes that result in obesity and insulin resistance or diabetes as well as endocrine and immune dysfunction (53, 54,115,117,183,261). The gene mutation in the ob/ob mouse results in a complete deficiency of or a truncated and biologically inactive ob gene product (287); the latter subsequently was given the name leptin (95), from the Greek word "leptos" (meaning "thin"), because when this protein was given to the obese ob/ob mice they lost significant amounts of body weight. It was then recognized that the db gene codes for the leptin receptor (140). Consequently, exogenously administered leptin reduces body weight and resolves the metabolic, endocrine, and immune disturbances in ob/ob mice but has no effects in db/db mice (100, 111, 28...

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“…This is despite the presence of markers of leptin resistance, including increased basal SOCS3 mRNA that is measured in DIO rodents that are leptin-resistant [24,25,45,53] and the absence of leptin-stimulated increases in pSTAT3 and SOCS3. While there are notable differences in the manner by which rats and humans respond to a KD, elucidation of the neural and endocrine effects of decreased carbohydrate and chronically elevated ketone bodies provides insight into how dietary macronutrients affect individual systems involved in overall regulation of energy balance.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity to the Anorectic Effects of Leptin Is Retained in Rats Maintained on a Ketogenic Diet despite Increased Adiposity

et al. 2010

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Background: Rats maintained on a ketogenic diet (KD; 80% fat, 15% protein, 5% carbohydrate) have increased adiposity and leptin as compared to chow-fed controls (CH; 16% fat, 19% protein, 65% carbohydrate), although body weights and daily caloric intakes do not differ. Methods: Rats maintained on a KD or CH were assessed for responsivity to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) leptin. Hypothalamic gene expression was evaluated to determine the effects of KD on proopiomelanocortin (POMC) mRNA expression and components of the leptin-signaling system. Results: Caloric intake by KD rats was decreased at a lower dose of i.p. leptin (100 µg) than was required to reduce intake by CH rats (leptin, caloric intake was reduced in KD rats as compared to intake following i.p. saline; p < 0.05). In a separate experiment to evaluate responsivity to i.c.v. leptin, the minimal dose of leptin required to significantly reduce 24-hour caloric intake did not differ between the groups. In the arcuate nucleus, POMC mRNA was elevated after a lower dose of i.c.v. leptin in KD rats (5 µg) than was required to increase POMC mRNA expression in CH rats (15 µg) or reduce caloric intake in either group. Finally, evaluation of the level of phosphorylated STAT3 (pSTAT3) in the arcuate and SOCS3 mRNA in the hypothalamus revealed significantly more pSTAT3-positive cells and increased SOCS3 mRNA expression at baseline for KD rats, compared to CH, neither of which was further increased following i.p. leptin administration. Conclusion: These data demonstrate that despite increased adiposity, leptin and markers of leptin resistance, responsivity to the anorectic effects of exogenous leptin is retainable during maintenance on a KD.

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Acute Hyperleptinemia Does Not Modify Insulin Sensitivityin vivoin the Rat

Cited by 17 publications

References 20 publications

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

Leptin in human physiology and pathophysiology

Sensitivity to the Anorectic Effects of Leptin Is Retained in Rats Maintained on a Ketogenic Diet despite Increased Adiposity

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