Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Generally accepted biological effects of leptin are inhibition of food intake and stimulation of metabolic rate in ob/ob mice that are defective in the leptin gene. In contrast to these centrally mediated effects of leptin, we are reporting here on leptin effects on isolated rat adipocytes. Leptin impairs several metabolic actions of insulin, i.e. stimulation of glucose transport, glycogen synthase, lipogenesis, inhibition of isoproterenol-induced lipolysis, and protein kinase A activation, as well as stimulation of protein synthesis. Insulin effects were reduced by leptin (2 nM) with a half-life of about 8 h. At low leptin concentrations (<1 nM), the insulin sensitivity was reduced leading to a shift to the right in the dose-response curve. At higher concentrations the responsiveness was diminished, resulting in nearly complete inhibition of insulin effects at >30 nM leptin. The IC 50 value of leptin was 3.1 ؎ 1 nM after 15 h of preincubation of adipocytes in primary culture. The natural splice variant des-Gln 49 -leptin exhibited a significantly lower potency. Adipocytes regained full insulin sensitivity within a few hours after leptin removal. The stimulation of glucose transport by vanadate was not affected by leptin. These data show specific and potent impairment of insulin action by leptin in the physiological concentration range of both leptin and insulin, which may be related to the pathophysiology of insulin resistance in both non-insulin-dependent diabetes mellitus and obesity.

The recently identified hormone leptin (ob protein) secreted by white adipose tissue is widely thought to provide a feedback signal limiting fat storage by decreasing food intake. By artificially rearing leptin-treated and control littermates fed identical amounts of milk, however, we show here that lean suckling-age rats treated with recombinant murine leptin can reduce fat storage solely by increasing energy expenditure. Continuous measurements of core temperature and metabolic rate show that this increase is not uniform throughout the day but is especially prominent in the morning when rat pups usually conserve energy by entering a torpor-like state. Leptin's alleviation of hypometabolic, torpor-like states is thus not restricted to cases of impaired hormone production but seems instead to be a normal biological function independent of its effects on food intake.

The high prevalence of obesity and its association with the cardiovascular risk factors diabetes mellitus, dyslipidaemia and hypertension represents a major health problem for the industrialized world. Numerous studies have documented that the dysregulation of energy homeostasis and the susceptibility to obesity results from a complex interplay between genetic and environmental factors. However, the exact mechanisms involved in this process are insufficiently understood.Brown adipose tissue (BAT) has been proposed to play an important role in the regulation of energy balance [1,2]. BAT is distinguished by the unique presence of uncoupling protein (UCP), a mitochondrial proton transporter which uncouples oxidative metabolism from ATP synthesis. This capacity permits BAT to expend calories unrelated to the performance of work, the net result being the generation of heat [3,4]. BAT activity is stimulated by the sympathetic nervous system during cold exposure (nonshivering thermogenesis) and during the ingestion of excess calories (diet-induced thermogenesis) [1,2,5]. The hypothesis that BAT activity might provide a cellular and molecular explanation for protection Diabetologia (1997) 40: 810-815 Chronic leptin treatment does not prevent the development of obesity in transgenic mice with brown fat deficiency Summary With the exception of ob/ob mice, circulating plasma leptin is elevated in all other obese rodents as well as in obese humans, suggesting that leptin resistance rather than leptin deficiency is a characteristic feature of obesity. The exact molecular mechanisms leading to leptin resistance and the applicability of exogenous leptin to overcome resistance to the anorectic effect of the hormone, are insufficiently characterized. The aim of this study was to investigate whether chronic leptin administration could prevent the development of obesity and its associated disorders in transgenic mice with toxigene mediated ablation of brown adipose tissue (BAT). Daily injections of leptin were started at the age of 6 weeks, when body weight, food intake and plasma leptin levels of transgenics were not different from control mice. Over the next 6 weeks, leptin treated transgenics showed the same excessive body weight gain as transgenic mice injected with saline. Leptin treatment was furthermore not able to prevent the development of hyperphagia, hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in transgenic mice. In contrast, control mice injected with leptin had significantly lower body weight, food intake and plasma triglycerides than those treated with saline. In summary, leptin treatment was not able to prevent the development of obesity and its associated abnormalities in transgenic mice with BAT deficiency. This data suggests that intact BAT function is of critical importance for leptin's effect on food intake and energy expenditure, and that primary dysfunction of BAT is associated with leptin resistance, even when hyperleptinaemia is not yet present. [Diabetologia (1997) 40: 810-815]