Fat tissue is the most important energy depot in vertebrates. The release of free fatty acids (FFAs) from stored fat requires the enzymatic activity of lipases. We showed that genetic inactivation of adipose triglyceride lipase (ATGL) in mice increases adipose mass and leads to triacylglycerol deposition in multiple tissues. ATGL-deficient mice accumulated large amounts of lipid in the heart, causing cardiac dysfunction and premature death. Defective cold adaptation indicated that the enzyme provides FFAs to fuel thermogenesis. The reduced availability of ATGL-derived FFAs leads to increased glucose use, increased glucose tolerance, and increased insulin sensitivity. These results indicate that ATGL is rate limiting in the catabolism of cellular fat depots and plays an important role in energy homeostasis.
The Madagascan fat-tailed dwarf lemur, Cheirogaleus medius, hibernates in tree holes for seven months of the year, even though winter temperatures rise to over 30 degrees C. Here we show that this tropical primate relies on a flexible thermal response that depends on the properties of its tree hole: if the hole is poorly insulated, body temperature fluctuates widely, passively following the ambient temperature; if well insulated, body temperature stays fairly constant and the animal undergoes regular spells of arousal. Our findings indicate that arousals are determined by maximum body temperatures and that hypometabolism in hibernating animals is not necessarily coupled to a low body temperature.
The endocannabinoid system (ECS) plays a critical role in obesity development. The pharmacological blockade of cannabinoid receptor type 1 (CB(1)) has been shown to reduce body weight and to alleviate obesity-related metabolic disorders. An unsolved question is at which anatomical level CB(1) modulates energy balance and the mechanisms involved in its action. Here, we demonstrate that CB(1) receptors expressed in forebrain and sympathetic neurons play a key role in the pathophysiological development of diet-induced obesity. Conditional mutant mice lacking CB(1) expression in neurons known to control energy balance, but not in nonneuronal peripheral organs, displayed a lean phenotype and resistance to diet-induced obesity. This phenotype results from an increase in lipid oxidation and thermogenesis as a consequence of an enhanced sympathetic tone and a decrease in energy absorption. In conclusion, CB(1) signaling in the forebrain and sympathetic neurons is a key determinant of the ECS control of energy balance.
Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa. Molecular Psychiatry (2000) 5, 476-481.Keywords: food intake; food restriction; energy metabolism; neuroendocrine control of appetite; locomotor activity; running wheels Hyperactivity is observed in 40-80% of patients with anorexia nervosa (AN). 1,2 Caloric deprivation severe enough to result in significant weight loss possibly provokes sensations of behavioral arousal and activation in individuals with an innate vulnerability to develop AN. 3 Indeed, reduced food intake and enhanced activity have been viewed as the core symptomatology in AN, because only these behavioral measures consistently distinguish AN from other disorders. 4 Semi-starvation induced hyperactivity (SIH) is a well characterized phenomenon in laboratory animals. 5,6 Rats supplied with food for only 1 h per day manage to survive, but die within a short period of time when exposed to a running wheel. The enhancement of activity is related to the severity of food restriction; total food deprivation results in a disruption of the nocturnal activity pattern. 6 Leptin is assumed to be the major hormone underlying the regulatory phenomena that lead to an adaptation of an organism to reduced energy supplies. 7 Thus, in mice exogenously applied leptin has been shown to blunt the semi-starvation-induced downregulation of the hypothalamic-pituitary gonadal and thyroid axes as well as the upregulation of the hypothalamic-pituitary adrenal axis. 7 The rapid decline in leptin secretion associated with caloric restriction and weight loss 7,8 could represent the initial trigger underlying the hyperactivity observed in SIH and AN. As an initial step towards testing this hypothesis we investigated the effect of continuous leptin treatment via minipum...
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