Voluntary exercise improves high-fat diet-induced leptin resistance independent of adiposity.

The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high-fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW.

Central nervous system and control of endogenous glucose production.

Recent evidence points to the crucial role of the central nervous system in controlling glucose homeostasis. Hypothalamic centers involved in the regulation of energy balance and endogenous glucose production constantly sense fuel availability by receiving and integrating inputs from circulating nutrients and hormones such as insulin and leptin. In response to these peripheral signals, the hypothalamus sends out efferent impulses that restrain food intake and endogenous glucose production. This promotes energy homeostasis and keeps blood glucose levels in the normal range. Disruption of this intricate neural control is likely to occur in type 2 diabetes and obesity and may contribute to defects of glucose homeostasis and insulin resistance common to both diseases. This review summarizes the latest findings on the hypothalamic control of endogenous glucose production, and focuses on the central effects of circulating macronutrients and nutrient-induced hormones.

How the hypothalamus controls glucose production: an update.

Recent evidence highlights a crucial role of the brain in the control of glucose homeostasis. The hypothalamus senses and integrates signals of fuel abundance, such as circulating macronutrients (glucose and fatty acids) and nutrient-induced hormones (insulin and leptin). This, in turn, results in the activation of neural pathways that return circulating nutrients to baseline by reducing hepatic glucose production and food intake. In Type 2 diabetes and obesity, the ability of the brain to sense and respond to circulating signals is impaired. In this review, the neuroendocrine circuits that have recently been involved in the regulation of endogenous glucose production in rodents will be described. The study of these neural pathways promises to unveil new targets for the therapy of Type 2 diabetes and obesity.