Jeffrey L. Halaas

Leptin and the regulation of body weight in mammals

The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life. In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution. However, the presence of excess adipose tissue can be maladaptive. A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level. Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system. Leptin also signals nutritional status to several other physiological systems and modulates their function. Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity.

Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects

Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.

Acute stimulation of glucose metabolism in mice by leptin treatment

Leptin is an adipocyte hormone that functions as an afferent signal in a negative feedback loop regulating body weight, and acts by interacting with a receptor in the hypothalamus and other tissues. Leptin treatment has potent effects on lipid metabolism, and leads to a large, specific reduction of adipose tissue mass after several days. Here we show that leptin also acts acutely to increase glucose metabolism, although studies of leptins effect on glucose metabolism have typically been confounded by the weight-reducing actions of leptin treatment, which by itself could affect glucose homoeostasis. We have demonstrated acute in vivo effects of intravenous and intracerebroventricular administrations of leptin on glucose metabolism. A five-hour intravenous infusion of leptin into wild-type mice increased glucose turnover and glucose uptake, but decreased hepatic glycogen content. The plasma levels of insulin and glucose did not change. Similar effects were observed after both intravenous and intracerebroventricular infusion of leptin, suggesting that effects of leptin on glucose metabolism are mediated by the central nervous system (CNS). These data indicate that leptin induces a complex metabolic response with effects on glucose as well as lipid metabolism. This response is unique to leptin, which suggests that new efferent signals emanate from the CNS after leptin treatment.