Role of leptin in the neuroendocrine response to fasting

A TOTAL deficiency in or resistance to the protein leptin causes severe obesity(1-4). As leptin levels rise with increasing adiposity in rodents(5) and man(6,7), it is proposed to act as a negative feedback 'adipostatic signal' to brain centres controlling energy homeostasis, limiting obesity in times of nutritional abundance(1,3). Starvation is also a threat to homeostasis that triggers adaptive responses(8-12), but whether leptin plays a role in the physiology of starvation is unknown. Leptin concentration falls during starvation(13) and totally leptin-deficient ob/ob mice have neuroendocrine abnormalities similar to those of starvation(14), suggesting that this may be the case. Here we show that preventing the starvation-induced fall in leptin with exogenous leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starvation-induced delay in ovulation in female mice. In contrast, leptin repletion during this period of starvation has little or no effect on body weight, blood glucose or ketones. We propose that regulation of the neuroendocrine system during starvation could be the main physiological role of leptin.