Aging is associated with resistance to effects of leptin on fat distribution and insulin action.

Leptin has been shown to modulate total body fat and visceral fat distribution and to enhance insulin action in young rats. We hypothesize that failure of leptin action may contribute to the increase in visceral fat and insulin resistance in aging. By chronic subcutaneous infusion of leptin over 7 days, we increased leptin levels in young rats to match the levels in aging ad libitum fed rats. Leptin induced an approximately 50% decrease in food intake compared with saline controls, an approximately 50% decrease in visceral fat, and improved hepatic (fourfold) and peripheral (30%) insulin action (euglycemic hyperinsulinemic clamp technique) compared with the pair-fed group (p <.001). Although the plasma leptin level was doubled in aging rats, leptin failed to produce a significant change in food intake, in fat mass and its distribution, and in hepatic and peripheral insulin action. Increasing plasma leptin levels failed to suppress leptin gene expression in aging rats as compared with the approximately 50% suppression seen in young rats (p <.01). We propose that leptin resistance may play a causative role in the metabolic decline seen with aging.