LEPTIN IMPAIRS METABOLIC ACTIONS OF INSULIN IN ISOLATED RAT ADIPOCYTES

Leptin is an adipocyte hormone involved in the regulation of energy ho meostasis. Generally accepted biological effects of leptin are inhibit ion of food intake and stimulation of metabolic rate in ob/ob mice tha t are defective in the leptin gene. In contrast to these centrally med iated effects of leptin, we are reporting here on leptin effects on is olated rat adipocytes. Leptin impairs several metabolic actions of ins ulin, i.e. stimulation of glucose transport, glycogen synthase, lipoge nesis, inhibition of isoproterenol-induced Lipolysis, and protein kina se A activation, as well as stimulation of protein synthesis. Insulin effects were reduced by leptin (2 nm) with a half-life of about 8 h. A t low leptin concentrations (<1 nM), the insulin sensitivity was reduc ed leading to a shift to the right in the dose-response curve. At high er concentrations the responsiveness was diminished resulting in nearl y complete inhibition of insulin effects at >30 nM leptin. The IC50 va lue of leptin was 3.1+/-1 nM after 15 h of preincubation of adipocytes in primary culture. The natural splice variant des-Gln49-leptin exhib ited a significantly lower potency. Adipocytes regained full insulin s ensitivity within a few hours after leptin removal. The stimulation of glucose transport by vanadate was not affected by leptin. These data show specific and potent impairment of insulin action by leptin in the physiological concentration range of both leptin and insulin, which m ay be related to the pathophysiology of insulin resistance in both non -insulin-dependent diabetes mellitus and obesity.