Mechanisms of leptin secretion from white adipocytes

Department of Physiology, Faculty of Medicine, Laval University, Quebec, Canada G1K 7P4 The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective -agonists), or CL-316243 (potent 3 ) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 ( 1 ) or ICI-118551 ( 2 ), the 2 -antagonist being less effective than the 1 . Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity 3 -adrenoceptors but also via the high-affinity 1 / 2 -adrenoceptors. Moreover, it is suggested that 1 ) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2 ) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system. lipolytic hormones; phosphodiesterases; 1 -, 2 -, and 3 -adrenoceptors