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RESEARCH COMMUNICATION |
a Departments of Nutrition and Medicine, The University of Tennessee, Knoxville, Tennessee 37996, USA
b Zen-Bio, Inc., Research Triangle Park, North Carolina 27709, USA
Overexpression of the murine agouti gene results in obesity. The human homologue of agouti is expressed primarily in human adipocytes, and we have shown recombinant agouti protein to increase adipocyte intracellular Ca2+([Ca2+]i) and thereby stimulate lipogenesis. However, since recent data demonstrate that increasing adipocyte [Ca2+]i may also inhibit lipolysis, we have investigated the role of agouti-induced [Ca2+]i increases in regulating lipolysis in human adipocytes. Short-term (1 h) exposure to recombinant agouti (100 nM) protein had no effect on basal lipolysis, although longer term treatment (24 h) caused a 60% decrease in basal lipolysis (P<0.0001). Short-term agouti treatment totally inhibited ACTH-induced lipolysis (P<0.05). Since melanocortin receptors (MCR) are involved in some actions of agouti, we next determined whether agouti's antilipolytic effect is exerted through competitive antagonism of the ACTH receptor (MCR-2). Forskolin (1 µM), an adenylate cyclase activator, induced a 48% increase in lipolysis in human adipocytes (P<0.05); this effect was reversed by 100 nM agouti (P<005), demonstrating that the antilipolytic effect of agouti is distal to the ACTH receptor. To determine the role of [Ca2+]i in the antilipolytic effect of agouti, human adipocytes were treated with KCl or arginine vasopressin to stimulate voltage- and receptor-stimulated Ca2+ influx, respectively. Both agents caused inhibition of forskolin-induced lipolysis (P<0.005). Furthermore, agouti's antilipolytic effect was also blocked by the Ca2+ channel blocker nitrendipine. These data demonstrate that agouti exerts a potent antilipolytic effect in human adipocytes via a Ca2+-dependent mechanism. This effect, combined with agouti-induced lipogenesis, represents a coordinate control of adipocyte lipid metabolism that may contribute to an agouti-induced obesity syndrome.—Xue, B., Moustaid-Moussa, N., Wilkison, W. O., Zemel, M. B. The agouti gene product inhibits lipolysis in human adipocytes via a Ca2+-dependent mechanism. FASEB J. 12, 1391–1396 (1998)
Key Words: calcium • agouti polypeptide • MSH • melanocortin receptor
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