Agouti modulation of both adipocyte and pancreatic islet function via a Ca²⁺-dependent mechanism

Dominant mutations at the promoter of the mouse agouti gene results in a yellow coat color as well as obesity, hyperinsulinemia, insulin resistance and gender-dependent hyperglycemia. Both central and peripheral actions of agouti contribute to agouti-induced obesity syndromeThe human analogue of agouti is expressed in adipose tissue and exerts potent peripheral effects. Recombinant agouti protein has been shown to stimulate adipocyte intracellular calcium ([Ca²⁺]i) and up-regulate fatty acid synthase (FAS), a key enzyme in de novo lipogenesis in human adipocytes via a Ca²⁺-dependent mechanism, thereby promoting lipid storage in adipose tissue. However, transgenic mice overexpressing agouti only in adipose tissue under the control of aP2 promoter do not become obese unless hyperinsulinemia is concomitantly present, suggesting an interaction between hyperinsulinemia and adipose tissue agouti expression. In addition, adipocyte lipolysis is also impaired in agouti mutants compared to wild type animals. We therefore further investigated the effect of recombinant agouti protein on both human adipocyte and pancreatic islet function. We demonstrated that the human homologue of agouti is expressed in the pancreas. Agouti protein also induced a significant Ca²⁺ influx into human pancreatic islets, and serves as a potent secretagogue for both insulin and amylin release in human pancreatic islets, which may contribute to hyperinsulinemia and hyperamylinemia. In human adipocyte, recombinant agouti protein potently inhibited both ACTH- and forskolin-induced lipolysis via a Ca²⁺-dependent mechanism, indicating a post receptor event. Further investigation of the mechanism whereby increasing in [Ca²⁺]i results in inhibition of lipolysis demonstrated that the anti-lipolytic effect of increasing [Ca²⁺]i is exerted by the activation of adipocyte phosphodiesterase (PDE 3B), leading to a decrease in cAMP, a net decrease in hormone sensitive lipase phosphorylation and inhibition of lipolysis. In addition, we demonstrated that human adipocyte agouti is up-regulated during adipocyte differentiation. Using human adipose tissue obtained from plastic surgery with body mass index (BMI) ranging from 21 to 31, we found a positive correlation between adipose tissue agouti content and FAS activity, as well as between adipose tissue agouti mRNA level and FAS mRNA levelThese data suggest that agouti may modulate both adipocyte and pancreatic islet function via a Ca²⁺- dependent mechanismIn the pancreas, agouti-induced hyperinsulinemia and hyperamylinemia may serve as a compensatory system in regulating blood glucose by coordinately regulating glucose input and clearance, respectively. However, agouti- induced hyperinsulinemia may contribute to insulin resistance and obesity. In addition, agouti stimulation of amylin release may result in islet amyloid deposits, impaired B-cell function and diabetes. In the adipose tissue, agouti potently inhibits agonists-stimulated lipolysis by activating adipocyte PDE 3B, thereby resulting in a coordinated regulation of adipocyte lipid metabolism, which may contribute to adipose tissue lipid storageIn addition, we have shown a correlation between human adipose tissue agouti expression and FAS activity and expression. As humans normally express agouti in adipose tissue and pancreas, it is possible that agouti and FAS may be regulated in a similar manner. Alternatively, agouti may be one of adipocyte synthesized factors that may in part contribute to the modulation of adipose tissue lipid metabolism in vivo. Finally, agouti-induced hyperinsulinemia may synergistically act with adipocyte agouti in modulating adipocyte lipid metabolism, thereby contributing to obesity.