GIP Signaling Integrates with Insulin Signaling to Regulate Glucose and Lipid Metabolism in Human Adipocytes

Recent studies suggest that activation of GIP (glucose-dependent insulinotropic peptide) receptor in conjunction with GLP-1 and/or glucagon receptors reduces adiposity and body weight in mice. Incretin actions of GIP on pancreatic beta cells are well characterized, but functions of GIP on adipose tissue are incompletely understood. Using differentiated human adipocytes we investigated GIP regulation of carbohydrate and lipid metabolism in the context of insulin signaling. GIP dose-dependently stimulated lipolysis without affecting ATGL or HSL lipolytic enzyme mRNA expression. Insulin dose-dependently suppressed lipolysis, and addition of GIP attenuated insulin effects on lipolysis without affecting Akt phosphorylation at Thr308or Ser473. Insulin administration increased lipogenesis, but GIP, in the presence or absence of insulin, had little effect on lipogenesis in [14C]glucose incorporation assays. GIP increased glucose utilization in adipocytes, as measured by depletion of glucose in culture media over a 24 hour period. Notably GIP dose-dependently enhanced insulin-stimulated glucose uptake ([14C]-2-deoxyglucose), but GIP alone did not appreciably regulate acute glucose uptake. We propose a new mechanistic model in which GIP signaling integrates with insulin signaling to regulate glucose and lipid metabolism. In the presence of low plasma insulin levels resembling a fasting state, GIP can increase lipolysis to mobilize nutrients from adipocytes. When insulin levels rise in a fed state, GIP can increase insulin-mediated glucose uptake in adipocytes to augment efficiency of energy storage. Further elucidation of the integration of insulin and GIP signaling will be needed to support efforts to counteract dysregulated nutrient metabolism in obesity and diabetes.