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Adiponutrin is a newly described white adipose tissue (WAT)-derived protein whose function and regulation remain widely unclear in humans though it is suggested to be related to insulin sensitivity. Recently, we found that adiponutrin expression is reduced in type 2 diabetic subjects in basal and insulin-stimulated states. To examine adiponutrin regulation by the insulin pathway in relation to other WAT-related proteins with well-known relation to insulin signaling and action, we examined in healthy young men (1) the association of adiponutrin with p85alpha PI3K and HKII, leptin, adiponectin, and acylation-stimulating protein (ASP) and (2) the regulation of adiponutrin and WAT-derived proteins by 3-h hyperinsulinemic euglycemic clamp (HIEG). At baseline (N = 20), adiponutrin expressions were positively correlated with those of p85alpha PI3K (R = 0.54, P = 0.017), HKII (R = 0.58, P = 0.010), and serum leptin (R = 0.51, P = 0.036), but not with any other parameter measured including insulin sensitivity. Hyperinsulinemia (N = 10, +2365% above baseline) significantly increased the expression of adiponutrin (+770%, P = 0.002), p85alpha PI3K (+150%, P = 0.033), HKII (+147%, P = 0.007), and serum leptin (+11%, P = 0.031), while it decreased serum adiponectin (-15%, P = 0.001). In the insulin-stimulated state, adiponutrin mRNA expression levels correlated with basal p85alpha PI3K (R = 0.76, P = 0.018) and HKII (R = 0.86, P = 0.003) expression levels, with percentage increase in insulin (R = 0.73, P = 0.040), and with insulin-stimulated state HKII (R = 0.82, P = 0.007), leptin (R = 0.84, P = 0.005), and adiponectin (R = 0.85, P = 0.004) mRNA levels. In healthy young men, adiponutrin expression is upregulated [corrected] by hyperinsulinemia and is related to basal and/or insulin-stimulated p85alpha PI3K, HKII, adiponectin, and leptin expression levels. We hypothesize that insulin-mediated regulation of adiponutrin expression is under the PI3K pathway. The relevance of the present findings to reduced adiponutrin expression in type 2 diabetes is discussed.

Insulin regulation of gene expression and concentrations of white adipose tissue-derived proteins in vivo in healthy men: relation to adiponutrin