16. Hyperinsulinemia Promotes Obesity-associated Adipose Tissue Inflammation (1847-P)

In obesity, adipose tissue (AT) dysfunction is associated with inflammation, systemic insulin resistance and hyperinsulinemia. However, the mechanisms that drive AT inflammation in obesity and disrupt adipocyte metabolic functions are incompletely understood. Here we show that reducing circulating insulin levels about 50% in obese mice by streptozotocin or diazoxide treatments surprisingly suppressed the elevated adipose tissue inflammation, as measured by a reduction of AT crown-like structures and by a decrease in macrophage markers and pro-inflammatory cytokine expression. This decreased cytokine expression in the AT of streptozotocin treated obese mice was associated with partial restoration of expression of enzymes in the de novo lipogenesis (DNL) pathway and of 14C-glucose conversion into triglyceride-fatty acids. Lowering insulin levels in obese mice also enhanced insulin stimulated Akt protein kinase phosphorylation and restored insulin responsiveness of AT DNL. Moreover, responsiveness of blood glucose to injected insulin was improved by streptozotocin and diazoxide treatments without changes in body weight and blood glucose levels. Additionally, chronic insulin treatment in mature 3T3-L1 adipocytes led to a 10-fold increase in CCL2 mRNA level within 6 h. Interest ingly, pre-treatment of 3T3-L1 adipocytes with the ERK inhibitor PD98059 ablated the insulin-induced increase in CCL2 expression, indicating that chronically elevated insulin promotes CCL2 expression in mature adipocytes in an ERK-dependent manner. Taken together, these results indicate that obesity-associated hyperinsulinemia unexpectedly drives AT inflammation in obese mice, which may in turn contribute to factors that suppress DNL and systemic insulin sensitivity.