Abstract
Insulin resistance (IR), a metabolic feature of obesity, drives a number of diseases. Recently, the focus of obesity research has been adipocyte‐immune cell crosstalk and its influence on systemic insulin sensitivity (IS). Currently, obesity induced IR is thought to arise secondary to inflammation due to infiltration of adipose tissue (AT) with pro‐inflammatory immune cells. Obesity is a progressive disease, and metabolic alterations in AT following acute nutrient excess, prior to development of obesity, are not well understood. Phosphotidylinositol 3‐kinase (PI3K) has been proposed as the integration point between immune cell infiltration and adipocyte insulin action. Global knockdown of pik3r1 (gene encoding regulatory subunits (p85α/p55α/p50α) of PI3K) resulted in enhanced adipocyte and systemic IS, with parallel decrease in AT macrophage infiltration despite marked obesity. Here we demonstrate that acute (3d) high fat diet (HFD) significantly increases bodyweight due to a significant increase in food intake in wild type mice. Body composition analysis by NMR indicates a significant increase in percent body fat with a concomitant decrease in lean mass. Energy expenditure measured by indirect calorimetry was also significantly decreased after 3d HFD. Importantly, both systemic IS measured by oral glucose challenge and insulin‐stimulated adipocyte 2‐deoxyglucose uptake was significantly reduced. No difference was found in adipocyte chemokine or cytokine secretion. We propose that reduction in adipocyte IS and subsequent systemic IS, is due to an increase in AT p50α/p55α abundance and occurs prior to initiation of a pro‐inflammatory response. Identifying primary steps in development of IR may guide treatments for obesity related metabolic diseases.NIH DK095926 (CEM)
Published Version
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