Brown Fat Lipoatrophy and Increased Visceral Adiposity through a Concerted Adipocytokines Overexpression Induces Vascular Insulin Resistance and Dysfunction

In this study, we analyzed the role played by concerted expression of adipocytokines associated with brown fat lipoatrophy and increased visceral adiposity on triggering vascular insulin resistance and dysfunction in brown adipose tissue (BAT) insulin receptor knockout (BATIRKO) mice. In addition, we assessed whether vascular insulin resistance may aggravate vascular damage. The 52-wk-old, but not 33-wk-old, BATIRKO mice had a significant decrease of BAT mass associated with a significant increase of visceral white adipose tissue (WAT) mass, without changes in body weight. Brown fat lipoatrophy and increased visceral adiposity enhanced the concerted expression of adipocytokines (TNF-alpha, leptin, and plasminogen activator inhibitor 1) and nuclear factor-kappa B binding activity in BAT and visceral WAT, mainly in the gonadal depot, and aorta. Although those mice showed insulin sensitivity in the liver and skeletal muscle, insulin signaling in WAT (gonadal depot) and aorta was markedly impaired. Treatment with anti-TNF-alpha antibody impaired the inflammatory activity in visceral adipose tissue, attenuated insulin resistance in WAT and aorta and induced glucose tolerance. Finally, 52-wk-old BATIRKO mice showed vascular dysfunction, macrophage infiltration, oxidative stress, and a significant increase of gene markers of endothelial activation and inflammation, the latter effect being totally reverted by anti-TNF-alpha antibody treatment. Our results suggest that brown fat lipoatrophy and increased visceral adiposity through the concerted overexpression of cytoadipokines induces nuclear factor-kappa B-mediated inflammatory signaling, vascular insulin resistance, and vascular dysfunction. Inhibition of inflammatory activity by anti-TNF-alpha antibody treatment attenuates vascular insulin resistance and impairs gene expression of vascular dysfunction markers. (Endocrinology 153: 1242-1255, 2012)