Exercise and mitochondrial function in adipose biology: all roads lead to NO.

Abstract

Insulin resistance in rodents and humans is highly correlated with inflammation of white adipose tissue (WAT) and the presence of proinflammatory immune cells. Such chronic immune challenge leads to a variety of metabolic effects in the adipocyte, including endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and altered adipokine and cytokine secretion, which in sum play a major role in affecting whole-body insulin sensitivity (1–3). Of the factors regulating mitochondrial biogenesis, the regulation of the endothelial nitric oxide synthase (eNOS) has garnered considerable attention as a major metabolic control point. eNOS is a constitutively expressed nitric oxide (NO)–producing enzyme classically linked to smooth muscle contraction and platelet aggregation (4). However, eNOS and downstream NO signaling are now appreciated as a major metabolic determinant of the peroxisome proliferator–activated receptor γ coactivator 1α (PGC1α) (5). Although the molecular mechanism(s) is still not completely understood, NO signaling and activation of the soluble guanylyl cyclase–protein kinase G (PKG) system upregulate PGC1α expression and, moreover, are required for increased expression of SirT1, the major NAD+-dependent deacetylase controlling PGC1α activity (6–8). NO signaling via PKG stimulates the expression of the entire mitochondrial biogenesis program, including the activation of Nrf1 and Tfam, two major transcription factors regulating expression of mitochondrial enzymes. A second major theme controlling mitochondrial biogenesis linked to sympathetic drive and eNOS is G-protein–coupled receptor–dependent activation …