Adipocyte-Specific Deletion of Manganese Superoxide Dismutase Protects From Diet-Induced Obesity Through Increased Mitochondrial Uncoupling and Biogenesis

Abstract

Obesity and insulin resistance are associated with oxidative stress (OS). The causal role of adipose OS in the pathogenesis of these conditions is unknown. To address this issue, we generated mice with an adipocyte-selective deletion of manganese superoxide dismutase (MnSOD). When fed a high-fat diet (HFD), the AdSod2 knockout (KO) mice exhibited less adiposity, reduced adipocyte hypertrophy, and decreased circulating leptin. The resistance to diet-induced adiposity was the result of an increased metabolic rate and energy expenditure. Furthermore, palmitate oxidation was elevated in the white adipose tissue (WAT) and brown adipose tissue of AdSod2 KO mice fed an HFD, and the expression of key fatty acid oxidation genes was increased. To gain mechanistic insight into the increased fat oxidation in HFD-fed AdSod2 KO mice, we quantified the mitochondrial function and mitochondrial content in WAT and found that MnSOD deletion increased mitochondrial oxygen consumption and induced mitochondrial biogenesis. This effect was preserved in cultured adipocytes from AdSod2 KO mice in vitro. As expected from the enhanced fat oxidation, circulating levels of free fatty acids were reduced in the HFD-fed AdSod2 KO mice. Finally, HFD-fed AdSod2 KO mice were protected from hepatic steatosis, adipose tissue inflammation, and glucose and insulin intolerance. Taken together, these results demonstrate that MnSOD deletion in adipocytes triggered an adaptive stress response that activated mitochondrial biogenesis and enhanced mitochondrial fatty acid oxidation, thereby preventing diet-induced obesity and insulin resistance.

Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes

“…SOD2 levels were also found increased in diabetic compared to non-diabetic patients by WB, using a second cohort of patients (Supplementary Fig. 3B), in agreement with earlier studies [47], [48]. To further illustrate the above-described degree of coordinated behavior in aging and T2DM comparisons, the cumulative frequency distribution of protein changes (Zq) was plotted for the least redundant categories within the aging and T2DM clusters (Fig.…”

Brown and Beige Adipose Tissues in Health and Disease

“…Moreover, BAT and beige fat primarily utilize FFAs to fuel their thermogenesis; hence, activation of BAT and beige fat are expected to decrease both circulating FFA levels and uptake of FFAs into the liver, thereby protecting against liver steatosis. In line with this notion, activation of BAT and beige fat protects against NAFLD in mice, whereas inhibition of BAT and beige fat has the opposite effect (99, 114, 195, 219, 281). Notably, BAT activity is associated with reduced risk for NAFLD (233, 353), suggesting that BAT activation similarly protects against NAFLD in humans.…”

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

“…(iii) 4-HNE may be a relevant modifying species by allosterically potentiating fatty acid-dependent leak through UCP1. Although 4-HNE may potentiate UCP1 activation by fatty acids in vitro, other cysteine-reactive species may be more relevant in the context of in vivo thermogenesis because 4-HNE levels do not appear to change following chronic cold exposure in BAT (22) or in models of ROS-dependent thermogenesis in vivo (23).…”