Adipocyte-Specific Deletion of Manganese Superoxide Dismutase Protects From Diet-Induced Obesity Through Increased Mitochondrial Uncoupling and Biogenesis.
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.
Department of Nutrition and Integrative Physiology; Division of Endocrinology, Metabolism and Diabetes; and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT.
Yong Hwan
YH
Han
Department of Nutrition and Integrative Physiology; Division of Endocrinology, Metabolism and Diabetes; and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT.
Márcio
M
Buffolo
Department of Nutrition and Integrative Physiology; Division of Endocrinology, Metabolism and Diabetes; and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT.
Karla Maria
KM
Pires
Department of Nutrition and Integrative Physiology; Division of Endocrinology, Metabolism and Diabetes; and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT.
Shaobo
S
Pei
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX.
Philipp E
PE
Scherer
Department of Nutrition and Integrative Physiology; Division of Endocrinology, Metabolism and Diabetes; and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT sihem.boudina@hmbg.utah.edu.
Sihem
S
Boudina
D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D059305:Diet, High-Fat / Q000009:adverse effects*; D005455:Fluorescent Antibody Technique; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D010168:Palmitates / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000172:deficiency / Q000378:metabolism*
D052242:Adiponectin; D010168:Palmitates; D013482:Superoxide Dismutase