The Effects of Succinate Treatment on Obesity, Insulin Resistance, and Skeletal Muscle Mitochondrial Respiration

Abstract

Obesity is a major public health problem that affects approximately 35% of US adults. Identifying novel interventions that can reduce adiposity are essential to decrease the burden of obesity on our health care system. Since obesity is associated with mitochondrial dysfunction, interventions targeting the mitochondria may be effective anti-obesity treatments. PURPOSE: We sought to determine the effect of succinate, a mitochondrial complex II electron donor, on adiposity, insulin resistance, and muscle mitochondrial respiration. METHODS: C57B6 male mice were assigned to a low fat diet (LFD) or a high fat diet (HFD) for 20 weeks. After 14 weeks of the dietary intervention, mice from were assigned to a control or succinate (0.75 mg/ml in drinking water) group. Caloric intake and body mass were assessed weekly, while glucose tolerance (GT), insulin tolerance (IT), and pyruvate tolerance (PT) were assessed during the last 2 weeks of succinate treatment. Measurements of mitochondrial respiration in soleus muscle were performed using permeabilized fiber respirometry. RESULTS: The HFD significantly increased body mass (48.5±0.9 vs. 31.0±0.6 g), epididymal white adipose tissue (EWAT) mass (1.9±0.2 vs. 0.87±0.2 g), and reduced the area under the curve (AUC) for GT (59732±1741 vs. 47119±1308), IT (26547±2214 vs. 15425±1650), and PT (37846±1972 vs. 25470±540). The HFD did not significantly alter soleus muscle mitochondrial respiration. Succinate treatment had no effect on caloric intake and body mass, but significantly reduced EWAT mass (1.9±0.2 vs. 1.3±0.1) in HFD mice. Although succinate treatment did not improve GT or IT, PT was significantly improved in HFD mice (AUC: 37846±1972 vs. 32513±1252). Finally, there was a trend for succinate treatment to increase complex I+II driven state 3 respiration, and complex IV activity, but these changes did not reach statistical significance. CONCLUSION: We observed no effect of succinate treatment on body mass; however, EWAT mass was significantly lower in mice treated with succinate. In the soleus muscle, there was a tendency for increased state 3 respiration, owed to greater mitochondrial content, suggestive of a succinate-induced mitochondrial biogenesis. Furthermore, succinate treatment significantly improve PT, indicating a reduction in hepatic gluconeogenesis.