Adipocyte‐Specific Ablation of Long‐Chain Acyl‐CoA Synthetase‐4 (ACSL4) in Mice Protects Against Diet‐Induced Obesity‐Associated Decreases in White Adipocyte Oxygen Consumption and Whole Body Energy Expenditure

Obesity‐associated alterations in adipocyte metabolism are important to the development of metabolic disorders, including type 2 diabetes, a leading cause of chronic disease and death in the United States. However, we have limited understanding of the role of white adipocyte oxygen consumption in the development of obesity and its complications. Of particular interest, long‐chain acyl‐CoA synthetases (ACSL) catalyze the addition of a coenzyme‐A group to fatty acids (FA) within cells and have been hypothesized to direct FA to distinct fates within cells. Intriguingly, the ACSL4 isoform is suggested to preferentially activate polyunsaturated fatty acids, but little is known about its function in regulating adipocyte metabolism. Previously, we have demonstrated that mice with adipocyte‐specific ACSL4 ablation (Ad‐KO) on a high fat diet (HFD) are protected against obesity‐associated body weight & fat mass gain and insulin resistance compared to their wildtype littermates (ACSL4 floxed ) without any phenotypic differences on a low fat diet (Killion et al., FASEB Journal , 2015; 29:743.1). The purpose of the current research is to investigate the role of ACSL4 in regulating obesity‐associated adipocyte dysfunction, including adipocyte oxygen consumption and systemic energy expenditure. Energy expenditure in ACSL4 floxed and Ad‐KO mice was measured by TSE metabolic chamber system before mice were switched to HFD, 3 weeks of HFD, and 7 weeks of HFD (before body composition differences are observed between ACSL4 floxed and Ad‐KO mice). Interestingly, after 7 weeks on HFD, but not earlier, rates of energy expenditure (kcal/gram lean mass/day) were 10% higher in Ad‐KO mice than ACSL4 floxed littermates without differences in food intake or activity. To specifically determine the role of white adipocyte oxygen consumption, gonadal white adipocytes were isolated from mice after 12 weeks of HFD and ex vivo oxygen consumption of isolated adipocytes was measured using a Clark electrode. Remarkably, isolated adipocytes from Ad‐KO mice have 4‐fold higher rates of basal respiration in the presence of glucose (nmol O 2 /min/10 6 adipocytes) without differences in FCCP uncoupled respiration or changes in UCP1 expression compared to ACSL4 floxed littermates. In conclusion, adipocyte ablation of ACSL4 significantly protects against diet‐induced obesity‐associated decreases in adipocyte oxygen consumption and whole body energy expenditure without beiging of white adipocytes. Support or Funding Information Funding for this work is supported by NIH Training Grant 5T32DK062032‐20, DK098606‐02, P30‐DK‐46200, USDA agreement #58‐1950‐7‐70, and NIH K01DK094943.