Slc7a8 Deletion Is Protective against Diet-Induced Obesity and Attenuates Lipid Accumulation in Multiple Organs

SIMPLE SUMMARY: The development of obesity can be attributed to adipocyte hypertrophy or hyperplasia which lead to increased adiposity. The C57BL/6 mouse is an excellent model to study metabolic syndromes often associated with obesity development. Mice fed on a high-fat diet are susceptible to weight gain, leading to the development of obesity and its associated metabolic syndrome. Here, we report findings from targeting a novel potential human adipogenic gene (SLC7A8) under conditions of obesity development using a mouse model of diet-induced obesity (DIO). The results indicate that deleting slc7a8 in mice significantly protects against DIO and improves glucose metabolism. Deficiency in slc7a8 was observed to significantly attenuate adipocyte hypertrophy in white and brown adipose tissue and to reduce lipid accumulation in many organs. Furthermore, inflammation was significantly reduced in the adipose tissue and liver of slc7a8-deficient mice with DIO. Overall, the results from this study show that slc7a8 is an important molecular regulator of obesity development and mediates its function by reducing lipid accumulation in multiple organs. Hence, SLC7A8 could serve as a potential therapeutic target to combat the development of obesity and other pathophysiological conditions associated with excess lipid accumulation. ABSTRACT: Adipogenesis, through adipocyte hyperplasia and/or hypertrophy, leads to increased adiposity, giving rise to obesity. A genome-wide transcriptome analysis of in vitro adipogenesis in human adipose-derived stromal/stem cells identified SLC7A8 (Solute Carrier Family 7 Member 8) as a potential novel mediator. The current study has investigated the role of SLC7A8 in adipose tissue biology using a mouse model of diet-induced obesity. slc7a8 knockout (KO) and wildtype (WT) C57BL/6J mice were fed either a control diet (CD) or a high-fat diet (HFD) for 14 weeks. On the HFD, both WT and KO mice (WTHFD and KOHFD) gained significantly more weight than their CD counterparts. However, KOHFD gained significantly less weight than WTHFD. KOHFD had significantly reduced levels of glucose intolerance compared with those observed in WTHFD. KOHFD also had significantly reduced adipocyte mass and hypertrophy in inguinal, mesenteric, perigonadal, and brown adipose depots, with a corresponding decrease in macrophage infiltration. Additionally, KOHFD had decreased lipid accumulation in the liver, heart, gastrocnemius muscle, lung, and kidney. This study demonstrates that targeting slc7a8 protects against diet-induced obesity by reducing lipid accumulation in multiple organs and suggests that if targeted, has the potential to mitigate the development of obesity-associated comorbidities.