| Description |
Metabolic syndrome develops when organisms lose capacity to utilize and manage available energy efficiently. Adipose tissue and liver are the main organs regulating energy turnover. Obesity can impair liver and fat function. Impairment of function in either liver or fat is sufficient to induce metabolic disease such as Type 2 diabetes. Immune cells in hepatic and adipose tissues play a significant role in metabolic health. Vitamin A is a critical regulator of immune gene expression that drives differentiation during immune response. Upregulation of vitamin A carrier retinol binding protein 4 (RBP4) precedes metabolic disease in obese mice and humans. CD11c+ immune cells mediate the negative effects of obesity. What remains unclear is the regulatory mechanism of how RBP4 drives obesity induced inflammation. Graham laboratory has discovered a novel RBP4 receptor STRA6L. The CD11c+ cells that drive metabolic disease also express the specific RBP4 receptor STRA6 and metabolize vitamin A for other immune cells to sustain an immune response. Since vitamin A is critical for balancing inflammatory and tolerogenic signals, we proposed that STRA6L is important in developing the phenotype driven by CD11c+ immune cells on a high fat diet. Using the Cre-LoxP method, we generated a novel mouse strain with specific deletion of RBP4 receptor STRA6L in CD11c+ lineage, and therefore without a retinol transporter in CD11c+ immune cells. When maintained on 4 IU/g of dietary vitamin A, young KO animals displayed same metabolic baseline as WT siblings, but these animals iv were protected from glucose intolerance and insulin resistance when maintained on a high fat diet. Our results suggest that STRA6L expression in CD11c+ immune cells can regulate tissue plasticity, organ health, and function. Adipocytes in STRA6L KO animals did not develop hypertrophy. In the absence of functional STRA6L in CD11c+ cells, mouse immune cells do not activate a sustained high fat diet-induced inflammatory response that leads to metabolic tissue remodeling and insulin resistance. This study utilizes an in vivo mouse model, ex vivo primary mouse immune cell culture, imaging, molecular, and biochemical techniques. We demonstrate that STRA6L expression in CD11c+ cells can regulate obesity induced insulin resistance. |
