It is well established that obesity leads to a drastic change in the immune cell landscape. This change results in insulin resistance. However, the reverse is understudied: does changing the immune cell landscape lead to obesity? CD11c+ cells are key cells in the immune system and have been shown to play a role in regulating systemic metabolism. The tuberous sclerosis 1 - mechanistic target of rapamycin complex 1 (Tsc1-mTORC1) pathway is the cell's major nutrient-level-sensing pathway. It determines whether energy-intensive processes, such as protein translation, should take place depending on availability of nutrients and growth factors. Given this knowledge, we asked: how does perturbing nutrient sensing in immune cells affect systemic metabolism? To test this, an animal model was developed in which Tsc1 was specifically knocked out in CD11c+ cells: Tsc1flox/flox (?control; CTRL?) and CD11cCre x Tsc1flox/flox (?knockout; KO?) mice on a C57BL/6J background. We observed that KO mice were protected from high fat diet (HFD)-induced weight gain and insulin resistance. The proposed work aims to test the hypothesis that activation of nutrient sensing pathways in CD11c+ immune cells is sufficient to modulate systemic metabolism.
Aim 1 will determine how nutrient sensing by immune cells regulates body weight, adiposity and insulin action. To test this, I will characterize the metabolic phenotype of KO and CTRL mice under different dietary stress and housing temperatures.
Aim 2 will investigate the molecular mechanisms by which alterations in nutrient sensing in immune cells regulates glucose and energy homeostasis. My preliminary data suggests that FGF21 is a potential secreted factor that can regulate systemic metabolism in these animals. Completion of this project will further our understanding of the role immune cells play in regulating systemic metabolism and have immediate translational implications for the treatment of obesity and insulin resistance.
PROJECTIVE NARRATIVE Approximately 100 million Americans suffer from obesity and more importantly obesity related morbidities, such as insulin resistance and type 2 diabetes. Using a mouse model we have developed, this project will dissect functions of immune cell nutrient sensing pathway (Tsc1-mTORC1) in regulation of obesity and insulin resistance. Completion of these studies will broaden our understanding of how immune cells regulate systemic metabolism and might yield new insights for therapeutic intervention in obesity and metabolic diseases. 1!