The gut-fat crosstalk in metabolic regulation

Beckman Research Institute/City Of Hope, Duarte CA

Investigators

Abstract

Project Summary Current treatments are still limited in their ability to safely mitigate obesity and its complications. Obesity develops due to an imbalance between nutrient intake and energy expenditure; therefore, there is still a need to better understand the mechanisms governing nutrition and energy balance, with the long-term goal of developing novel strategies to treat obesity and associated metabolic diseases. My objective in this proposal is to identify and characterize an important new mechanism of intestine– white adipose tissue (WAT) communication via intestinal mTOR. I hypothesize that intestinal mTOR crosstalk with WAT browning regulates glucose homeostasis and energy metabolism by modulating the anti-microbial peptide (AMP)-controlled composition of gut microbiota (GM). My hypothesis is based on the following results from our preliminary results: 1) Significantly increased mTOR phosphorylation in the duodenum of patients with obesity and T2D; 2) an enhanced WAT browning and glucose homeostasis in intestinal epithelium-specific mTOR knockout (mTOR-IKO) mice compared to littermate controls (mTORfl/fl); 3) significantly altered gut microbiota composition and gut microbiome-derived metabolites in mTOR-IKO mice; 4) enhanced WAT browning and glucose homeostasis in WT mice after fecal microbiota transplantation (FMT) with feces from mTOR-IKO mice; 5) intestinal mTOR-mediated expression of intestinal anti-microbial peptides (AMPs), including REG3 and RELMb, which directly targets bacteria. I propose two aims to test my hypothesis. In Aim 1, I will continue to determine the role of gut microbiota and gut microbiome-derived metabolites in mediating the effects of intestinal mTOR on WAT browning and metabolic homeostasis. I will perform FMT from mTORfl/fl and mTOR-IKO mice to germ-free mice; in addition, I will identify the candidate metabolites linked to WAT browning phenotype; then I will screen culture collections to identify responsible bacterial strains which can produce the candidate metabolites; Moreover, I will perform the functional validation for the responsible bacterial stains using GF mice. In Aim 2, I will identify the mechanism by which mTOR modulates the gut microbiota profile. My preliminary studies support the hypothesis that intestinal mTOR controls gut microbiota composition through AMPs expression. I will determine gut epithelial differentiation in mTOR-IKO mice compared to mTORfl/fl mice. In addition, I will elucidate the molecular mechanism by which intestinal mTOR regulates the expression of Reg3r, RELBb and other AMPs.