Project 456675

Obesity and type 2 diabetes (T2D) are chronic diseases that affect millions of people worldwide. A variety of diets have been proposed to offset obesity and T2D but the focus has been mainly to reduce fat and carbohydrates. However, very little consideration is given to the composition of dietary proteins and how they can impact weight gain and T2D risk. We now wish to further explore the role of dietary proteins in obesity-linked insulin resistance and T2D. We will design new diets containing diversified protein sources from either meat, dairy, or plant-based and test their influence on obesity and T2D in mice fed dietary fat to promote obesity. Research objectives are to: 1) To determine whether intestinal production of branched-chair fatty acids (BCFA) mediates the metabolic effect of dietary proteins by activating liver mTORC1, a nutrient sensing complex, and altering hepatic glucose metabolism. 2) To assess whether dietary proteins and BCFA alter mitochondrial lipid oxidation through nitrogen sensing mechanisms and increased urea cycle activity in the liver 3) To determine whether the abundance of intestinal bacterium Akkermansia muciniphila and its impact on intestinal GLP-1 production and activation of brown adipose tissue are involved in the metabolic effect of dietary proteins These studies will be performed in both male and female mice, using dietary and genetic mouse models and using microbiome technologies and relevant organs to identify new therapeutic targets causally related to the impact of dietary proteins on obesity, insulin resistance and T2D. This research represents a major leap forward in the molecular understanding of how specific protein sources or their components impact on obesity and insulin resistance. We hope these studies will help define novel dietary strategies for the prevention and treatment of obesity-linked metabolic diseases.