Location: Children's Nutrition Research Center
Project Number: 3092-10700-069-050-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2019
End Date: Mar 31, 2024
Objective:
Objective 1: Determine if maternal obesity and high-fat diet during gestation induce adipogenic and metabolic program alterations in Wt1 expressing white adipocyte progenitor cells during development. Progenitor cell proliferation, differentiation, metabolic efficiencies will be determined, and critical transcriptional regulators will be identified.
Objective 2: Assess whether carbohydrate response element binding protein alters macrophage intracellular metabolism and inflammatory response.
Objective 3: Assess whether macrophage carbohydrate response element binding protein activity affects adipose tissue inflammation and the development of diet induced obesity and insulin resistance.
Objective 4: Use wild type mice and an obese transgenic mouse model lacking leptin to determine organ specific metabolism of fatty acids (FA) of varying carbon chain lengths, and study their effects on the progression and/or treatment of diet induced obesity and its related metabolic disorders.
Subobjective 4A: To determine the effect of FAs of varying carbon chain lengths on progression of diet-induced obesity in wild type and ob/ob mice.
Subobjective 4B: To determine the effect of dietary FAs of varying carbon chain lengths on diet-induced insulin resistance and fatty liver in wild type and ob/ob mice.
Subobjective 4C: To determine the effect of dietary FAs of varying carbon chain lengths on organ specific distribution and metabolism of FAs in wild type and ob/ob mice.
Objective 5: Understand phenylalanine metabolism in adipogenesis
Sub-objective 5.A Define the role of phenylalanine in adipocyte differentiation and adipogenesis in vitro
Sub-objective 5.B Determine the dependency of phenylalanine in the development of obesity in vivo.
Sub-objective 5.C Evaluate dietary phenylalanine restriction in established obese mouse models.
Approach:
Our goal is to enhance the understanding of the mechanisms through which diet impacts adipose tissue during development and the understanding of the progression of obesity and related pathologies after birth. High fat-diet induced obesity is a well-recognized risk factor for a diverse array of health problems, including type II diabetes, heart diseases, and certain types of cancer. However, the mechanistic links between a high-fat diet and cellular injuries during development and after birth remain to be fully elucidated. This research will use mouse models of diet induced obesity and will focus on three general problems associated with obesity: 1) the developmental effects of maternal obesity on offspring adiposity, 2) adipose tissue inflammation that may lead to medical complications, and 3) the effects of dietary fatty acid composition on obesity. We will analyze the effects of maternal obesity on Wilms tumor 1 (Wt1) expressing white adipocyte progenitor cell development, and of the function of the intracellular glucose sensor ChREBP in macrophages and its contribution to the inflammation of fat tissues induced after long-term (months) feeding of a high fat diet. We will investigate the uptake and metabolism of dietary fatty acids of varying carbon chain lengths in different tissues, including fat tissue and their effects on progression of obesity and related disorders in wild type and obese leptin deficient mice. An expected outcome of this research is an improved understanding of the relationship between diet induced obesity and fat tissue development, inflammation, insulin resistance, and uptake and metabolism of dietary fatty acids.
Researchers will also test the hypothesis that phenylalanine is essential for adipocyte differentiation and adipogenesis, and restriction of phenylalanine is anti-obesity. Outcomes from this research will provide knowledge on amino acid metabolism during adipocyte differentiation and adipogenesis and provide new avenues for targeting obesity.
