Location: Children's Nutrition Research Center
2020 Annual Report
Objectives
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.
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.
Progress Report
Obesity has many negative effects not only on the overall health of adults but also on the health of childbearing women and the growth of children born to these women. Specifically, children born to obese mothers tend to become obese and may develop Type II diabetes in later life. Obesity can induce changes in the development and function of many tissues, including the fat tissues. In this project, we examined obesity induced changes in fat tissues in the following objectives. For Objective 1, our research focuses on how maternal obesity affects development of white fat in children using mice as our animal model. To address this, we have generated mice expressing a white fat cell specific gene, Wilms tumor 1 (Wt1), and established procedures to identify these white fat cells. We have also measured the body and white fat tissue weights of female mice that received regular diet and their offspring and directly analyzed tissue sections containing the Wt1 expressing white fat cells from these mice. We have also begun feeding these mice a high fat diet to generate obese female mice. We will produce offspring born to these obese female mice and compare the body weights, white fat tissue weights, and Wt1 expressing fat cells of these mice to those of the mice fed with regular diet. For Objectives 2 and 3, we examined obesity induced chronic inflammation in fat tissues. During inflammation, white blood cells migrate into inflamed tissues. There are many different types of white blood cells, some of which promote inflammation, while others inhibit the process. We are studying one type of white blood cell found in fat tissues during the development of obesity, macrophages, and how a glucose-sensor, carbohydrate response element binding protein, impacts how these cells respond in fat tissues and liver during the progression of obesity. This year, we established cell culture models to address Objective 2 and have established mouse models fed a high fat diet, which promotes obesity, to address Objective 3. For Objective 4, we studied the specific metabolism of fatty acids of varying carbon chain lengths, and their effects on the progression and/or treatment of obesity caused by diet and its related metabolic disorders (insulin resistance and fatty liver). We have submitted and obtained approval from our institutional animal advisory committee to perform all of the proposed experiments. We have obtained different fatty acid components and formulated the diets to be tested under study investigation. Wild type mice animals required for the protocols were purchased and mated, however, due to COVID19 restrictions on animal facility and minimizing cage numbers, we were limited on animal breeding capacity. Since this objective will be tested in wild type mice, we anticipate being able to create the appropriate groups for testing when COVID-19 restrictions on animal research numbers and research effort are lifted.
Accomplishments
