Location: Children's Nutrition Research Center
2021 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 is a health risk factor for many diseases in adults and can negatively impact pregnancy outcomes. Children born to obese mothers have a greater chance of becoming obese themselves later in adult life. Obesity can impact fat tissue development and function. In this project, we continued our research on the impacts of obesity on fat tissue.
For Objective 1, we focused on how maternal obesity affects the development of white fat cells in children. For this, we used a white fat cell specific gene, Wt1, as a marker to identify white fat cells in our mouse model. By feeding female mice a high fat diet, we successfully generated obese female mice and produced offspring born to these obese female mice. The offspring from female mice that had consumed a high fat diet had greater body and white fat tissue weights than those born from female mice that consumed a regular diet. In addition, we also isolated white fat cells from offspring born to the regular diet treated female mice and measured how well the offspring grew and matured. Currently, we are generating more offspring from the high fat diet treated females for comparison.
For Objectives 2 and 3, the project experienced a significant slow-down due to the COVID-19 pandemic from March 2020 through May 2021. However, we were able to reestablish cell cultures and restart animal experimentation for our project, and continue to optimize the cell culture experiments and breed animals for experiments described in our project plan. Not all fats are the same since they differ in their fatty acid composition and how they are processed, and exert their effects. For Objective 4, we continued to study whether and how diets containing different types of fatty acids (based on carbon chain length) lead to obesity and its health-associated complications. We have conducted a pilot study to measure the palatability of these diets and finished half of the studies on the effects of different fatty acids on body weight and composition (Sub-objective 4A). We have finished 50% of dietary intervention studies on glucose and insulin tolerance tests (insulin resistance) and liver lipid analyses (fatty liver) (Sub-objective 4B). We have continued to study how these fatty acids are stored and processed in different body tissues by adding labeled fatty acids (tracers) in the diets. We finished 50% of the tracer experiments, collected tissues, and fecal samples. We continue to analyze the samples for fatty acid concentration and tracer enrichment (Sub-objective 4C).
Accomplishments
