The incidence of obesity has rapidly increased in Wisconsin and across the United States, and more than 65 percent of adults are overweight. Obese individuals are at increased risk for severe diseases including obesity-induced type 2 diabetes, cardiovascular disease, stroke and cancer. Previous research has shown that low levels of ALAS1, an enzyme involved in making the iron-carrying molecule heme for hemoglobin (a process known as heme biosynthesis), correlates with high body mass index and higher risk of developing type 2 diabetes. For this project, researchers hypothesized that ALAS1 may function as a metabolic sink to control the breakdown of amino acids in brown fat tissue. This project gave researchers a better understanding of the role ALAS1 plays in energy expenditure as it relates to obesity.
The Challenge
Fat cells seen under a microscope
The incidence of obesity has rapidly increased in Wisconsin and across the United States, and more than 65 percent of adults are overweight. Obese individuals are at increased risk for severe diseases including obesity-induced type 2 diabetes, cardiovascular disease, stroke, and cancer. Previous research has shown that low levels of ALAS1, an enzyme involved in heme biosynthesis, correlates with high body mass index (BMI) and higher risk of developing type 2 diabetes.
Project Goals
Researchers hypothesize that ALAS1, an enzyme involved in heme biosynthesis, may function as a metabolic sink to control the breakdown of amino acids in brown fat tissue. The project will test this idea through two specific aims. First, the research team intends to characterize the mitochondrial dysfunction of ALAS1 deficient brown fat cells. Second, they plan to use mouse models to characterize the dysfunction of ALAS1 to better understand the impact of heme biosynthesis in brown fat cells
Results
Researchers made significant progress in understanding how heme biosynthesis in fat tissue controls brown fat function and systemic homeostasis. They found that chemical inhibition of heme biosynthesis or deletion of ALAS1 results in severe heme deficiency in brown fat cells leading to mitochondrial dysfunction and downregulation of the UCP1 gene.
Using mouse models, the team found that loss of ALAS1 in brown fat tissue impairs mitochondria and thermogenesis, as well as alters systemic branched-chain amino acid (BCAA) homeostasis more drastically in female mice. Based on these results, they propose a model where BCAA catabolism is functionally linked to heme biosynthesis in brown adipose tissue to support mitochondrial function and regulate the oxidative stress response.
This work has been published in Nature Metabolism, and researchers have submitted a NIH grant application to expand upon these results in the future.
