Over 70% of US adults are overweight and over one-third are obese. This causes an alarming increase in the prevalence of obesity co-morbidities, such as type II diabetes, heart diseases, and certain types of cancer. Many environmental factors, such as a sedentary lifestyle and high calorie diets contribute to this epidemic; however, the predisposition of individuals to develop obesity under these conditions has a strong genetic component. Numerous Genome-Wide Association Studies have found significant associations between specific genes, obesity, and obesity associated diseases. By understanding gene-environment interactions that lead to obesity, it will be easier to develop approaches and therapies to reduce obesity levels and/or associated co-morbidities, which will increase the general public health and reduce financial burden associated with extra medical care. In this application, we propose in depth studies of the mechanism of action of MTCH2 (mitochondrial carrier 2), one of the strongest obesity-associated genes. In our preliminary studies in several model systems (cells, worms, and mice), we discovered that activating this gene is sufficient to induce obesity, while knocking down this gene significantly reduces adiposity indicating that MTCH2 is both required and sufficient for lipid accumulation. In addition to energy storage, fatty acids and their derivatives can serve as signaling molecules. Since MTCH2 influences fatty acid processing enzymes, it is possible that composition of lipids and therefore their signaling functions change, which might be the reason for some of the MTCH2 phenotypes. We will investigate this possibility by assessing the composition of lipids using biochemical and mass spectrometry approaches in cultured cells and animals with MTCH2 mutated or overexpressed. In addition to regulation of fat content, we showed that this gene influences fertility and longevity; however, the mechanisms by which MTCH2 regulates all three processes remain elusive. MTCH2 was found to be residing mainly on the outer mitochondrial membrane, and our preliminary data suggest that it interacts and could affect estrogen receptor 1 (ESR1) function. We hypothesize that MTCH2 might sequester hormone receptors to the mitochondria to alter mitochondrial function, or to be part of mitochondria-ER-nuclear membrane contact sites. It is possible that these MTCH2 functions are responsible for the observed metabolic phenotypes. We will use in depth localization, co-localization, and interaction studies in cells, worms, and mice to investigate where MTCH2 is located (intracellularly and tissue distribution), what other proteins it binds to, and which tissues are critical for MTCH2 regulation of adiposity, fertility and longevity. Finally, we will use C. elegans genetics (sterility suppressor screen and analysis of available point mutations) to discover the pathways and specific genes that mediate MTCH2 impact on lipid homeostasis, fertility, and lifespan.

Public Health Relevance

High obesity levels among US adults lead to an increased rates of related comorbidities such as type 2 diabetes, cardiovascular complications, inflammation, and certain cancers. The MTCH2 gene is highly associated with obesity in humans, and we demonstrated that elevated levels of this gene influence adiposity, fertility, and a lifespan in model organisms. This project studies the molecular mechanism by which MTCH2 functions to control lipid homeostasis, reproduction, and possibly longevity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG060490-01A1
Application #
9740283
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Fridell, Yih-Woei
Project Start
2019-07-15
Project End
2024-04-30
Budget Start
2019-07-15
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Graduate Schools
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704