Insulin resistance represents a rapidly expanding health care burden in the United States, contributing to the pathogenesis of a number of cardiometabolic disorders. Recent evidence has emerged that microbes resident in the human intestine represent a key transmissible environmental factor contributing to insulin resistance and associated cardiometabolic disease. However, mechanisms by which gut microbial-derived factors signal to the host to promote insulin resistance are largely unknown. We have recently discovered a meta-organismal pathway where nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme flavin-containing monooxygenase 3 (FMO3) to produce trimethylamine-N- oxide (TMAO). Preliminary studies here demonstrate that the TMAO pathway is linked to insulin resistance and the development of type 2 diabetes in humans and animal models. Moreover, we show that pharmacologic inhibition of TMAO production confers striking protection against insulin resistance in mice. Mechanistically, we have found that host metabolic reprogramming driven by the glucocorticoid receptor (GR) requires direct transcriptional regulation of FMO3. Collectively, our preliminary data have led us to propose the following central hypothesis: The gut microbial metabolite TMAO is a GR-sensitive mediator of host stress responses that promote insulin resistance.
The specific aims are:
Aim 1. Testing the hypothesis that the gut microbial TMAO pathway directly impacts susceptibility for high fat diet-driven insulin resistance;
and Aim 2. To determine whether transcriptional regulation of the host TMAO-producing enzyme FMO3 is necessary for GR-driven immunosuppression and metabolic reprogramming. We anticipate our studies to reveal new molecular mechanisms linking gut microbe-derived factors to insulin resistance and associated cardiometabolic disorder, which will ultimately be leveraged into to the first ever gut microbe-targeted therapeutics for the treatment of type 2 diabetes.

Public Health Relevance

Data obtained from these studies are expected to define novel molecular mechanisms driving type II diabetes. By elucidating the molecular mechanisms by which gut microbial choline metabolism impacts insulin resistance this project has the potential to have broad impact on future drug discovery programs diabetes related disorders in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK120679-01
Application #
9711448
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2019-06-01
Project End
2023-03-31
Budget Start
2019-06-01
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195