Obesity, which affects one in three Americans, is a major risk factor for hyperlipidemia, hypertension, insulin resistance, type 2 diabetes (T2D), cardiovascular disease, and certain types of cancer. Recent studies have suggested that alterations in the gut microbiota may be a major contributor to this increased prevalence of obesity, however the mechanism by which this occurs is unknown. The Overarching Hypothesis guiding the aims of this grant, based on our recent studies, is that a high-fat diet (HFD) increases net production of acetate by the gut microbiota, leading to activation of the parasympathetic nervous system, which in turn promotes increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia, obesity and its related sequelae of hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. These findings open the door to new therapeutic interventions, but the current lack of understanding of the underlying mechanisms, risk factors, and effect of existing T2D drugs is a significant roadblock. In this proposal, we present a plan to first determine how HFD increases net acetate production by the microbiota. Second, we will assess whether human gut microbiomes, which vary broadly between individuals, are differentially susceptible or resistant to HFD-induced acetate production. Finally, we will determine whether changes in the microbiota with metformin therapy may contribute to its efficacy for the control of hyperglycemia in T2DM patients. Specifically, we will test the hypothesis that metformin causes changes in the intestinal microbiome that contribute to reduced postprandial hyperglycemia via altered acetate production.

Public Health Relevance

Based upon our preliminary studies, we propose the novel hypothesis that increased production of acetate by the gut microbiota leads to activation of the parasympathetic nervous system which in turn promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, obesity and other features of the metabolic syndrome. We will examine 1.) how high fat diet increases net acetate production by the microbiota, 2.) whether human gut microbiomes are differentially susceptible or resistant to HFD-induced acetate production, and 3.) whether metformin alters microbial acetate production thereby contributing to glycemic control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK114793-02
Application #
9656998
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2018-04-01
Project End
2022-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Petersen, Max C; Shulman, Gerald I (2018) Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 98:2133-2223
Madiraju, Anila K; Qiu, Yang; Perry, Rachel J et al. (2018) Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med 24:1384-1394