Date of Award

Fall 12-15-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Andrew T. Gewirtz

Second Advisor

Didier Merlin

Third Advisor

Hang Shi

Fourth Advisor

Benoit Chassaing

Abstract

Metabolic syndrome (MetS) is a group of obesity-related metabolic abnormalities that predisposes to type II diabetes mellitus (T2DM) and cardiovascular disease. The dramatic increase in incidence of obesity and MetS over the last 25 years amidst relatively constant host genetics supports the role for non-genetic factors such as gut microbiota composition as an important contributor to the development of these disorders. Microbiota can interact with the host, in a manner influenced by genetics and diet that result in low-grade chronic inflammation. A critical risk factor for the pathogenesis of obesity and its related MetS involves alteration of gut microbiota composition with increased innate immune system activation in the intestine increasing risk. Diet-induced obesity is often modeled by comparing mice fed high-fat diet (HFD), which is made from purified ingredients, vs. normal chow diet (NCD), which is a low-fat assemblage of relatively unrefined plant and animal products. The mechanism by which HFD promotes adiposity is complex but thought to involve low-grade inflammation and altered gutmicrobiota. Here, I investigated the extent to which physiological effects to which HFD-induced adiposity is driven by fat content per se vs. other factors that differentiate HFD vs. NCD or other compositionally-defined diets (CDD) and, moreover sought to define the mechanisms that drove such effects. Relative to NCD, HFD, and to a lesser but nonetheless significant extent, CDD induced increased adiposity in addition to a rapid and marked loss of cecal and colonic mass, indicating that both lipid content and other aspects of HFD are obesogenic.CDD-induced effects were not affected by adjusting dietary protein levels/types but could be largely eliminated by exchanging insoluble fiber (cellulose) for soluble fiber (inulin). Moreover, replacing cellulose with inulin in HFD protected mice against decreased intestinal mass, hyperphagia and increased adiposity. Such protective effects of inulin correlated with increased levels of short-chain fatty acids, which are the products of bacterial fermentation of inulin. Lack of a microbiota, achieved by use of germ-free mice prevented generation of SCFA and eliminated the beneficial effects of inulin. Together, these results indicate that HFD-induced obesity is promoted by its lack of soluble fiber, which, when present, supports microbiota-mediated intestinal epithelia homeostasis that prevents inflammation driving obesity and MetS.

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