Rates of obesity and diabetes are increasing at an alarming rate throughout the world, in both developed and developing countries. A link between the intestinal microbiota, low-grade chronic inflammation and metabolic syndrome has been recently established in our and other laboratories. Specifically, our studies demonstrate that mice lacking toll-like receptor 5 (TLR5), which is predominantly expressed by intestinal epithelial cels, develop spontaneous colitis because of an inability to maintain intestinal bacterial homeostasis. Further, upon rederivation of TLR5KO mice via embryonic transfer, ocurence of spontaneous colitis was substantialy reduced as was inflammation. Such low-grade inflammation in TLR5KO mice resulted in hyperglycemia, hyperlipidemia, hyperphagia, insulin resistance, obesity, hepatic steatosis and hypertension, collectively referred to as metabolic syndrome. Further experimentation with these mice indicated that an altered intestinal microbiota composition is responsible for the development of metabolic syndrome as we can transfer metabolic syndrome by transplanting cecal microbiota from TLR5KO mice to germ-free WT mice. However, the molecular mechanism for the development of metabolic syndrome is not clear. This grant proposal aims to clarify the role of lipid metabolism in the development of colits and metabolic syndrome in TLR5KO mice. Stearoyl Coenzyme A Desaturase-1 (SCD-1) synthesizes monounsaturated fatty acids (MUFA;C16:1 and C18:1) from dietary or de novo saturated fatty acids (SFA;C16:0 and C18:0). It has been proposed that SFA are highly lipotoxic and SCD-1 converts them into less toxic MUFA. These MUFA serve as precursors for the synthesis of hepatic lipids (triglycerides (TG) and cholesterol esters (CE) and thus play a role in the development of hepatic steatosis. Interestingly, SCD-1 deficiency exacerbates intestinal inflammation in an acute model of Dextran Sodium Sulfate (DSS) and C. rodentium induced colitis and SCD-1 overexpression significantly attenuated such colitis. In addition, diets rich in oleic acid protected against mouse models of colitis. Our hypothesis is that TLR5KO mice, which exhibit hyperphagia and an increased bacterial burden, generate large amounts of SFA which enter the liver via enterohepatic circulation and may be driving inflammation. Such a mechanism suggests that, to protect against lipotoxic effects of large amounts of SFA, TLR5KO mice convert them into less toxic MUFA which leads to increased hepatic lipogenesis. Our preliminary results indicate that TLR5KO mice have elevated levels of the SCD-1 product C18:1 n9 (oleic acid) in liver lipids, particularly TG and CE, supporting our hypothesis. We propose to study the role of SCD-1 in the development of colitis and metabolic syndrome by generating SCD-1/TLR5 double knockout mice. Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify whether SCD-1 can be targeted to prevent colitis and metabolic diseases !

Public Health Relevance

The proposed studies will demonstrate the role of a fat synthesizing enzyme in the development of spontaneous colitis, obesity and diabetes in mice deficient in recognizing a bacterial protein. Our hypothesis is that increased fat synthesis is a 'metabolic adaptation'to protect against the spontaneous inflammation that eventually results in obesity and diabetes. This study may help in designing therapeutic dietary formulations to treat inflammatory/metabolic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Georgia State University
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United States
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Yeoh, Beng San; Aguilera Olvera, Rodrigo; Singh, Vishal et al. (2016) Epigallocatechin-3-Gallate Inhibition of Myeloperoxidase and Its Counter-Regulation by Dietary Iron and Lipocalin 2 in Murine Model of Gut Inflammation. Am J Pathol 186:912-26
Singh, Vishal; Kumar, Manish; San Yeoh, Beng et al. (2016) Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice. Inflamm Bowel Dis 22:841-52
Singh, Vishal; Chassaing, Benoit; Zhang, Limin et al. (2015) Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice. Cell Metab 22:983-96
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