Project 453491

Changes in the type of gut microbes (known of the microbiota) can promote obesity and diabetes. We showed that type 2 diabetes alters bacteria in adipose tissues and the liver in obese persons and we now propose that alterations in the immune system and how bacteria adapt may facilitate their presence in metabolic tissues and how they can block insulin action in obesity. A classical mechanism of host defense against bacteria is the production of nitric oxide (NO) by enzyme called iNOS. While iNOS can stop bacterial invaders, it can also causes insulin resistance when unchecked. iNOS expression is also increased in human adipose tissues from persons with obesity and correlates with poor lipid control and inflammation. iNOS expression is also increased in the gut of obesity where it can changes the composition of the gut microbiota. We propose that chronic activation of iNOS in the intestine favors pathogenic bacteria to subvert the gut barrier during obesity. This would allow some of these microbes to breach the intestinal barrier and reach extra-intestinal tissues to impair insulin action. The following hypotheses will be tested : 1) iNOS dictates bacterial tissue invation and insulin resistance in obesity; 2) iNOS is a key determinant of bacterial invasion to human tissues; 3) iNOS invasion in metabolic tissue determines obesity-linked insulin resistance; 4) Restoring intestinal iNOS and microbiota balance will prevent bacterial invasion and prevent diabetes.