ABSTRACT Type 2 diabetes (T2D) is one of the most serious medical diseases facing our society, and understanding the events leading to T2D, specifically the genesis of obesity and insulin resistance, key components of T2D, is critical. Fiber, which is known to be protective against T2D, is fermented by gut bacteria, resulting in the synthesis of short chain fatty acids (SCFAs), predominantly acetate, propionate, and butyrate. This is one of the key proposed mechanisms that the gut microbiome protects against these metabolic conditions. Importantly, free fatty acid receptors 2 (FFA2) and -3 (FFA3), which sense and mediate the action of SCFAs, have altered expression in obesity and insulin resistant states. These receptors are expressed in β cells and in enteroendocrine (L) cells, where they are suggested to contribute to the secretion of glucagon- like peptide-1 (GLP-1) regulating β cell function, which collectively contribute to the secretion of insulin. These receptors, therefore, are primed to mediate the interaction between bacterial fermentation to SCFAs and hormonal secretion. We propose to use novel genetic knockout (KO) murine models to dissect how fiber (via SCFA production) mediates metabolic outcomes such as obesity and insulin resistance where we will explore at the whole body (global, Aim 1) and tissue- specific level (Aim 2), focused on the enteroinsular axis, and assess the translational component of these receptors to human tissues (Aim 3). Overall, this study will reveal that a novel SCFA- sensing mechanism influences host metabolic response to obesogenic challenge.