Obesity is associated with altered gut microbiota composition and impaired gut barrier function. These changes, together with interrelated mesenteric adipose tissue inflammation, result in increased release of pro-inflammatory cytokines, bacteria-derived factors, and lipids into the portal circulation, promoting the development of (hepatic) insulin resistance. Herein, the potential impact of obesity-related changes in gut and visceral adipose tissue biology on the development of insulin resistance and Type 2 diabetes is reviewed.