Figure 3.

Complexity and cross-talk between contributors to obesity and T2D. Westernized diets [1], gut microbiota [2], the intestinal barrier and immune system [3] and metabolic inflammation [4] play a significant role in the development of obesity [5] and type 2 diabetes [6]. [1] Diet likely exerts a “one way effect” (indicated by red arrows) on glucose homeostasis, while high fat diets also affect the intestinal immune system and barrier function which can lead to [4] metabolic inflammation (indirect effects are indicated with dashed arrows). [2] Changes in microbiota composition and diversity have been associated with obesity, dysregulated glucose metabolism and T2D, with metabolic inflammation, and the intestinal immune and barrier system. Conversely, microbiota may also affect the dietary intake through inducing behavioral changes and cravings. [3] The intestines are known to shape microbiota and facilitate metabolic inflammation through barrier defects, but the intestines can also directly affect body weight and glucose homeostasis through gut hormone production and via expression of effector molecules and pathways in intestinal epithelial cells. [4] Metabolic inflammation contributes to obesity and T2D development through inducing insulin resistance. How metabolic inflammation may directly affect microbiota is not yet clear, but may occur indirectly through effects on intestinal barrier and immune function. [5] Obesity contributes to metabolic inflammation, but is associated with intestinal inflammation, barrier dysfunction and altered microbiota. Obesity may also influence diet and/or food intake through dysregulation in signaling related to satiety. A potentially direct effect of obesity on T2D development may involve the increased release of free fatty acid from adipose tissue which can induce insulin resistance through oxidative stress and lipid metabolites. [6] Type 2 diabetes and dysregulated glucose homeostasis may induce obesity in the sense that insulin resistance and hyperglycemia lead to increased lipogenesis and lipid storage but a direct pathway to increased body weight is likely the result of anti-diabetic drugs and their side effects. Hyperglycemia may induce metabolic inflammation directly via increased oxidative stress and indirectly through decreasing intestinal barrier function and altered microbiota composition. IgA, immunoglobulin A; LPS, lipopolysaccharide; T2D, type 2 diabetes.