Fig. 5

GLP-1 signaling pathway in obesity pathogenesis. The anti-obesity effect of GLP-1 can be mediated by either peripheral or central signals. In the periphery, the activation of GLP-R by gut-derived GLP-1 enhances the glucose-stimulated insulin secretion, through PKA-dependent or Epac2 pathway. By enhanced PKA activity, GLP-1 alleviates insulin resistance and leads to weight loss in obese diabetic mice by reducing ER stress and improving β-cell function. It also improves insulin sensitivity in peripheral tissue by suppressing AMPK-related pathway and elevating glyoxalase. By interacting with multiple signaling pathways including PI3K, MAPK, and Wnt4-β-catenin pathways, GLP-1 promotes pre-adipocyte differentiation by up-regulating PPARγ and FABP4, but suppresses lipogenesis in mature adipocytes by decreasing fatty acid synthase expression. GLP-1 also enhances lipolysis in WAT by increasing the expression and activity of Sirt1, through yet unknown mechanisms. Additionally, GLP-1 participates in the regulation of thermogenesis by inhibiting BMP4-related signaling pathway and thus induces the expression of thermogenic genes like UCP1. Gut-derived GLP-1 also interacts with GLP-R expressed in vagus, through which the information is transmitted upward to the CNS, which in turns suppresses vagal activity and gastric emptying, so as to increase satiety and reduce food intake. Besides, peripheral GLP-1 plays a role in the regulation of insulin sensitivity and BAT-related thermogenesis in a CNS-dependent manner. the latter is partially mediated by suppressing AMPK signaling pathway. Central GLP-1 produced by neurons in the caudal medulla is transmitted into the hypothalamus and functions to reduce food intake by activating POMC neurons while suppressing AgRP/NPY neurons in this area