Fig. 7
From: Relevance and consequence of chronic inflammation for obesity development
Gut hormone-derived incretins contribute to hypothalamic inflammation and modulate insulin- and leptin-resistance. Over-nutrition activates GIP production in the gut, which in turn activates glucose-dependent insulin secretion in the pancreas and also exhibits extra-pancreatic functions. Interestingly, in mice, it has been shown that deletion and overexpression of GIP is associated with improved diabetes and resistance to DIO. Centrally administered GIP leads to a reduction of JAK-STAT-activation and therefore diminishes leptin activity in the hypothalamus and upregulates SOCS3 and IL-6 in mice. Concordantly, intracerebral application of monoclonal antibodies against GIPR leads to a suppression of SOCS3 and IL-6 and induces weight loss in mice and non-human primates. This effect is enhanced when combined with GLP-1R agonist. Paradoxically, the GIPR-GLP-1R co-agonist also leads to weight loss, reduced food intake, and a decrease in fat mass. These incretins and their receptors propose immense pharmacological potential in targeting DIO and its co-morbidities