Glucose-dependent insulinotropic polypeptide (GIP) signaling in visceral and subcutaneous adipose tissue: implications for obesity and metabolic disease-a narrative review with a structured literature search.

Glucose-dependent insulinotropic polypeptide is one of the principal incretin hormones involved in the regulation of glucose homeostasis, lipid metabolism, and adipocyte function. Increasing evidence indicates that its biological actions differ substantially between adipose tissue depots. The aim of this narrative review with a structured literature search was to summarize current evidence on the role of GIP in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), incorporating preclinical, clinical, and genetic data. Animal studies have demonstrated that VAT is characterized by higher expression of the GIP receptor (GIPR) and greater sensitivity to the lipogenic and proinflammatory effects of GIP. Activation of GIPR in VAT promotes lipid accumulation, inflammation, and insulin resistance. Conversely, pharmacological blockade or genetic deletion of GIPR confers protection against diet-induced obesity and leads to improvements in metabolic parameters. In SAT, GIP exerts more heterogeneous and metabolically context-dependent effects that differ according to insulin sensitivity and obesity status. Moreover, under specific conditions, GIP may promote lipolysis in SAT, distinguishing its actions in this depot from those observed in VAT. These observations may help explain the efficacy of dual and triple incretin receptor agonists, including tirzepatide and retatrutide, which produce significant improvements in body weight and metabolic outcomes. Collectively, current evidence supports a depot-specific and context-dependent role of GIP in adipose tissue biology and underscores the therapeutic potential of targeting the GIP/GIPR axis in obesity and metabolic disease.