Reviews in endocrine & metabolic disordersOct 22, 2026

GIP signaling in belly and under-skin fat: possible links to obesity and metabolic disease

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 23, 2026

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) shows higher expression of its receptor in visceral adipose tissue compared to subcutaneous adipose tissue.

Visceral adipose tissue (VAT) exhibits greater sensitivity to the lipogenic and proinflammatory effects of GIP due to higher GIP receptor expression.
Activation of the GIP receptor in VAT is associated with increased lipid accumulation, inflammation, and insulin resistance.
Blocking or deleting the GIP receptor may protect against obesity and improve metabolic health.
In subcutaneous adipose tissue (SAT), the effects of GIP are more variable and depend on factors like insulin sensitivity and obesity status.
Under certain conditions, GIP may encourage fat breakdown in SAT, contrasting its actions in VAT.
The findings may help clarify the effectiveness of dual and triple incretin receptor agonists in improving weight and metabolic outcomes.

Simplified

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.

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GIP signaling in belly and under-skin fat: possible links to obesity and metabolic disease

Abstract

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