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Glucose-dependent insulinotropic polypeptide ameliorates obesity and insulin resistance by attenuating S100A8/9 in myeloid cells

ABSTRACT: Our data mark GIP as a beneficial immunoregulator during obesity and suggest a novel untapped therapeutic potential for specific targeted GIP analogs. Emerging studies suggest that glucose-dependent insulin tropic polypeptide (GIP) affect obesity-associated inflammation. Yet, whether GIP can directly regulate immune cell activity and the respective metabolic consequences remained unknown. Here, we targeted GIP-receptor-deficiency to immune cells using bone marrow (BM) chimerism approach and the reconstituted chimeric mice were subjected to a high fat diet (HFD) regimen. Mice reconstituted with Gipr-/- BM gained significantly more weight, despite similar food consumption. This was accompanied by increased epididymal adipose tissue (epiWAT) mass, adipocyte hypertrophy, enhanced hepatic steatosis, insulin resistance and significant myelopoiesis in the circulation, epiWAT and inguinal adipose tissue (ingWAT). In accordance these mice also exhibited reduced energy expenditure and ingWAT beiging. Mechanistically, impaired GIP-governed regulation of S100A8/9 in myeloid cells was responsible for the perturbed energy homeostasis, increased insulin resistance and intensified inflammatory response under nutrient overload. Collectively, our results outline a beneficial immunoregulatory role for GIP in immune cells during obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE109371 | GEO | 2019/01/02

REPOSITORIES: GEO

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Glucose-dependent Insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake

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2019-07-24 | GSE134726 | GEO

Chronic GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese insulin resistant mice

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