Inhibition of DPP-4 Attenuates Endotoxemia-Induced NLRC4 Inflammasome and Inflammation in Visceral Adipose Tissue of Mice Fed a High-Fat Diet

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Abstract
Inflammasomes are protein complexes that trigger pro-inflammatory responses and promote many diseases, including adipose tissue dysfunction. Linagliptin (L), a DPP-4 inhibitor used for type 2 diabetes therapy, has putative anti-inflammatory effects. This work explores L effects on inflammasome regulation, inflammation, and adipose tissue dysfunction in obese mice. Male C57BL/6N mice were fed a normal chow (NC) diet, high-fat (HF) diet, or HF diet with L (HFL) for 15 weeks. Gene expression and histological examinations were performed on visceral (VAT) and subcutaneous (SAT) adipose tissue samples. Biomarkers were quantified on sera. Murine macrophages were utilized for in vitro analyses. L decreased HF-induced endotoxemia and circulating inflammatory indicators. Despite having no effect on body weight, L reduced VAT inflammation by decreasing endotoxemia-induced NLRC4 inflammasome, inflammation severity, and fat cell hypertrophy. Although SAT response differed from VAT, inflammation was slightly reduced in this tissue too. In vitro, L modulated inflammation by directly reducing the pro-inflammatory macrophage phenotype. In obesity, increased NLRC4 inflammasome expression links endotoxemia and VAT inflammation. L protected against endotoxemia, maybe by affecting gut permeability and VAT responses. The decreased polarization of macrophages toward a pro-inflammatory phenotype and the reduction in adipocyte hypertrophy are involved in the response to L.
Funding Information
  • Italian Ministry of Health-Ricerca Corrente (IRCCS Istituto Auxologico Italiano, Milan, Italy)
  • “Fondazione Romeo ed Enrica Invernizzi” (Università degli Studi di Milano, Milan, Italy)
  • PSR Linea 2 2022 Università degli Studi di Milano

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