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Published on: September 9, 2021
Intestinal epithelial peroxisome proliferator-activated receptor γ deficiency exacerbates insulin resistance in mice
Yun-Cheng Hsieh1, Bernd Schnabl2, Yi-Hsiang Huang1
1Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Abstract:
Peroxisome proliferator-activated receptor γ (PPARγ) is highly expressed in the intestinal epithelium and protects against intestinal inflammation. Intestinal inflammation and bacterial translocation contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH). We aimed to investigate the role of intestinal PPARγ in diet-induced MASH. Mice with intestinal epithelial cell-specific PPARγ deficiency (PPARγΔIEC) were generated using a villin-Cre transgene and floxed Pparg allele. Littermate mice carrying only the floxed Pparg allele (PPARγf/f), served as controls. MASH was induced by feeding a fast-food diet (FFD) for 24 weeks. FFD-fed mice developed characteristics of MASH, including obesity, insulin resistance and liver injury. While weight gain and liver injury were comparable between genotypes, PPARγΔIEC-FFD mice displayed more severe insulin resistance. Intestinal epithelial PPARγ deficiency exacerbated intestinal inflammation and down-regulated tight junction proteins (occludin, claudin-1/2) in the ileum and colon of FFD-fed mice. Increased gut permeability and bacterial translocation with elevated circulating lipopolysaccharide levels were observed in PPARγΔIEC-FFD mice. Furthermore, 16S rRNA analysis of fecal samples revealed that intestinal PPARγ deficiency facilitated the expansion of Desulfovibrio, Romboutsia, and Streptococcaceae under FFD feeding, which positively correlated with gut barrier dysfunction and endotoxemia. In addition, PPARγΔIEC-FFD mice showed greater adipose tissue inflammation and impaired insulin signaling in skeletal muscle. Intestinal epithelial PPARγ deficiency disrupted gut barrier integrity, promoted gut dysbiosis, and aggravated systemic insulin resistance, without further worsening hepatic injury in FFD-fed mice. These findings suggested that preserving intestinal PPARγ activity may be critical for mitigating metabolic dysfunction in MASH.
