Intestinal HIF1α is dispensable for bariatric surgery-mediated metabolic benefits but protects against diet-induced obesity and hepatic steatosis.

Abstract

Intestinal hypoxia-inducible factor 1α (HIF1α) orchestrates epithelial adaptation to luminal hypoxia and has been linked to metabolic homeostasis, yet its contribution to obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and bariatric surgery-mediated benefits remain unclear. In this study, we combined diet-induced models and genetic approaches to interrogate intestinal epithelial HIF1α function in obesity/MASLD progression and in the metabolic improvements elicited by sleeve gastrectomy (SG). Intestinal epithelial HIF1α deletion did not alter diet-induced weight gain, glucose homeostasis, or the metabolic and hepatoprotective effects of SG under either High-fat diet (HFD) or high-fat/high-fructose diets (HFFD) feeding. Notably, despite largely unchanged systemic metabolic phenotypes, intestinal HIF1α deficiency increased hepatic triglyceride and cholesterol accumulation and reshaped hepatic metabolic gene expression, indicating a selective impact on liver lipid handling. In contrast, activation of intestinal HIF1α protected against diet-induced obesity and hepatic steatosis. 16S rRNA profiling showed that intestinal HIF1α activation was associated with a distinct microbial shift, including enrichment of Ruminococcus and reduction of Desulfovibrio. Although activated after SG, intestinal epithelial HIF1α is not required for SG-induced metabolic improvements but exerts context-dependent protection against diet-induced obesity and hepatic steatosis, accompanied by gut microbial remodeling.