Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice

Yuan Liang, Chao Luo, Lijun Sun, Tiange Feng, Wenzhen Yin, Yunhua Zhang, Michael W. Mulholland, Weizhen Zhang () and Yue Yin ()
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Yuan Liang: Peking University
Chao Luo: Peking University
Lijun Sun: Peking University
Tiange Feng: Peking University
Wenzhen Yin: Peking University
Yunhua Zhang: Peking University
Michael W. Mulholland: University of Michigan Medical Center
Weizhen Zhang: Peking University
Yue Yin: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

Date: 2024
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DOI: 10.1038/s41467-024-48622-5

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