| Literature DB >> 35657352 |
Zhipeng Li1,2, Manoj Gurung1, Richard R Rodrigues3,4,5, Jyothi Padiadpu3, Nolan K Newman3, Nathan P Manes6, Jacob W Pederson1, Renee L Greer1, Stephany Vasquez-Perez1, Hyekyoung You1, Kaito A Hioki3, Zoe Moulton1, Anna Fel6, Dominic De Nardo7, Amiran K Dzutsev4, Aleksandra Nita-Lazar6, Giorgio Trinchieri4, Natalia Shulzhenko1, Andrey Morgun3.
Abstract
Microbiota contribute to the induction of type 2 diabetes by high-fat/high-sugar (HFHS) diet, but which organs/pathways are impacted by microbiota remain unknown. Using multiorgan network and transkingdom analyses, we found that microbiota-dependent impairment of OXPHOS/mitochondria in white adipose tissue (WAT) plays a primary role in regulating systemic glucose metabolism. The follow-up analysis established that Mmp12+ macrophages link microbiota-dependent inflammation and OXPHOS damage in WAT. Moreover, the molecular signature of Mmp12+ macrophages in WAT was associated with insulin resistance in obese patients. Next, we tested the functional effects of MMP12 and found that Mmp12 genetic deficiency or MMP12 inhibition improved glucose metabolism in conventional, but not in germ-free mice. MMP12 treatment induced insulin resistance in adipocytes. TLR2-ligands present in Oscillibacter valericigenes bacteria, which are expanded by HFHS, induce Mmp12 in WAT macrophages in a MYD88-ATF3-dependent manner. Thus, HFHS induces Mmp12+ macrophages and MMP12, representing a microbiota-dependent bridge between inflammation and mitochondrial damage in WAT and causing insulin resistance.Entities:
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Year: 2022 PMID： 35657352 PMCID： PMC9170383 DOI： 10.1084/jem.20220017
Source DB: PubMed Journal: J Exp Med ISSN： 0022-1007 Impact factor: 17.579