Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages

Zhipeng Li, Manoj Gurung, Richard R. Rodrigues, Jyothi Padiadpu, Nolan K. Newman, Nathan P. Manes, Jacob W. Pederson, Renee L. Greer, Stephany Vasquez-Perez, Hyekyoung You, Kaito A. Hioki, Zoe Moulton, Anna Fel, Dominic De Nardo, Amiran K. Dzutsev, Aleksandra Nita-Lazar, Giorgio Trinchieri, Natalia Shulzhenko, Andrey Morgun

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22 Citations (Scopus)


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.

Original languageEnglish
Article numbere20220017
Number of pages23
JournalJournal of Experimental Medicine
Issue number7
Publication statusPublished - 3 Jun 2022

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