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

Authors: LI, ZHIPENG - Oregon State University; Gurung, Manoj; RODRIGUES, ROCHARD - Oregon State University; PADIADPU, JYOYHI - Oregon State University; NEWMAN, NOLAN - Oregon State University; MANES, NATHAN - Nih, National Institutes Of Allergy And Infectious Diseases; PEDERSON, JACOB - Oregon State University; GREER, RENEE - Oregon State Department Of Environmental Quality; MORGUN, ANDRY - Oregon State Department Of Environmental Quality; SHULZHENKO, NATALIA - Oregon State University

Submitted to: Journal of Experimental Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/5/2022
Publication Date: 6/3/2022
Citation: Li, Z., Gurung, M., Rodrigues, R.R., Padiadpu, J., Newman, N.K., Manes, N.P., Pederson, J.W., Greer, R.L., Morgun, A., Shulzhenko, N. 2022. Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages. Journal of Experimental Medicine. 219(7):e20220017. https://doi.org/10.1084/jem.20220017.
DOI: https://doi.org/10.1084/jem.20220017

Interpretive Summary: Obesity and related metabolic diseases like Type 2 diabetes are a global pandemic. Several factors like high fat/high sugar diets, a sedentary lifestyle, and genetics contribute to these conditions. Consumption of high-fat/high-sugar diets modifies microbes in our gastrointestinal tract which also contributes to Type 2 diabetes. However, how these microbes and which microbes affect the organs are involved in Type 2 diabetes is not well understood. We used a mouse model of Type 2 diabetes by feeding high-fat high sugar diets. Using this animal model and computational analysis, we found that gut microbes contribute to the damage of mitochondria in the white fat during obesity. This damage will in turn promote insulin resistance in which the body's capacity to lower blood glucose levels is reduced even in the presence of normal insulin levels. We also identified that in mice with normal microbes, a gene named MMP12 is associated with insulin resistance. However, in germ-free mice, which lack any kind of microbes in the body, this association was not present. We were also able to pinpoint a microbe named Oscillibacter valericigenes that promotes MMP12 increase when mice are fed high fat and high diet but not in the healthy diet fed. These findings, thus, contribute to a better understanding of the role of generally beneficial microbes in diet-induced type 2 diabetes and established a gene in the white fat as a potential target of type 2 diabetes drug development.

Technical 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.