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

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.

Multi-omic network analysis identified betacellulin as a novel target of omega-3 fatty acid attenuation of western diet-induced nonalcoholic steatohepatitis

“…Interestingly, we also observed the restoration Elovl5 (Figure S3B), a key enzyme involved in the elongation of mono-and polyunsaturated fatty acids (35). Together, these results validate the implemented network analysis for lipidomic data (previously used and experimentally validated only for other omics (31,34), thereby reinforcing a potential importance of other lipids highly ranked in our analysis. Among top ranked lipids were phosphatidic acid (PA) and phosphatidyl glycerol (PGs) such as PA 38:6, PG 38:6, and PG 38:3; all of these lipids are precursors of cardiolipin (unique mitochondrial membrane phospholipid) and restored by DHA (Figure 3C).…”

“…Specifically, nodes of high degree (also called hubs) usually represent master regulators of a part of the large network (clusters or subnetworks) in which these hubs are situated ( 32, 33 ). High ranked BiBC nodes would represent factors mediating impact of one part (e.g., module/cluster) of a network on another ( 31, 34 ). Thus, we selected nodes from lipids/metabolites that are part of the network, top ranked in BiBC (top 10%) and have high degree (top 10%), also regulated by DHA (M&M).…”

Reversing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

“…Taken together, these findings reveal that TXN benefits the host by acting on IR-ATMs via changes in the composition of the gut microbiota. These findings may have translational potential as we previously showed this macrophage signature shows a strong overlap with that found in a meta-analysis of T2D patients [21]; suggesting TXN treatment could benefit obese patients with MetS conditions.…”

“…Stromal cells from epididymal fat tissue of four C57BL/6J male mice were isolated as described previously [21] and pooled prior to scRNA-seq. All cells were resuspended in DPBS with 0.04% BSA, and immediately processed for scRNA-seq as follows.…”

“…First, we found genes reversed by TXN in the adipose tissue were enriched for mitochondrial processes such as antioxidant activity and oxidoreductase activity (Figure S2D). Next, we identified 87 mitochondrial genes (MitoCarta 3.0, MitoGenes [21,39] in the adipose tissue network that were reversed by TXN.…”