Research sheds light on why not all obese patients develop t
Type 2 diabetes is a serious metabolic disease that affects roughly one in 10 Americans. Formerly known as adult-onset diabetes, it is a chronic condition affecting the way the body metabolizes glucose, a sugar that's a key source of energy. This type of diabetes is frequently associated with obesity. For some patients, that means their body does not properly respond to insulin—it resists the effects of insulin, the hormone produced by the pancreas that opens the door for sugar to enter cells. In the later disease stages, when the pancreas is exhausted, patients don't produce enough insulin to maintain normal glucose levels.

In either case, sugar builds up in the bloodstream and, if left untreated, the effect impairs many major organs, sometimes to disabling or life-threatening degrees. A key risk factor for type 2 diabetes is being overweight, often a result of eating too much fat and sugar in combination with low physical activity. Findings, which show that a particular type of gut microbe leads to white adipose tissue containing macrophage cells—large cells that are part of the immune system—associated with insulin resistance.

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.