Human adipose insulin resistance

Adipocytes play a major role in whole body fuel homeostasis. Integrated proteomic analysis of adipose from insulin resistant versus healthy humans or mice or in 3T3-L1 adipocytes revealed defects in the mevalonate/coenzyme Q (CoQ) biosynthesis pathway as a unifying feature of adipocyte insulin resistance. CoQ was decreased selectively in mitochondria in all insulin resistant conditions and this was associated with a selective increase in mitochondrial oxidative stress. CoQ supplementation lowered mitochondrial oxidative stress and reversed insulin resistance in vitro and in vivo. Decreasing mitochondrial CoQ by genetic or pharmacological means caused insulin resistance by increasing mitochondrial oxidants from complex II. Our data suggest that loss of mitochondrial CoQ is a proximal driver of mitochondrial oxidative stress and insulin resistance. These findings may explain why statin use is associated with insulin resistance, and suggest that mitochondrial CoQ may be an effective therapeutic target for treating insulin resistance in humans.