Insulin resistance and altered hepatic mitochondrial function are central features of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), but the etiological role of these processes in disease progression remains unclear. We investigated the molecular links between insulin resistance, mitochondrial remodeling, and hepatic lipid accumulation in a rodent model of T2D / NAFLD. Livers from obese, insulin resistant mice displayed augmented mitochondrial content and increased TCA cycle and pyruvate dehydrogenase (PDH) activities. Insulin sensitization with pioglitazone mitigated pyruvate-driven TCA cycle activity and PDH activation via both covalent (PDK4 and PDP2) and allosteric (intracellular pyruvate availability) mechanisms. Interestingly, improvements in insulin sensitivity and mitochondrial function were entirely dissociated from changes in hepatic triglycerides, diacylglycerides or fatty acids. Instead, we show that the mitochondrial phospholipid cardiolipin undergoes pathological remodeling in livers from obese mice and that this is reversed by insulin sensitization. Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.

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