Retinol as a cofactor for PKCd-mediated impairment of insulin sensitivity in a mouse model of diet-induced obesity

Abstract

We previously defined that the mitochondrialocalized PKCδ signaling complex stimulates the conversion of pyruvate to acetyl-coenzyme A by the pyruvate dehydrogenase complex. We demonstrated in vitro and ex vivo that retinol supplementation enhances ATP synthesis in the presence of the PKCδ signalosome. Here, we tested in vivo if a persistent oversupply of retinol would further impair glucose metabolism in a mouse model of dietinduced insulin resistance. We crossed mice overexpressing human retinol-binding protein (hRBP) under the muscle creatine kinase (MCK) promoter (MCKhRBP) with the PKCδ-/- strain to generate mice with a different status of the PKCd signalosome and retinoid levels. Mice with a functional PKCδ signalosome and elevated retinoid levels (PKCδ+/+hRBP) developed the most advanced stage of insulinresistance. In contrast, elevationof retinoid levels in mice with inactivePKCδ did not affect remarkably their metabolism, resulting in phenotypic similarity between PKCδ-/-RBP and PKCδ-/- mice. Therefore, in addition to the well-defined role of PKCδ in the etiology of metabolic syndrome, we present a novel PKCδ signaling pathway that requires retinol as ametabolic cofactor and is involved in the regulation of fuel utilization in mitochondria. The distinct role in whole-body energy homeostasis establishes the PKCδ signalosome as a promising target for therapeutic intervention in metabolic disorders.