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

Abstract

We previously defined that the mitochondria-localized 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 diet-induced 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 PKCδ signalosome and retinoid levels. Mice with a functional PKCδ signalosome and elevated retinoid levels (PKCδ(+/+)hRBP) developed the most advanced stage of insulin resistance. In contrast, elevation of retinoid levels in mice with inactive PKCδ did not affect remarkably their metabolism, resulting in phenotypic similarity between PKCδ(-/-)hRBP 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 a metabolic 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.

Biomarkers of Nutrition for Development (BOND)—Vitamin A Review

“…In mice with active protein kinase C, retinol supplementation showed that retinol is a metabolic cofactor involved in the regulation of mitochondrial fuel utilization ( 179 ).…”

All-Trans Retinoic Acid Inhibits Bone Marrow Mesenchymal Stem Cell Commitment to Adipocytes via Upregulating FRA1 Signaling

“…Its physiological functions include maintaining visual function [32], promoting immunoglobulin synthesis [33], and maintaining the stability of reproductive epithelial cells [34]. Recent research has focused on the physiological functions of vitamin A, and its metabolite atRA, such as regulating energy metabolism, insulin sensitivity, and lipid metabolism [35,36]. An epidemiological investigation reported that a low serum retinol concentration was a risk factor for obesity.…”

Retinol saturase modulates lipid metabolism and the production of reactive oxygen species

“…Another possibility is that the effect of RetSat on ROS is mediated by the saturation of the all- trans -retinol moiety associated with protein kinase Cδ (PCKδ). The π-conjugated system of all- trans -retinol mediates electron transfer from cytochrome c leading to the activation of PCKδ [33] signalosome with ensuing effects on glycolytic energy generation [34, 35]. It is, therefore, possible that RetSat may interfere with this pathway by breaking the π-conjugation system via the saturation of the C13-C14 double bond of all- trans -retinol.…”