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

作者：Shabrova Elena; Hoyos Beatrice; Vinogradov Valerie; Kim Youn Kyung; Wassef Lesley; Leitges Michael; Quadro Loredana; Hammerling Ulrich

来源：The FASEB Journal, 2016, 30(3): 1339-1355.

DOI：10.1096/fj.15-281543

• vitamin A
• PKC delta signalosome
• metabolic syndrome

We previously defined that the mitochondria-localized PKC delta 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 PKC delta 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 PKC delta(-/-) strain to generate mice with a different status of the PKC delta signalosome and retinoid levels. Mice with a functional PKC delta signalosome and elevated retinoid levels (PKC delta(+/+)hRBP) developed the most advanced stage of insulin resistance. In contrast, elevation of retinoid levels in mice with inactive PKC delta did not affect remarkably their metabolism, resulting in phenotypic similarity between PKC delta(-/-)hRBP and PKC delta(-/-) mice. Therefore, in addition to the well-defined role of PKC delta in the etiology of metabolic syndrome, we present a novel PKC delta 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 PKC delta signalosome as a promising target for therapeutic intervention in metabolic disorders.

• 出版日期2016-3