title: 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.
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Elena
authors.initials: E
authors.lastname: Shabrova
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Hoyos
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Valerie
authors.initials: V
authors.lastname: Vinogradov
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Youn-Kyung
authors.initials: YK
authors.lastname: Kim
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Lesley
authors.initials: L
authors.lastname: Wassef
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Loredana
authors.initials: L
authors.lastname: Quadro
authors.affiliation: *Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Food Science, Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA; and Biotechnology Center of Oslo, University of Oslo, Oslo, Norway uhammerling@gmail.com.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hammerling
mesh_terms: D000818:Animals; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D012176:Retinoids; D012177:Retinol-Binding Proteins; D014801:Vitamin A; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta; D005947:Glucose
keywords: PKCδ signalosome; metabolic syndrome; vitamin A