title: The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis.
abstract: Circadian rhythms have an essential role in feeding behavior and metabolism. RORα is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phosphoenolpyruvate carboxykinase c (PEPCKc), whose gene is a RORα target in the liver. RORα-deficient mice (staggerer, ROR(sg/sg)) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of RORα, and we further evaluated the role of RORα in hepatocyte gluconeogenesis. In vivo investigations comparing ROR(sg/sg) mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of RORα, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the ROR(sg/sg) mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with RORα agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not ROR(sg/sg) mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by RORα. This study demonstrates the physiological function of RORα in regulating both glucose and FFA homeostasis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U938, Paris, France; Sorbonne Université, University Pierre et Marie Curie; Univ Paris-6, UMR_S 938, l'Institut de Cardiométabolisme et Nutrition, Paris, France; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kadiri
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U938, Paris, France; Sorbonne Université, University Pierre et Marie Curie; Univ Paris-6, UMR_S 938, l'Institut de Cardiométabolisme et Nutrition, Paris, France; and.
authors.forename: Chloé
authors.initials: C
authors.lastname: Monnier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U938, Paris, France; Sorbonne Université, University Pierre et Marie Curie; Univ Paris-6, UMR_S 938, l'Institut de Cardiométabolisme et Nutrition, Paris, France; and.
authors.forename: Munkhzul
authors.initials: M
authors.lastname: Ganbold
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U938, Paris, France; Sorbonne Université, University Pierre et Marie Curie; Univ Paris-6, UMR_S 938, l'Institut de Cardiométabolisme et Nutrition, Paris, France; and.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ledent
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U938, Paris, France; Sorbonne Université, University Pierre et Marie Curie; Univ Paris-6, UMR_S 938, l'Institut de Cardiométabolisme et Nutrition, Paris, France; and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U938, Paris, France; Sorbonne Université, University Pierre et Marie Curie; Univ Paris-6, UMR_S 938, l'Institut de Cardiométabolisme et Nutrition, Paris, France; and Centre National de la Recherche Scientifique, UMR_S 938, Paris, France benedicte.antoine@inserm.fr.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Antoine
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000502:physiology*
chemical_list: D005230:Fatty Acids, Nonesterified; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539739:Rora protein, mouse; D005947:Glucose; D005990:Glycerol
keywords: adipose tissue; glyceroneogenesis; nuclear retinoid-related orphan receptor-α; phosphoenolpyruvate carboxykinase c