1. Pharmacological modulation of RORα controls fat browning, adaptive thermogenesis, and body weight in mice
- Author
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Natacha Roblot, Bruno Fève, Martine Auclair, Bénédicte Antoine, Emilie Capel, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Antoine, Benedicte, Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
- Subjects
0301 basic medicine ,Physiology ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Adipose tissue ,synthetic ligands ,White adipose tissue ,Mice ,0302 clinical medicine ,Adipose Tissue, Brown ,Adipocytes ,RORα ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,PRDM16 ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Sulfonamides ,Chemistry ,Nuclear Receptor Subfamily 1, Group F, Member 1 ,Thermogenesis ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,in vivo ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Benzamides ,Female ,Research Article ,Agonist ,Adult ,medicine.medical_specialty ,medicine.drug_class ,Adipose Tissue, White ,030209 endocrinology & metabolism ,Thiophenes ,03 medical and health sciences ,white adipose tissue ,In vivo ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Transcription factor ,browning ,Cold-Shock Response ,Body Weight ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Thiazoles ,030104 developmental biology ,Endocrinology ,Cell Transdifferentiation ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Ex vivo - Abstract
International audience; Beiging is an attractive therapeutic strategy to fight against obesity and its side metabolic complications. The loss of function of the nuclear transcription factor RORa has been related to a lean phenotype with higher thermogenesis in sg/sg mice lacking this protein. Here we show that pharmacological modulation of RORa activity exerts reciprocal and cell-autonomous effect on UCP1 expression ex vivo, in cellulo, and in vivo. The RORa inverse-agonist SR3335 upregulated UCP1 expression in brown and subcutaneous white adipose tissue (scWAT) explants of wild-type (WT) mice, whereas the RORa agonist SR1078 had the opposite effect. We confirmed the reciprocal action of these synthetic RORa ligands on gene expression, mitochondrial mass, and uncoupled oxygen consumption rate in cultured murine and human adipocytes. Time course analysis revealed stepwise variation in gene expression, first of TLE3, an inhibitor of the thermogenic program, followed by a reciprocal effect on PRDM16 and UCP1. Finally, RORa ligands were shown to be useful tools to modulate in vivo UCP1 expression in scWAT with associated changes in this fat depot mass. SR3335 and SR1078 provoked the opposite effects on the WT mice body weight, but without any effect on sg/sg mice. This slimming effect of SR3335 was related to an increased adaptive thermogenesis of the mice, as assessed by the rectal temperature of cold-stressed mice and induction of UCP1 in scWAT, as well as by indirect calorimetry in presence or not of a b3-adrenoceptor agonist. These data confirmed that RORa ligands could be useful tools to modulate thermogenesis and energy homeostasis. NEW & NOTEWORTHY The regulation of adipose tissue browning was not fully deciphered and required further studies explaining how the regulation of this process may be of interest for tackling obesity and related metabolic disorders. Our data confirmed the involvement of the transcription factor RORa in the regulation of nonshivering thermogenesis, and importantly, revealed the possibility to in vivo modulate its activity by synthetic ligands with beneficial consequences on fat mass and body weight of the mice.
- Published
- 2020