title: Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue.
abstract: Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Florian W
authors.initials: FW
authors.lastname: Kiefer
authors.forename: Cecile
authors.initials: C
authors.lastname: Vernochet
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Brien
authors.forename: Steffen
authors.initials: S
authors.lastname: Spoerl
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Brown
authors.forename: Shriram
authors.initials: S
authors.lastname: Nallamshetty
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism*; D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000502:physiology*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000502:physiology; D050697:Retinal Dehydrogenase; D022722:Thermogenesis; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase