title: Decreased brown adipocyte recruitment and thermogenic capacity in mice with impaired peroxisome proliferator-activated receptor (P465L PPARgamma) function.
abstract: Mice with a dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutation (P465L) unexpectedly had normal amounts of adipose tissue. Here, we investigate the adipose tissue of the PPARgamma P465L mouse in detail. Microscopic analysis of interscapular adipose tissue of P465L PPARgamma mice revealed brown adipocytes with larger unilocular lipid droplets, indicative of reduced thermogenic capacity. Under conditions of cold exposure, the brown adipose tissue of the PPARgamma P465L mice was less active, a fact reflected in decreased uncoupling protein 1 levels. Analysis of the white adipocytes confirmed their normal cytoarchitecture and development, yet classical white adipose depots of the P465L PPARgamma mice had a striking reduction in brown adipocyte recruitment, a finding supported by reduced expression of UCP1 in the perigonadal adipose depot. Taken together, these data suggest that whole animal impairment of PPARgamma alters the cellular composition of the adipose organ to a more "white" adipose phenotype. Physiologically, this impairment in brown adipocyte recruitment is associated with decreased nonshivering thermogenic capacity after cold acclimation as revealed by norepinephrine responsiveness. Our results indicate that maintenance of oxidative brown-like adipose tissue is more dependent on PPARgamma function for development than white adipose tissue, an observation that may be relevant when considering PPARgamma-dependent strategies for the treatment of obesity.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
authors.forename: Edoardo
authors.initials: E
authors.lastname: Dalla Nora
authors.forename: Emma C
authors.initials: EC
authors.lastname: Backlund
authors.forename: Monia
authors.initials: M
authors.lastname: Manieri
authors.forename: Sam
authors.initials: S
authors.lastname: Virtue
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cortright
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
mesh_terms: D000064:Acclimatization / Q000235:genetics / Q000502:physiology; D052437:Adipocytes, Brown / Q000166:cytology / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000033:anatomy & histology; D000818:Animals; D002452:Cell Count; D003080:Cold Temperature; D005260:Female; D006066:Gonads / Q000166:cytology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D020125:Mutation, Missense; D047495:PPAR gamma / Q000235:genetics* / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D022722:Thermogenesis / Q000235:genetics* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1