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This version published online on September 15, 2006
Endocrinology, doi:10.1210/en.2006-0684
A more recent version of this article appeared on December 1, 2006
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Submitted on May 19, 2006
Accepted on September 7, 2006

Decreased brown adipocyte recruitment and thermogenic capacity in mice with impaired PPAR{gamma} (P465L PPAR{gamma}) function

Sarah L. Gray, Edoardo Dalla Nora, Emma C. Backlund, Monia Manieri, Sam Virtue, Robert C. Noland, Stephen O’Rahilly, Ronald N. Cortright, Saverio Cinti, Barbara Cannon, and Antonio Vidal-Puig*

Dept. Clinical Biochemistry, University of Cambridge, Box 232 Level 4 Addenbrooke’s Hospital, Hills Rd., Cambridge, UK CB2 2QR; The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden; Dept. of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy, 60020; Dept. Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Rd., Cambridge, UK CB2 2QR; Ward Sports Medicine Building and Brody School of Medicine, Depts. of Exercise and Sport Science and Physiology, East Carolina University, Greenville, NC, USA, 27858

* To whom correspondence should be addressed. E-mail: ajv22{at}cam.ac.uk.

Mice with a dominant-negative PPAR{gamma} mutation (P465L) unexpectedly had normal amounts of adipose tissue. Here we investigate the adipose tissue of the PPAR{gamma} P465L mouse in detail. Microscopic analysis of interscapular adipose tissue of P465L PPAR{gamma} mice revealed brown adipocytes with larger unilocular lipid droplets, indicative of reduced thermogenic capacity. Under conditions of cold exposure the BAT of the PPAR{gamma} P465L mice was less active, a fact reflected in decreased UCP1 protein levels. Analysis of the white adipocytes confirmed their normal cytoarchitecture and development, yet classical white adipose depots of the P465L PPAR{gamma} 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 PPAR{gamma} 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 non-shivering 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 PPAR{gamma} function for development than white adipose tissue, an observation that may be relevant when considering PPAR{gamma} dependent strategies for the treatment of obesity.






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