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Decreased Brown Adipocyte Recruitment and Thermogenic Capacity in Mice with Impaired Peroxisome Proliferator-Activated Receptor (P465L PPAR) Function

Departments of Clinical Biochemistry (S.L.G., E.D.N., S.V., S.O., A.V.-P.) and Medicine (S.O., A.V.-P.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom; The Wenner-Gren Institute (E.C.B., B.C.), The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden; Department of Normal Human Morphology (M.M., S.C.), Faculty of Medicine, Ancona University, 60020 Ancona, Italy; and Ward Sports Medicine Building and Brody School of Medicine (R.C.N., R.N.C.), Departments of Exercise and Sport Science and Physiology, East Carolina University, Greenville, North Carolina 27858

Address all correspondence and requests for reprints to: Antonio Vidal-Puig, Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom. E-mail: ajv22{at}cam.ac.uk.

Mice with a dominant-negative peroxisome proliferator-activated receptor (PPAR) mutation (P465L) unexpectedly had normal amounts of adipose tissue. Here, we investigate the adipose tissue of the PPAR P465L mouse in detail. Microscopic analysis of interscapular adipose tissue of P465L PPAR 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 PPAR 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 PPAR 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 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 PPAR function for development than white adipose tissue, an observation that may be relevant when considering PPAR-dependent strategies for the treatment of obesity.