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Ontogenic Loss of Brown Adipose Tissue Sensitivity to ß-Adrenergic Stimulation in the Ovine

Divisions of Biomedical Science (M.A.L., G.K., A.K.) and Molecular Biology (F.S.), Imperial College, Wye Campus, Ashford, Kent TN25 5AH, United Kingdom; Liverpool Centre for Nutritional Genomics (P.T.), Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, University Clinical Departments, Liverpool L69 3GA, United Kingdom; and School of Biological Sciences (D.G.H.), University of Aberdeen, Aberdeen AB24 5UH, United Kingdom

Address all correspondence and requests for reprints to: M. A. Lomax, Division of Biomedical Science, Imperial College, Ashford, Kent TN25 5AH, United Kingdom. E-mail: m.lomax{at}imperial.ac.uk.

In ruminants and other large animals, expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) is confined to the perinatal period when it plays a key role in nonshivering thermogenesis. This study determined whether loss of expression of the BAT phenotype was due to reduced response to a ß-agonist, isoprenaline, and expression of the peroxisome proliferator-activated receptor (PPAR) family [PPAR, PPAR, PPAR coactivator 1 (PGC-1)], which regulates UCP1 gene expression. Perirenal adipose tissue (PAT) was sampled from ovine fetuses, newborn lambs, and lambs on d 1, 5, 7, and 21 of life. UCP1 mRNA and protein in PAT increased from d 123 of fetal life to reach a maximum at birth followed by a rapid decrease over the first 5 d of life. Expression of the coactivator, PGC-1 and PPAR , peaked between fetal day 123 and birth, and then declined to undetectable levels in the first days of life. In vivo administration of isoprenaline was able to induce expression of UCP1, PGC-1, and PPAR in BAT up to 5 d of age but thereafter was ineffective. In vitro addition of ß-receptor, PPAR, and PPAR agonists were unable to overcome the suppression of UCP1, PPAR, and PPAR expression observed in differentiated adipocytes prepared from 30-d-old compared with 1-d-old lambs. These data are consistent with a model in which postnatal loss of UCP1 expression and ß-adrenergic induction of the brown adipocyte phenotype is due to loss of expression of PGC-1 and PPAR.

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