Peroxisome proliferator-activated receptor-gamma-mediated positive energy balance in the rat is associated with reduced sympathetic drive to adipose tissues and thyroid status.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPARgamma activation. Administration of the PPARgamma agonist rosiglitazone (15 mg/kg.d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT (>50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T(4) and T(3)) and mRNA levels of BAT and liver T(3)-generating enzymes iodothyronine type 2 (-40%) and type 1 (-32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms alpha1 (-34%) and beta (-66%) in BAT and isoforms alpha1 (-20%) and alpha2 (-47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNA levels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPARgamma-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo.
Festuccia
William T
WT
Laval Hospital Research Centre, Faculty of Medicine, Laval University, Laval Hospital-d'Youville Y3110, 2725 Chemin Sainte-Foy, Quebec, Canada G1V 4G5.
Oztezcan
Serdar
S
Laplante
Mathieu
M
Berthiaume
Magalie
M
Michel
Chantal
C
Dohgu
Shinya
S
Denis
Raphaël G
RG
Brito
Marcia N
MN
Brito
Nilton A
NA
Miller
David S
DS
Banks
William A
WA
Bartness
Timothy J
TJ
Richard
Denis
D
Deshaies
Yves
Y
D000273:Adipose Tissue / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D000320:Adrenergic Fibers / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D022722:Thermogenesis / Q000187:drug effects / Q000235:genetics; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013961:Thyroid Gland / Q000187:drug effects / Q000502:physiology*; D000071256:Uncoupling Protein 1; D015854:Up-Regulation / Q000187:drug effects; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D007473:Ion Channels; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000071256:Uncoupling Protein 1; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D000077154:Rosiglitazone