Peroxisome proliferator-activated receptor-gamma-mediated positive energy balance in the rat is associated with reduced sympathetic drive to adipose tissues and thyroid status

Endocrinology. 2008 May;149(5):2121-30. doi: 10.1210/en.2007-1553. Epub 2008 Jan 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / innervation*
  • Adipose Tissue / metabolism
  • Adrenergic Fibers / drug effects*
  • Adrenergic Fibers / physiology
  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Body Weight / drug effects
  • Eating / drug effects
  • Energy Metabolism / drug effects*
  • Energy Metabolism / physiology
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Injections, Intraventricular
  • Ion Channels / metabolism
  • Male
  • Mice
  • Mitochondrial Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Rosiglitazone
  • Thermogenesis / drug effects
  • Thermogenesis / genetics
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / pharmacokinetics
  • Thiazolidinediones / pharmacology*
  • Thyroid Gland / drug effects
  • Thyroid Gland / physiology*
  • Uncoupling Protein 1
  • Up-Regulation / drug effects


  • Ion Channels
  • Mitochondrial Proteins
  • Nerve Tissue Proteins
  • PPAR gamma
  • Thiazolidinediones
  • Uncoupling Protein 1
  • cocaine- and amphetamine-regulated transcript protein
  • Rosiglitazone