PPAR gamma activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1 alpha and D2

Festuccia WT, Blanchard PG, Oliveira TB, Magdalon J, Paschoal VA, Richard D, Deshaies Y. PPAR gamma activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1 alpha and D2. Am J Physiol Regul Integr Comp Physiol 303: R1277-R1285, 2012. First published October 24, 2012; doi:10.1152/ajpregu.00299.2012.-Here, we investigated whether pharmacological PPAR gamma activation modulates key early events in brown adipose tissue (BAT) recruitment induced by acute cold exposure with the aim of unraveling the interrelationships between sympathetic and PPAR gamma signaling. Sprague-Dawley rats treated or not with the PPAR gamma ligand rosiglitazone (15 mg.kg(-1).day(-1), 7 days) were kept at 23 degrees C or exposed to cold (5 degrees C) for 24 h and evaluated for BAT gene expression, sympathetic activity, thyroid status, and adrenergic signaling. Rosiglitazone did not affect the reduction in body weight gain and the increase in feed efficiency, VO2, and BAT sympathetic activity induced by 24-h cold exposure. Rosiglitazone strongly attenuated the increase in serum total and free T4 and T3 levels and BAT iodothyronine deiodinase type 2 (D2) and PGC-1 alpha mRNA levels and potentiated the reduction in BAT thyroid hormone receptor (THR) beta mRNA levels induced by cold. Administration of T3 to rosiglitazone-treated rats exacerbated the cold-induced increase in energy expenditure but did not restore a proper activation of D2 and PGC-1 alpha, nor further increased uncoupling protein 1 expression. Regarding adrenergic signaling, rosiglitazone did not affect the changes in BAT cAMP content and PKA activity induced by cold. Rosiglitazone alone or in combination with cold increased CREB binding to DNA, but it markedly reduced the expression of one of its major coactivators, CREB binding protein. In conclusion, pharmacological PPAR gamma activation impairs short-term cold elicitation of BAT adrenergic and thyroid signaling, which may result in abnormal tissue recruitment and thermogenic activity.

beta(1) Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice

Brown adipose tissue (BAT) is predominantly regulated by the sympathetic nervous system (SNS) and the adrenergic receptor signaling pathway. Knowing that a mouse with triple beta-receptor knockout (KO) is cold intolerant and obese, we evaluated the independent role played by the beta(1) isoform in energy homeostasis. First, the 30 min i.v. infusion of norepinephrine (NE) or the beta(1) selective agonist dobutamine (DB) resulted in similar interscapular BAT (iBAT) thermal response in WT mice. Secondly, mice with targeted disruption of the beta(1) gene (KO of beta(1) adrenergic receptor (beta 1KO)) developed hypothermia during cold exposure and exhibited decreased iBAT thermal response to NE or DB infusion. Thirdly, when placed on a high-fat diet (HFD; 40% fat) for 5 weeks, beta 1KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis as assessed by BAT Ucp1 mRNA levels and oxygen consumption. Furthermore, beta 1KO mice exhibited fasting hyperglycemia and more intense glucose intolerance, hypercholesterolemia, and hypertriglyceridemia when placed on the HFD, developing marked non-alcoholic steatohepatitis. In conclusion, the beta(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis. Journal of Endocrinology (2012) 214, 359-365