Peroxisome Proliferator-Activated Receptor γ Agonism Increases the Capacity for Sympathetically Mediated Thermogenesis in Lean andob/obMice

Abstract

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…expression of lipases and other lipolysis-related proteins), thus allowing it to respond more robustly to adrenergic stimulation. Such amplification of the lipolytic potential by PPARγ agonism strikingly resembles that of the thermogenic potential reported in our previous study [35].…”

“…That DBcAMP was approximately as efficient as noradrenaline in stimulating lipolysis excludes the possibility of increased β-adrenergic receptor functionality and signal transduction as a mechanism of action of rosiglitazone on lipolysis. Such a conclusion is further supported by the mild downregulatory action of PPARγ agonism on β 3 -receptor expression [35]. Instead, it appears that rosiglitazone increases levels of components of the lipolytic machinery (e.g.…”

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…A first level of interaction is the expression level of the PPARg receptor itself, known to be upregulated by GC 27 and downregulated by its own agonists, 11,28 and that of 11b-HSD1, which is subject to feed-forward regulation by GC 29 and inhibition by PPARg agonism. 16 The present study confirms the downregulation of PPARg expression by its own agonists, and shows that chronic exposure to high levels of CORT did not affect PPARg expression or its agonist-mediated reduction, at least over the short time period studied here.…”

Brown and beige fat: development, function and therapeutic potential

“…Activation of Ppar-γ by synthetic TZD agonists enhances thermogenic gene expression in both white and brown adipocytes 12,[118][119][120][121][122] . TZDs induce UCP1 expression and increase mitochondrial biogenesis in adipocytes from mice and humans 12,36,123 .…”