Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase

Abstract

Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

“…We exclusively investigated here the role of the mevalonate pathway in mature brown adipocytes and in the conversion of white into brown adipocytes, and we could show that statins reduce thermogenic function and PPARg levels, without affecting the number of differentiated cells. We have recently shown that PPARg is required to maintain the thermogenic capacity of mature brown adipocytes (Lasar et al, 2018); thus it is possible that statins inhibit BAT function through regulation of this factor.…”

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

“…Brown adipose tissue (BAT)-specific GR-knockout mice (GR BATKO ) were generated by crossing Ucp1Cre ERT2 mice [36,37] with floxed GR mice. Knockout was induced in adult male animals by injection with 2 mg tamoxifen per day, for five consecutive days.…”

The role of DNA methylation in thermogenic adipose biology

“…Another protein involved in transgenerational regulation is PPARγ, which is the master transcription factor for both white and brown adipogenesis and is involved in brown adipocyte development and thermogenic gene regulation [64,65]. Offspring with obese mothers have persistently lower PPARγ expression due to higher epigenetic repression, such as DNA hypermethylation and fewer active histone markers, at the Pparg promoter region [66].…”