Circadian Rhythm Gene Period 3 Is an Inhibitor of the Adipocyte Cell Fate

Abstract

Glucocorticoids rapidly and robustly induce cell fate decisions in various multipotent cells, although the precise mechanisms of these important cellular events are not understood. Here we showed that glucocorticoids repressed Per3 expression and that this repression was critical for advancing mesenchymal stem cells to the adipocyte fate. Exogenous expression of Per3 inhibited adipogenesis, whereas knocking out Per3 enhanced that fate. Moreover, we found that PER3 formed a complex with PPAR␥ and inhibited PPAR␥-mediated transcriptional activation via Ppar␥ response elements. Consistent with these findings, Per3 knock-out mice displayed alterations in body composition, with both increased adipose and decreased muscle tissue compared with wild-type mice. Our findings identify Per3 as potent mediator of cell fate that functions by altering the transcriptional activity of PPAR␥.Glucocorticoids play a critical role in inducing the adipocyte cell fate and differentiation both in vivo and ex vivo (1-3). This regulatory process may be relevant to normal physiology and to disease states, as patients exposed chronically to excess glucocorticoids develop increased adiposity (4). Thus, glucocorticoids together with their cognate glucocorticoid receptor protein serve as powerful biological probes of the molecular pathways that govern this subset of cell fate and differentiation decisions. Studies of glucocorticoid receptor action in physiologic processes might eventually advance development of novel therapeutic agents for a broad array of diseases, including those that accompany obesity, such as diabetes and metabolic syndrome (insulin resistance, hypertension, dyslipidemia) (5). Therefore, to discern molecular mechanisms driving adipocyte fate and differentiation, we sought to identify glucocorticoid-regulated target genes whose products participate directly in these decisions and to characterize their activities.Mesenchymal stem cells, also called mesenchymal stem cells (MSCs), 6 are progenitor cells that reside in the bone marrow and vascular wall and are capable of differentiating into cells that form cartilage, muscle, bone, or fat (6 -8). MSCs are readily isolated and maintain their multipotency when purified ex vivo in tissue culture (9). Induction of MSC fate determination into distinct lineages can be initiated with defined reagents and monitored at the molecular level. In particular, glucocorticoids potently induce the adipocyte cell fate in these cells, thus, providing a well defined experimental starting point for analyses of mammalian cell fate decisions (10, 11) and for identifying mechanisms by which glucocorticoids control these decisions.As in other tissues (12-16), glucocorticoids modulate in primary MSCs the expression of various genes that control circadian rhythm (17). Interestingly, clock components affect adipogenesis (18, 19), although the mechanism of this connection is poorly understood. In view of these findings, we were curious to determine whether clock components play functional roles in the glu...

Immunometabolism: Is it under the eye of the clock?

“…Per3 deletion also leads to enhanced adipogenesis while ectopic expression of PER3 inhibits it [140]. Global Per3 knock out mice exhibit increased deposits of adipose tissue and reduced muscle tissue in comparison to wild-type mice [140]. PER proteins have also been linked to glucose storage with Per2-/-mice exhibiting a loss of rhythmic glycogen accumulation in the liver, impaired gluconeogenesis and elevated plasma insulin levels [141][142][143].…”

“…This was due to PER2 mediated suppression of Peroxisome proliferator-activated receptor gamma (PPAR␥), a nuclear receptor that is crucial in adipogenesis [139]. Per3 deletion also leads to enhanced adipogenesis while ectopic expression of PER3 inhibits it [140]. Global Per3 knock out mice exhibit increased deposits of adipose tissue and reduced muscle tissue in comparison to wild-type mice [140].…”

Per3 length polymorphism in patients with type 2 diabetes mellitus

“…Per3 could also have a possible functional role in the regulation of adipogenesis as constitutive expression of Per3 blocked the process of adipogenesis in mesenchymal stem cells, whereas elimination of Per3 promoted it [11]. Moreover, Per3 mutant mice exhibited a remarkable difference in their body mass and body composition [26] and had more adipose tissue content than wild type mice [11].…”

“…Although knowledge of Per3's role as a component of time-keeping system in humans is limited, a number of reports indicate that hPer3 can be involved in the functioning of sleep [8,24,25] and of certain metabolic processes [11,26]. Per3 alleles seem to influence sleep homeostasis and sleep/wake timing in individuals [8,9] and a strong correlation has been found between the amount of sleep time and Per3 protein secretion in individuals [27].…”

“…In Per3 mutant mice, circadian period and phase underwent changes in liver and other peripheral tissues [10]. Per3 has also been reported to regulate adipocyte fate [11].…”