It is proposed that various pathologies can be explained, at least in part, by overproduction and lack of degradation of H2O2 (tumorigenesis, myxedematous cretinism, and thyroiditis) and by failure of the H2O2 generation or its positive control system (congenital hypothyroidism).

SummaryThe increased incidence of obesity and metabolic disease underscores the importance of elucidating the biology of adipose tissue development. The recent discovery of cell surface markers for prospective identification of adipose precursor cells (APCs) in vivo will greatly facilitate these studies, yet tools for specifically targeting these cells in vivo have not been identified. Here, we survey three transgenic mouse lines, Fabp4-Cre, PdgfRα-Cre, and Prx1-Cre, precisely assessing Cre-mediated recombination in adipose stromal populations and mature tissues. Our data provide key insights into the utility of these tools to modulate gene expression in adipose tissues. In particular, Fabp4-Cre is not effective to target APCs, nor is its activity restricted to these cells. PdgfRα-Cre directs recombination in the vast majority of APCs, but also targets other populations. In contrast, adipose expression of Prx1-Cre is chiefly limited to subcutaneous inguinal APCs, which will be valuable for dissection of APC functions among adipose depots.

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...

Summary The generation of new adipocytes from precursor cells (adipogenesis) has implications for systemic metabolism and is a commonly used model for studying the process of cell differentiation in vitro. Previous studies from us, and others, suggested that the peripheral circadian clock can influence adipogenesis in vitro, but the mechanisms driving this activity and the relevance for adipogenesis in vivo are unknown. Here we reveal that mouse adipocyte precursor cells (APCs) contain a circadian clock that oscillates in vivo. We expose context-specific features of the clock in APCs: expression of the canonical core clock component Per1 does not significantly oscillate, whereas the lesser-understood paralog Per3 has a prominent rhythm. We discovered that deletion of Per3 promotes adipogenesis in vivo by a clock output pathway in which PER3 and BMAL1 directly regulate Klf15 expression. These findings demonstrate that Per3 has a major role in the APC clock and regulates adipogenesis in vivo.

The IPR/Pre-Natal index effectively incorporated quantitative and qualitative elements for the assessment of pre-natal care.