Search Results

Adipose tissue expansion, resulting from adipocyte hyperplasia and/or hypertrophy, is a hallmark of obesity. Adipocytes are derived from mesenchymal stem cells (MSCs) through adipogenesis, a process involving three key steps: proliferation, commitment and differentiation. Although studies have elaborated on the mechanisms regulating adipocyte commitment and differentiation, the factors that control MSC proliferation remain largely unknown. Previously, we demonstrated that bone morphogenetic protein 3 (Bmp3), the expression of which was upregulated in our rat model of hyperplasic visceral adiposity, potently stimulated MSC proliferation. In the present study, we investigate the molecular target of Bmp3. We conducted DNA microarray analysis on MSCs treated with and without Bmp3 and identified WNT1-inducible signaling pathway protein 1 (Wisp1) as a differentially expressed gene, whose expression was upregulated 3.7-fold by Bmp3. Wisp1 is a proliferative agent in various non-adipose cell types and is implicated in adipogenesis. Therefore, we tested the hypothesis that Wisp1 mediates Bmp3 stimulation of MSC proliferation. We showed that Bmp3 increased the expression of Wisp1 as early as 3 h following Bmp3 treatment in MSCs. Importantly, the upregulated Wisp1 expression preceded Bmp3-induced MSC proliferation, as determined by [³H]-thymidine incorporation. Furthermore, treatment of MSCs with recombinant Wisp1 led to a concentration-dependent increase in [³H]-thymidine incorporation with a maximal increase of 300%. In addition, siRNA-mediated knockdown of Wisp1 expression attenuated Bmp3-induced MSC proliferation. Taken together, our present findings reveal Wisp1 as a novel target of Bmp3 and suggest that the Bmp3/Wisp1 signaling pathway play a key role in MSC proliferation, and consequently adipogenesis.

The mechanisms of hypothalamic–pituitary–adrenal (HPA) axis regulation have been studied persistently but still are not elucidated. Considering the emerging roles of microRNA in stress response, we conducted a microRNA microarray in mice hypothalamus to identify the potential role of microRNAs in regulating the HPA axis. In total, 41 microRNAs changed during heat stress in which we found that miR-212 contains a binding sequence with corticotropin-releasing hormone (Crh) 3′UTR according to a sequence analysis. We observed that miR-212 expression in the hypothalamus was escalated by repeated heat and restraint stress. By overexpression or inhibition of miR-212 and the dual-luciferase reporter assay, we proved that miR-212 could bind with Crh 3′UTR to regulate its expression in mice hypothalamus primary cells and in the hippocampus neuron cell line HT-22. In addition, we injected miR-212 agomir or antagomir in mice hypothalamus to overexpress or inhibit miR-212, which leads to alterations of CRH expression and HPA axis activity in vivo. Furthermore, miR-212 and CRH were both transcribed by the cAMP response element-binding protein (CREB). Overexpression and inhibition of miR-212 affect CREB-dependent CRH expression. Taken together, our results suggest an inhibitory role of miR-212 on the HPA axis, which acts in a counter-regulatory manner.

Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3's activity both in vitro and in cardiomyocytes in vivo. MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner.