A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation

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Direct action of capsaicin in brown adipogenesis and activation of brown adipocytes

The ingestion of capsaicin, the principle pungent component of red and chili peppers, induces thermogenesis, in part, through the activation of brown adipocytes expressing genes related to mitochondrial biogenesis and uncoupling such as peroxisome proliferator‐activated receptor (Ppar) γ coactivator‐1α (Pgc‐1α) and uncoupling protein 1 (Ucp1). Capsaicin has been suggested to induce the activation of brown adipocytes, which is mediated by the stimulation of sympathetic nerves. However, capsaicin may directly affect the differentiation of brown preadipocytes, brown adipocyte function, or both, through its significant absorption. We herein demonstrated that Trpv1, a capsaicin receptor, is expressed in brown adipose tissue, and that its expression level is increased during the differentiation of HB2 brown preadipocytes. Furthermore, capsaicin induced calcium influx in brown preadipocytes. A treatment with capsaicin in the early stage of brown adipogenesis did not affect lipid accumulation or the expression levels of Fabp4 (a gene expressed in mature adipocytes), Pparγ2 (a master regulator of adipogenesis) or brown adipocyte‐selective genes. In contrast, a treatment with capsaicin in the late stage of brown adipogenesis slightly increased the expression levels of Fabp4, Pparγ2 and Pgc‐1α. Although capsaicin did not affect the basal expression level of Ucp1, Ucp1 induction by forskolin was partially inhibited by capsaicin, irrespective of the dose of capsaicin. The results of the present study suggest the direct effects of capsaicin on brown adipocytes or in the late stage of brown adipogenesis.     

Changes in osteoblast, chondrocyte, and adipocyte lineages mediate the bone anabolic actions of PTH and small molecule GSK-3 inhibitor

Parathyroid hormone (PTH) and glycogen synthase kinase-3 (GSK-3) inhibitor 603281-31-8, administered once daily increased bone formation in vivo. We investigated the molecular mechanisms of the anabolic responses of PTH and 603281-31-8 in rat osteopenia model. Female 6-month-old rats were ovariectomized (Ovx) and permitted to lose bone for 1 month, followed by treatment with PTH (1-38) at 10 microg/kg/day s.c. or 603281-31-8 at 3 mg/kg/day p.o. for 60 days. Twenty-four hours after the last treatment, RNA from distal femur metaphysis was subjected to gene expression analysis. Differentially expressed genes (P<0.05) were subjected to pathway analysis to delineate relevant bio-processes involved in skeletal biology. Genes involved in morphogenesis, cell growth/differentiation, and apoptosis were significantly altered by Ovx and the treatments. Analysis of morphogenesis genes showed an overrepresentation of genes involved in osteogenesis, chondrogenesis, and adipogenesis. A striking finding was that Ovx decreased several markers of osteogenesis/chondrogenesis and increased markers of adipogenesis/lipid metabolism. Treatment with either PTH or the GSK-3 inhibitor reversed these effects, albeit at different levels. Histological analysis confirmed that osteopenia in Ovx animals was associated with three-fold increase in marrow adiposity. PTH and GSK-3 inhibitor restored bone volume, and reversed or normalized marrow adiposity. Ex vivo studies showed that PTH and GSK-3 inhibitor increased the ratio of colony forming marrow stromal progenitors (CFU-fs) that were alkaline phosphatase positive (putative osteoblasts). Our results suggest that the bone anabolic actions of PTH and GSK-3 inhibitor in vivo involve concerted effects on mesenchymal lineages; osteoblasts, chondrocytes, and adipocytes.     

Amplification of Adipogenic Commitment by VSTM2A

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De novo adipogenesis for reconstructive surgery

Autografting of lost soft tissue is an important subject of the plastic and reconstructive surgery and autograft of fat pads has been only technique for this goal. However, the results are disappointing because of absorption of the grafts with time. Adipoblasts or adipocyte precursor cells distribute widely in connective tissues and they can proliferate and mature into adipocytes even in the adult body. In experiments using mice, we found that de novo adipogenesis of endogenous precursor cells can be induced by injecting reconstituted basement membrane, Matrigel, supplemented with more than 1 ng/ml of bFGF. This adipogenesis was reproducibly induced by subcutaneous injection over the chest, lateral abdomen or head. Adipogenesis was induced even in ear cartilage or in muscle. To evaluate the possibility of future application of this de novo adipogenesis to plastic and reconstructive surgery, we have reviewed updated knowledge of the adipogenesis. This revised version was published online in August 2006 with corrections to the Cover Date.     

mTOR信号通路对脂肪生成的调控作用

脂肪组织是一种主要的能量储存和内分泌器官。脂肪生成是一系列复杂的细胞分化过程,受到细胞营养水平、激素和代谢物等调节。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)复合物包括哺乳动物雷帕霉素靶蛋白复合体1(mammalian target of rapamycin complex 1,mTORC1)和mTORC2两种蛋白质复合体。mTOR复合物含有的脂质激酶样域奠定了mTOR通路调控脂肪生成的基础。对mTORC1和mTORC2的部分组成蛋白质研究也验证了mTOR调控成脂的功能。基于前期的研究,我们综述了miR-199a-3p、miR-103、miR-188、68 kD有丝分裂中的Src相关底物(Src-associated substrate in mitosis of 68 kD,Sam68)、内皮抑素等物质通过mTORC1和mTORC2蛋白质复合体调控脂肪生成的机制。同时,进一步构建了包括胰岛素/IGF通路、PI3K-AKT通路、氨基酸通路、AMPK通路、cAMP通路、cGMP通路、NOTCH通路以及影响上述通路的bta-miR-15...