Adiponectin has recently received a great deal of attention due to its beneficial effects on insulin resistance and metabolic disorders. One of the mechanisms through which adiponectin exerts such effects involves an increase in fatty acid oxidation in muscle and liver. In the present study, we demonstrate that 5-AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) are involved in the activation of peroxisome proliferator-activated receptor (PPAR)␣ by adiponectin in muscle cells. Adiponectin increases the transcriptional activity of PPAR␣ and the expression of its target genes, including ACO, CPT1, and FABP3 in C2C12 myotubes. These effects were suppressed by the overexpression of a dominant-negative form of AMPK. Moreover, chemical inhibitors of AMPK and p38 MAPK potently repressed fatty acid oxidation and the induction of PPAR␣ target gene expression by adiponectin. Interestingly, araA, an AMPK inhibitor, prevented the activation of p38 MAPK, whereas SB203580, a p38 MAPK inhibitor, did not affect AMPK activation, suggesting that p38 MAPK is a downstream signaling factor of AMPK. Taken together, these results suggest that adiponectin stimulates fatty acid oxidation in muscle cells by the sequential activation of AMPK, p38 MAPK, and PPAR␣.

Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies showing that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole-genome transcriptional profiling and compared senescent fibroblasts with their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNA interference did not affect senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, showing that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we show that OPN is expressed in senescent stroma within preneoplastic lesions that arise following 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatment of mice, suggesting that stromal-derived OPN-mediated signaling events affect neoplastic progression. [Cancer Res 2009;69(3):1230-9]

Specific cell type differentiation is driven by programmed regulation of gene expression, which is the result of coordinated modulation of the transcription machinery and chromatin-remodeling factors. We present evidence here that the down-regulation of histone deacetylases is an important process during adipocyte differentiation. In 3T3-L1 cells, histone hyperacetylation was selectively induced at the promoter regions of adipogenic genes during adipocyte differentiation. Interestingly, this was accompanied by a dramatic decrease in the expression level of several histone deacetylases including HDAC1, -2, and -5 and a reduction in overall histone deacetylase enzyme activity. Inhibition of histone deacetylase activity using sodium butyrate resulted in stimulation of adipogenic gene expression and adipocyte differentiation. Consistently, HDAC1 knock-down promoted adipogenesis whereas HDAC1 overexpression attenuated adipocyte differentiation in 3T3-L1 cells. Together, these results suggest that the regulation of not only adipogenic transcription factors, but also chromatin-modifying enzymes is crucial for the execution of bona fide adipogenesis.The architecture of the eukaryotic chromatin is dynamically modulated by post-translational modifications of the histones, including acetylation, methylation, phosphorylation, and ubiquitination (1). The changes in nucleosome structure influence gene expression by modulating the accessibility of the promoter regions to specific transcription factors. In particular, acetylation of histones H3 (Lys 9 and Lys 14 ) and H4 (Lys 8 and Lys 12 ), mediated by histone acetyltransferases (HATs) 4 such as p300, CBP, and P/CAF, is associated with transcriptional activation (2, 3). Methylation of H3 Lys 4 , H4 Arg 3 , and phosphorylation of H3 Ser 10 also results in gene activation (4 -7). In contrast, methylation of histone H3 Lys 9 generally correlates with gene repression (8, 9). Histone deacetylases (HDACs) repress gene expression by deacetylating histones and other proteins, such as transcription factors (10, 11). Until now, five yeast and eleven human HDACs have been identified, which are classified into three classes (12). Class I HDACs consist of HDAC1, -2, -3, and -8. HDAC 4, -5, -6, -7, -9, and -10 belong to the class II HDACs. Class III HDACs are members of the sirtuin family of HDACs (13-17). In addition, a new member of the HDAC family, HDAC11, has been recently identified (18). Class I HDACs are expressed ubiquitously, whereas class II HDACs are abundantly expressed in heart, skeletal muscle, and brain (12). The major function of HDACs is to remove acetyl groups from histones, which results in condensation of the chromatin structure. This, in turn, diminishes the access of transcription factors to the target DNA and ultimately leads to transcriptional repression.Chromatin modifications, notably histone acetylation and deacetylation, are crucial for the regulation of gene expression and development in eukaryotes (19,20). During tissue differentiation, early inductive processe...

BackgroundThe glomerulus is a specialized capillary bed that is involved in urine production and BP control. Glomerular injury is a major cause of CKD, which is epidemic and without therapeutic options. Single-cell transcriptomics has radically improved our ability to characterize complex organs, such as the kidney. Cells of the glomerulus, however, have been largely underrepresented in previous single-cell kidney studies due to their paucity and intractability.MethodsSingle-cell RNA sequencing comprehensively characterized the types of cells in the glomerulus from healthy mice and from four different disease models (nephrotoxic serum nephritis, diabetes, doxorubicin toxicity, and CD2AP deficiency).ResultsAll cell types in the glomerulus were identified using unsupervised clustering analysis. Novel marker genes and gene signatures of mesangial cells, vascular smooth muscle cells of the afferent and efferent arterioles, parietal epithelial cells, and three types of endothelial cells were identified. Analysis of the disease models revealed cell type–specific and injury type–specific responses in the glomerulus, including acute activation of the Hippo pathway in podocytes after nephrotoxic immune injury. Conditional deletion of YAP or TAZ resulted in more severe and prolonged proteinuria in response to injury, as well as worse glomerulosclerosis.ConclusionsGeneration of comprehensive high-resolution, single-cell transcriptomic profiles of the glomerulus from healthy and injured mice provides resources to identify novel disease-related genes and pathways.

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Liver X receptor (LXR)␣ and LXR␤ play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic ␤-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced ␤-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice.

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