Metabolic syndrome (MS) encompasses a clustering of risk factors for cardiovascular disease, including obesity, insulin resistance, and dyslipidemia. We characterized a new mouse model carrying a dominant mutation, C57BL/6J-Nmf15/+ (B6-Nmf15/+), which develops additional complications of MS such as adipose tissue inflammation and cardiomyopathy. A backcross was used to genetically map the Nmf15 locus. Mice were examined in the comprehensive laboratory animal monitoring system, and dual energy X-ray absorptiometry and blood chemistry analyses were performed. Hypothalamic LEPR, SOCS1, and STAT3 phosphorylation were examined. Cardiac function was assessed by echo- and electrocardiography. Adipose tissue inflammation was characterized by in situ hybridization and measurement of Jun kinase activity. The Nmf15 locus mapped to distal mouse chromosome 5 with an LOD (logarithm of odds) score of 13.8. Nmf15 mice developed obesity by 12 weeks of age. Plasma leptin levels were significantly elevated in pre-obese Nmf15 mice at 8 weeks of age and an attenuated STAT3 phosphorylation in the hypothalamus suggests a primary leptin resistance. Adipose tissue from Nmf15 mice showed a remarkable degree of inflammation and macrophage infiltration as indicated by expression of the F4/80 marker and increased phosphorylation of JUN N-terminal kinase 1/2. Lipidosis was observed in tubular epithelial cells and glomeruli of the kidney. Nmf15 mice demonstrate both histological and pathophysiological evidence of cardiomyopathy. The Nmf15 mouse model provides a new entry point into pathways mediating leptin resistance and obesity. It is one of few models that combine many aspects of MS and can be useful for testing new therapeutic approaches for combating obesity complications, particularly cardiomyopathy.
Yun Wang, Yue Zheng, Patsy M Nishina and Jürgen K Naggert
Yunshuang Yue, Yi Wang, Dan Li, Zhigang Song, Hongchao Jiao and Hai Lin
Bacterial lipopolysaccharide (LPS), also known as endotoxin, induces profound anorexia. However, the LPS-provoked pro-inflammatory signaling cascades and the neural mechanisms underlying the development of anorexia are not clear. Mammalian target of rapamycin (mTOR) is a key regulator of metabolism, cell growth, and protein synthesis. This study aimed to determine whether the mTOR pathway is involved in LPS-induced anorexia. Effects of LPS on hypothalamic gene/protein expression in mice were measured by RT-PCR or western blotting analysis. To determine whether inhibition of mTOR signaling could attenuate LPS-induced anorexia, we administered an i.c.v. injection of rapamycin, an mTOR inhibitor, on LPS-treated male mice. In this study, we showed that LPS stimulates the mTOR signaling pathway through the enhanced phosphorylation of mTORSer2448 and p70S6KThr389. We also showed that LPS administration increased the phosphorylation of FOXO1Ser256, the p65 subunit of nuclear factor kappa B (P<0.05), and FOXO1/3aThr 24 / 32 (P<0.01). Blocking the mTOR pathway significantly attenuated the LPS-induced anorexia by decreasing the phosphorylation of p70S6KThr389, FOXO1Ser256, and FOXO1/3aThr 24 / 32. These results suggest promising approaches for the prevention and treatment of LPS-induced anorexia.
Hai-Fan Yu, Zhan-Peng Yue, Kai Wang, Zhan-Qing Yang, Hong-Liang Zhang, Shuang Geng and Bin Guo
Although Gja1 has been proved to play an important role in uterine decidualization, its regulatory mechanism remains largely unknown. Here, we showed that Gja1 was highly expressed in the decidual cells and promoted the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1, which were two well-known differentiation markers for decidualization. Further analysis revealed that Gja1 might act downstream of Acvr1 and cAMP to regulate the differentiation of uterine stromal cells. Administration of cAMP analog 8-Br-cAMP to Acvr1 siRNA-transfected stromal cells resulted in an obvious increase of Gja1 expression, whereas PKA inhibitor H89 impeded the induction of Gja1 elicited by Acvr1 overexpression, indicating that cAMP–PKA signal mediates the regulation of Acvr1 on Gja1 expression. In uterine stromal cells, knockdown of Gja1 blocked the cAMP induction of Hand2. Moreover, siRNA-mediated downregulation of Hand2 impaired the stimulatory effects of Gja1 overexpression on the expression of Prl8a2 and Prl3c1, whereas constitutive expression of Hand2 reversed the inhibitory effects of Gja1 siRNA on stromal differentiation. Meanwhile, Gja1 might play a vital role in the crosstalk between Acvr1 and Hand2. Collectively, Gja1 may act downstream of cAMP–PKA signal to mediate the effects of Acvr1 on the differentiation of uterine stromal cells through targeting Hand2.
Yu Wang, Airong Wu, Liting Xi, Ji Yang, Wenjing Zhou, Yuming Wang, Shuang Liang, Weixin Yu, Yue Wang and Jinzhou Zhu
Can Liu, Mian Zhang, Meng-yue Hu, Hai-fang Guo, Jia Li, Yun-li Yu, Shi Jin, Xin-ting Wang, Li Liu and Xiao-dong Liu
Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in P. ginseng, have shown good antidiabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its antidiabetic effects via modulating GLP1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI-H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 or 300 mg/kg) daily for 4 weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase in glucose-induced GLP1 secretion and upregulation of proglucagon gene expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca2 + concentration. The metabolic inhibitor azide (3 mM), the KATP channel opener diazoxide (340 μM), and the Ca2 + channel blocker nifedipine (20 μM) significantly reversed Rb1-mediated GLP1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP1 secretion both in vivo and in vitro. The antidiabetic effects of ginsenosides may be a result of enhanced GLP1 secretion.