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RISS 인기검색어
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- 저자 : Lin Ligen (검색결과 3 건)
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Lin, Ligen,Lee, Jong Han,Wang, Ruitao,Wang, Ru,Sheikh‐,Hamad, David,Zang, Qun S.,Sun, Yuxiang MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.10
<P>Ghrelin via its receptor, the growth hormone secretagogue receptor (GHS-R), increases food intake and adiposity. The tissue-specific functions of GHS-R in peripheral tissues are mostly unknown. We previously reported that while GHS-R expression is very low in white and brown fat of young mice, expression increases during aging. To investigate whether GHS-R has cell-autonomous effects in adipose tissues, we generated <I>aP2</I>-Cre-mediated GHS-R knockdown mice (<I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I>). We studied young (5–6 months) and old (15–17 months) <I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I> mice and their age-matched controls. Interestingly, young <I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I> mice had normal body weight but reduced fat; old mice showed pronounced reductions of both body weight and body fat. Calorimetry analysis revealed that <I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I> mice had normal food intake and locomotor activity at both young and old age; but intriguingly, while energy expenditure was normal at young age, it was significantly increased at old age. Both young and old <I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I> mice exhibited improved insulin sensitivity and glucose tolerance. Importantly, old <I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I> mice maintained higher core body temperature at 4 °C, and showed higher expression of the thermogenic uncoupling protein 1 (<I>UCP1</I>) gene. The ex vivo studies further demonstrated that GHS-R deficient white adipocytes from old mice exhibit increased glucose uptake and lipolysis, promoting lipid mobilization. Despite the fact that the in vivo phenotypes of <I>aP2</I>-Cre/<I>Ghsr<SUP>f/f</SUP></I> mice may not be exclusively determined by GHS-R knockdown in adipose tissues, our data support that GHS-R has cell-autonomous effects in adipocytes. The anabolic effect of GHS-R in adipocytes is more pronounced in aging, which likely contributes to age-associated obesity and insulin resistance.</P>
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Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis
Wu, Chia-Shan,Bongmba, Odelia Y. N.,Yue, Jing,Lee, Jong Han,Lin, Ligen,Saito, Kenji,Pradhan, Geetali,Li, De-Pei,Pan, Hui-Lin,Xu, Allison,Guo, Shaodong,Xu, Yong,Sun, Yuxiang MDPI AG 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.4
<P>Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (<I>AgRP-Cre</I>;<I>Ghsr<SUP>f/f</SUP></I>). Our data showed that GHS-R in AgRP neurons is required for ghrelin’s stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.</P>
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Li Guodong,Li Dan,Wu Chun,Li Shengnan,Chen Feng,Li Peng,Ko Chung-Nga,Wang Wanhe,Lee Simon Ming-Yuen,Lin Ligen,Ma Dik-Lung,Leung Chung-Hang 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-
In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7_1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7_1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7_1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7_1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7_1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity.
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