Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators.
Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators.
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Nampt激活剂P7C3通过调节细胞代谢和脂质介质改善糖尿病和骨骼肌功能。
DOI：
10.1002/jcsm.12887
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Tipparaju SM
中科院分区：
文献类型：
--
作者：
Manickam R;Tur J;Badole SL;Chapalamadugu KC;Sinha P;Wang Z;Russ DW;Brotto M;Tipparaju SM
烟酰胺磷酸核糖转移酶（Nampt）是NAD补救途径中的关键酶，在代谢性疾病中表达降低，但其在骨骼肌功能中的确切作用尚不清楚。我们测试了P7 C3（3，6-二溴-α-[（苯氨基）甲基]-9H-咔唑-9-乙醇）激活Nampt可改善糖尿病和肌肉功能的假设。我们评估了2型糖尿病（db/db）小鼠骨骼肌中P7 C3治疗的功能、形态、生化和分子效应。Nampt+/-小鼠用于测试P7 C3的特异性。与野生型小鼠相比，糖尿病小鼠的胰岛素抵抗增加了1.6倍，并且在用P7 C3治疗4周后挽救了糖尿病（P < 0.05）。在db-P7 C3小鼠中，与C57 Bl/6 J野生型未处理对照小鼠相比，空腹血糖水平降低至0.96倍。在胰岛素和葡萄糖耐量试验中，沿着db‐ P7 C3小鼠中胰岛素分泌（1.76倍）和胰腺β细胞（3.92倍）增加，120 min时血糖水平分别降低至0.6倍和0.54倍。在db‐ P7 C3小鼠中，前肢和后肢握力分别增加至1.13倍和1.17倍，自愿跑轮距离增加14.2倍。P7 C3治疗导致胫骨前肌（TA）的中型和大型肌纤维横截面积增加1.4倍和7.1倍，同时较小尺寸的肌纤维减少0.5倍。透射电子显微镜图像还显示，与db‐Veh小鼠相比，db‐ P7 C3小鼠的趾长伸肌肌纤维直径增加1.67倍，线粒体面积减少2.9倍。在db-P7 C3 TA肌肉中，SDH阳性肌纤维的数量增加至1.74倍。腓肠肌和TA肌肉显示慢氧化肌球蛋白重链1型（MyHC 1）肌纤维表达（0.46倍）和免疫染色（6.4倍）分别减少。qPCR分析显示，在db‐ P7 C3小鼠中，Pdk 4和Cpt 1增加2.9倍和1.3倍，Fgf 21和16 S减少0.55倍和0.59倍。在db‐Veh小鼠中，Fabp 1和CD 36也增加了3.3倍和1.9倍。RNA-seq差异基因表达火山图显示db-P7 C3小鼠中有1415个基因上调，1726个基因下调（P < 0.05）。在db‐ P7 C3小鼠中，血清HDL升高1.02倍，低密度脂蛋白/极低密度脂蛋白比值降低0.9倍。腓肠肌的脂质分析显示，db-P7 C3小鼠中炎性脂质介质n-6、AA（0.83倍）和n-3、DHA（0.69倍）和EPA（0.81倍）减少，内源性大麻素2-AG减少0.66倍，AEA增加2.0倍。总之，我们证明P7 C3激活Nampt，改善db/db小鼠的2型糖尿病和骨骼肌功能。
Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6‐dibromo‐α‐[(phenylamino)methyl]‐9H‐carbazol‐9‐ethanol) ameliorates diabetes and muscle function. We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice. Nampt+/− mice were utilized to test the specificity of P7C3. Insulin resistance increased 1.6‐fold in diabetic mice compared with wild‐type mice and after 4 weeks treatment with P7C3 rescued diabetes (P < 0.05). In the db‐P7C3 mice fasting blood glucose levels decreased to 0.96‐fold compared with C57Bl/6J wild‐type naïve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6‐fold and 0.54‐folds, respectively, at 120 min along with an increase in insulin secretion (1.76‐fold) and pancreatic β‐cells (3.92‐fold) in db‐P7C3 mice. The fore‐limb and hind‐limb grip strengths were increased to 1.13‐fold and 1.17‐fold, respectively, together with a 14.2‐fold increase in voluntary running wheel distance in db‐P7C3 mice. P7C3 treatment resulted in a 1.4‐fold and 7.1‐fold increase in medium‐sized and larger‐sized myofibres cross‐sectional area, with a concomitant 0.5‐fold decrease in smaller‐sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67‐fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9‐fold decrease in mitochondrial area in db‐P7C3 mice compared with db‐Veh mice. The number of SDH positive myofibres were increased to 1.74‐fold in db‐P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46‐fold) and immunostaining (6.4‐fold), respectively. qPCR analysis displayed a 2.9‐fold and 1.3‐fold increase in Pdk4 and Cpt1, and 0.55‐fold and 0.59‐fold decrease in Fgf21 and 16S in db‐P7C3 mice. There was also a 3.3‐fold and 1.9‐fold increase in Fabp1 and CD36 in db‐Veh mice. RNA‐seq differential gene expression volcano plot displayed 1415 genes to be up‐regulated and 1726 genes down‐regulated (P < 0.05) in db‐P7C3 mice. There was 1.02‐fold increase in serum HDL, and 0.9‐fold decrease in low‐density lipoprotein/very low‐density lipoprotein ratio in db‐P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n‐6; AA (0.83‐fold), and n‐3; DHA (0.69‐fold) and EPA (0.81‐fold), and a 0.66‐fold decrease in endocannabinoid 2‐AG and 2.0‐fold increase in AEA in db‐P7C3 mice. Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db/db mice.
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影响因子：
29
作者：
Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
通讯作者：
Baur JA
DOI：
10.1046/j.1365-201x.2003.01162.x
发表时间：
2003-08-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
Hegarty, BD;Furler, SM;Kraegen, EW
通讯作者：
Kraegen, EW
影响因子：
7.7
作者：
Lee YS;Li P;Huh JY;Hwang IJ;Lu M;Kim JI;Ham M;Talukdar S;Chen A;Lu WJ;Bandyopadhyay GK;Schwendener R;Olefsky J;Kim JB
通讯作者：
Kim JB
影响因子：
3
作者：
Marrelli, Mauro Toledo;Wang, Zhiying;Brotto, Marco
通讯作者：
Brotto, Marco
影响因子：
4
作者：
Jensen J;Rustad PI;Kolnes AJ;Lai YC
通讯作者：
Lai YC