title: Novel small-molecule PGC-1α transcriptional regulator with beneficial effects on diabetic db/db mice.
abstract: Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1α expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1α mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1α expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1α and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1α and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1α in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. jli@mail.shcnc.ac.cn
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhang
authors.forename: Hua-Yong
authors.initials: HY
authors.lastname: Zhou
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Fu
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Gu
authors.forename: Ling-Yan
authors.initials: LY
authors.lastname: Wu
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Xia
authors.forename: Tian-Cheng
authors.initials: TC
authors.lastname: Dong
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Li
authors.forename: Jing-Kang
authors.initials: JK
authors.lastname: Shen
authors.forename: Jia
authors.initials: J
authors.lastname: Li
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D050171:Dyslipidemias; D005786:Gene Expression Regulation / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D018149:Glucose Intolerance; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D015394:Molecular Structure; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011897:Random Allocation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D001562:Benzimidazoles; D007004:Hypoglycemic Agents; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C581161:ZLN005