title: COH-SR4 reduces body weight, improves glycemic control and prevents hepatic steatosis in high fat diet-induced obese mice.
abstract: Obesity is a chronic metabolic disorder caused by imbalance between energy intake and expenditure, and is one of the principal causative factors in the development of metabolic syndrome, diabetes and cancer. COH-SR4 ("SR4") is a novel investigational compound that has anti-cancer and anti-adipogenic properties. In this study, the effects of SR4 on metabolic alterations in high fat diet (HFD)-induced obese C57BL/J6 mice were investigated. Oral feeding of SR4 (5 mg/kg body weight.) in HFD mice for 6 weeks significantly reduced body weight, prevented hyperlipidemia and improved glycemic control without affecting food intake. These changes were associated with marked decreases in epididymal fat mass, adipocyte hypertrophy, increased plasma adiponectin and reduced leptin levels. SR4 treatment also decreased liver triglycerides, prevented hepatic steatosis, and normalized liver enzymes. Western blots demonstrated increased AMPK activation in liver and adipose tissues of SR4-treated HFD obese mice, while gene analyses by real time PCR showed COH-SR4 significantly suppressed the mRNA expression of lipogenic genes such as sterol regulatory element binding protein-1c (Srebf1), acetyl-Coenzyme A carboxylase (Acaca), peroxisome proliferator-activated receptor gamma (Pparg), fatty acid synthase (Fasn), stearoyl-Coenzyme A desaturase 1 (Scd1), carnitine palmitoyltransferase 1a (Cpt1a) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr), as well as gluconeogenic genes phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc) in the liver of obese mice. In vitro, SR4 activates AMPK independent of upstream kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). Together, these data suggest that SR4, a novel AMPK activator, may be a promising therapeutic compound for treatment of obesity, fatty liver disease, and related metabolic disorders.
authors.affiliation: Departments of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: James Lester
authors.initials: JL
authors.lastname: Figarola
authors.affiliation: Departments of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singhal
authors.affiliation: Departments of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rahbar
authors.affiliation: Immunology and Mass Spectrometry and Proteomics Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Bogdan Gabriel
authors.initials: BG
authors.lastname: Gugiu
authors.affiliation: Departments of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America ; Medical Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.affiliation: Departments of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects*; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000009:adverse effects*; D050171:Dyslipidemias / Q000188:drug therapy; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006984:Hypertrophy; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000517:prevention & control*; D009765:Obesity / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
chemical_list: C577482:1,3-bis(3,5-dichlorophenyl)urea; D054392:Adipokines; D001786:Blood Glucose; D010671:Phenylurea Compounds; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases