title: Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating the IRS-1/PI3K/Akt and AMPK/ACC2 signaling pathways.
abstract: OBJECTIVE
  We have shown that rutaecarpine extracted from the dried fruit of Chinese herb Evodia rutaecarpa (Juss) Benth (Wu Zhu Yu) promotes glucose consumption and anti-inflammatory cytokine expression in insulin-resistant primary skeletal muscle cells. In this study we investigated whether rutaecarpine ameliorated the obesity profiles, lipid abnormality, glucose metabolism and insulin resistance in rat model of hyperlipidemia and hyperglycemia.
  
  
  METHODS
  Rats fed on a high-fat diet for 8 weeks, followed by injection of streptozotocin (30 mg/kg, ip) to induce hyperlipidemia and hyperglycemia. One week after streptozotocin injection, the fat-fed, streptozotocin-treated rats were orally treated with rutaecarpine (25 mg·kg(-1)·d(-1)) or a positive control drug metformin (250 mg·kg(-1)·d(-1)) for 7 weeks. The body weight, visceral fat, blood lipid profiles and glucose levels, insulin sensitivity were measured. Serum levels of inflammatory cytokines were analyzed. IRS-1 and Akt/PKB phosphorylation, PI3K and NF-κB protein levels in liver tissues were assessed; pathological changes of livers and pancreases were examined. Glucose uptake and AMPK/ACC2 phosphorylation were studied in cultured rat skeletal muscle cells in vitro.
  
  
  RESULTS
  Administration of rutaecarpine or metformin significantly decreased obesity, visceral fat accumulation, water consumption, and serum TC, TG and LDL-cholesterol levels in fat-fed, streptozotocin-treated rats. The two drugs also attenuated hyperglycemia and enhanced insulin sensitivity. Moreover, the two drugs significantly decreased NF-κB protein levels in liver tissues and plasma TNF-α, IL-6, CRP and MCP-1 levels, and ameliorated the pathological changes in livers and pancreases. In addition, the two drugs increased PI3K p85 subunit levels and Akt/PKB phosphorylation, but decreased IRS-1 phosphorylation in liver tissues. Treatment of cultured skeletal muscle cells with rutaecarpine (20-180 μmol/L) or metformin (20 μmol/L) promoted the phosphorylation of AMPK and ACC2, and increased glucose uptake.
  
  
  CONCLUSIONS
  Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating IRS-1/PI3K/Akt signaling pathway in liver and AMPK/ACC2 signaling pathway in skeletal muscles.
authors.affiliation: School of Pharmacy, Zunyi Medical University, Guizhou 563000, China.|Murad Research Center for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Xu-qiang
authors.initials: XQ
authors.lastname: Nie
authors.affiliation: The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou 310009, China.
authors.forename: Huai-hong
authors.initials: HH
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Zunyi Medical University, Guizhou 563000, China.
authors.forename: Jian-yong
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Zunyi Medical University, Guizhou 563000, China.
authors.forename: Yu-jing
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Zunyi Medical University, Guizhou 563000, China.
authors.forename: Jian-wen
authors.initials: JW
authors.lastname: Yang
authors.affiliation: Murad Research Center for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Hui-jun
authors.initials: HJ
authors.lastname: Pan
authors.affiliation: Department of Cell Biology & Molecular Genetics, University of Maryland, MD 20740, USA.
authors.forename: Wen-xia
authors.initials: WX
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Medicine, George Washington University, Washington DC 20037, USA.
authors.forename: Ferid
authors.initials: F
authors.lastname: Murad
authors.affiliation: School of Pharmacy, Zunyi Medical University, Guizhou 563000, China.
authors.forename: Yu-qi
authors.initials: YQ
authors.lastname: He
authors.affiliation: Murad Research Center for Modernized Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Department of Biochemistry and Molecular Medicine, George Washington University, Washington DC 20037, USA.
authors.forename: Ka
authors.initials: K
authors.lastname: Bian
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D026121:Indole Alkaloids / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D011799:Quinazolines / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013311:Streptozocin; D052999:Quinazolinones
chemical_list: D004041:Dietary Fats; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D026121:Indole Alkaloids; D011799:Quinazolines; D013311:Streptozocin; C028632:rutecarpine; D052999:Quinazolinones