共 49 条
Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in Mice
被引:122
作者:
Hwang, Jung Hwan
[1
]
Kim, Dong Wook
[1
]
Jo, Eun An
[2
]
Kim, Yong Kyung
[1
]
Jo, Young Suk
[1
]
Park, Ji Hoon
[3
]
Yoo, Sang Ku
[2
]
Park, Myung Kyu
[2
]
Kwak, Tae Hwan
[2
]
Kho, Young Lim
[4
]
Han, Jin
[5
]
Choi, Hueng-Sik
[6
]
Lee, Sang-Hee
[7
]
Kim, Jin Man
[7
]
Lee, InKyu
[8
]
Kyung, Taeyoon
[9
]
Jang, Cholsoon
[9
]
Chung, Jongkyeong
[9
]
Kweon, Gi Ryang
[3
]
Shong, Minho
[1
]
机构:
[1] Chungnam Natl Univ, Sch Med, Dept Internal Med, Taejon, South Korea
[2] Mazence Inc R&D Ctr, Suwon, South Korea
[3] Chungnam Natl Univ, Dept Biochem, Sch Med, Taejon, South Korea
[4] Seoul Hlth Coll, Dept Environm Hlth, Songnam, South Korea
[5] Inje Univ, Coll Med, Dept Physiol & Biophys, Pusan, South Korea
[6] Chonnam Natl Univ, Hormone Res Ctr, Kwangju, South Korea
[7] Chungnam Natl Univ, Sch Med, Dept Pathol, Taejon, South Korea
[8] Kyungpook Natl Univ, Sch Med, Dept Internal Med, Endocrinol Sect, Junggu, Daegu, South Korea
[9] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea
来源:
关键词:
ACTIVATED PROTEIN-KINASE;
ACETYL-COA CARBOXYLASE-2;
FATTY-ACID OXIDATION;
CALORIE RESTRICTION;
METABOLIC SYNDROME;
BETA-LAPACHONE;
MITOCHONDRIAL BIOGENESIS;
CELLULAR FUNCTIONS;
MAMMALIAN-CELL;
ENERGY-BALANCE;
D O I:
10.2337/db08-1183
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
OBJECTIVE-Nicotinamide adenine dinucleotides (NAD(+) and NADH) play a crucial role in cellular energy metabolism, and a dysregulated NAD(+)-to-NADH ratio is implicated in metabolic syndrome. However, it is still unknown whether a modulating intracellular NAD(+)-to-NADH ratio is beneficial in treating metabolic syndrome. We tried to determine whether pharmacological stimulation of NADH oxidation provides therapeutic effects in rodent models of metabolic syndrome. RESEARCH DESIGN AND METHODS-We used beta-lapachone (beta L), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation. The beta L-induced pharmacological effect on cellular energy metabolism was evaluated in cells derived from NQO1-deficient mice. In vivo therapeutic effects of beta L on metabolic syndrome were examined in diet-induced obesity (DIO) and ob/ob mice. RESULTS-NQO1-dependent NADH oxidation by beta L strongly provoked mitochondrial fatty acid oxidation in vitro and in vivo. These effects were accompanied by activation of AMP-activated protein kinase and carnitine palmitoyltransferase and suppression of acetyl-coenzyme A (CoA) carboxylase activity. Consistently, systemic beta L administration in rodent models of metabolic syndrome dramatically ameliorated their key symptoms such as increased adiposity, glucose intolerance, dyslipidemia, and fatty liver. The treated mice also showed higher expressions of the genes related to mitochondrial energy metabolism (PPAR gamma coactivator-1 alpha, nuclear respiratory factor-1) and caloric restriction (Sirt1) consistent with the increased mitochondrial biogenesis and energy expenditure. CONCLUSIONS-Pharmacological activation of NADH oxidation by NQO1 resolves obesity and related phenotypes in mice, opening the possibility that it may provide the basis for a new therapy for the treatment of metabolic syndrome. Diabetes 58: 965-974, 2009
引用
收藏
页码:965 / 974
页数:10
相关论文