title: Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity.
abstract: For examining whether dissipating excess energy in the liver is a possible therapeutic approach to high-fat diet-induced metabolic disorders, uncoupling protein-1 (UCP1) was expressed in murine liver using adenoviral vectors in mice with high-fat diet-induced diabetes and obesity, and in standard diet-fed lean mice. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance and, thus, diabetes and dyslipidemia. Decreased expressions of enzymes for lipid synthesis and glucose production and activation of AMP-activated kinase in the liver seem to contribute to these improvements. Hepatic UCP1 expression also reversed high-fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard diet-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, enhanced UCP expression in the liver is a new potential therapeutic target for the metabolic syndrome.
authors.affiliation: Division of Advanced and Therapeutics for Metabolic Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Takehide
authors.initials: T
authors.lastname: Ogihara
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Junhong
authors.initials: J
authors.lastname: Gao
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D007473:Ion Channels; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D010101:Oxygen Consumption; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1