Muscle-specific overexpression of heparin-binding epidermal growth factor-like growth factor increases peripheral glucose disposal and insulin sensitivity.
Physical exercise ameliorates metabolic disorders such as type 2 diabetes mellitus and obesity, but the molecular basis of these effects remains elusive. In the present study, we found that exercise up-regulates heparin-binding epidermal growth factor-like growth factor (HB-EGF) in skeletal muscle. To address the metabolic consequences of such gain of HB-EGF function, we generated mice that overexpress this protein specifically in muscle. The transgenic animals exhibited a higher respiratory quotient than did wild-type mice during indirect calorimetry, indicative of their selective use of carbohydrate rather than fat as an energy substrate. They also showed substantial increases in glucose tolerance, insulin sensitivity, and glucose uptake by skeletal muscle. These changes were accompanied by increased kinase activity of Akt in skeletal muscle and consequent inhibition of Forkhead box O1-dependent expression of the pyruvate dehydrogenase kinase 4 gene. Furthermore, mice with a high level of transgene expression were largely protected from obesity, hepatic steatosis, and insulin resistance, even when maintained on a high-fat diet. Our results suggest that HB-EGF produced by contracting muscle acts as an insulin sensitizer that facilitates peripheral glucose disposal.
Fukatsu
Yasuhide
Y
Department of Clinical Molecular Medicine, Division of Diabetes, Kobe University Graduate School of Medicine, Kobe, Japan.
Noguchi
Tetsuya
T
Hosooka
Tetsuya
T
Ogura
Takeshi
T
Kotani
Ko
K
Abe
Takaya
T
Shibakusa
Tetsuro
T
Inoue
Kazuo
K
Sakai
Mashito
M
Tobimatsu
Kazutoshi
K
Inagaki
Kenjiro
K
Yoshioka
Toyo
T
Matsuo
Masahiro
M
Nakae
Jun
J
Matsuki
Yasushi
Y
Hiramatsu
Ryuji
R
Kaku
Kohei
K
Okamura
Hitoshi
H
Fushiki
Tohru
T
Kasuga
Masato
M
D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology; D005234:Fatty Liver / Q000517:prevention & control; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000517:prevention & control; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose