Caveolin gene transfer improves glucose metabolism in diabetic mice.
Caveolin, a member of the membrane-anchoring protein family, accumulates various growth receptors in caveolae and inhibits their function. Upregulation of caveolin attenuates cellular proliferation and growth. However, the role of caveolin in regulating insulin signals remains controversial. Here, we demonstrate that caveolin potently enhances insulin receptor (IR) signaling when overexpressed in the liver in vivo. Adenovirus-mediated gene transfer was used to overexpress caveolin specifically in the liver of diabetic obese mice, which were generated with a high-fat diet. Expression of molecules involved in IR signaling, such as IR or Akt, remained unchanged after gene transfer. However, hepatic glycogen synthesis was markedly increased with a decrease in phosphoenolpyruvate carboxykinase protein expression. Insulin sensitivity was increased after caveolin gene transfer as determined by decreased blood glucose levels in response to insulin injection and fasting blood glucose levels. Glucose tolerant test performance was also improved. Similar improvements were obtained in KKA(y) genetically diabetic mice. Adenovirus-mediated overexpression of caveolin-3 in hepatic cells also enhanced IR signaling, as shown by increased phosphorylation of IR in response to insulin stimulation and higher glycogen synthesis at baseline. These effects were attributed mostly to increased insulin receptor activity and caveolin-mediated, direct inhibition of protein tyrosine phosphatase 1B, which was increased in obese mouse livers. In conclusion, our results suggest that caveolin is an important regulator of glucose metabolism that can enhance insulin signals.
Otsu
Koji
K
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Toya
Yoshiyuki
Y
Oshikawa
Jin
J
Kurotani
Reiko
R
Yazawa
Takuya
T
Sato
Motohiko
M
Yokoyama
Utako
U
Umemura
Satoshi
S
Minamisawa
Susumu
S
Okumura
Satoshi
S
Ishikawa
Yoshihiro
Y
D000256:Adenoviridae / Q000235:genetics; D000367:Age Factors; D000375:Aging / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D004041:Dietary Fats; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000096:biosynthesis; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood* / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D001786:Blood Glucose; C495549:Cav3 protein, rat; D051244:Caveolin 3; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D006003:Glycogen; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D010729:Phosphoenolpyruvate Carboxykinase (GTP)