Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that overexpress resistin.
OBJECTIVE
Resistin, the expression of which is suppressed by thiazolidinedione treatment in adipocytes, is one of the key molecules for the tight link between adiposity and insulin resistance. Here, we show the in vivo effects of resistin on insulin sensitivity in mature mice using a cell implantation method.


METHODS
Resistin cDNA was transfected into 3T3-L1 pre-adipocytes, which were then implanted into subcutaneous areas of nude mice. Metabolic analyses were performed 4 or 6 weeks after implantation.


RESULTS
The mice implanted with 3T3-L1 cells overexpressing resistin (R-mice) showed significantly (p<0.05) increased plasma resistin levels. After a glucose load plasma insulin levels were significantly greater in R-mice than in mice implanted with mock-transfected cells (M-mice). The AUC of insulin after glucose loading was positively correlated with circulating resistin levels. Significantly decreased glucose responses after insulin injection were observed in R-mice, compared to M-mice. The insulin-induced phosphorylation level of IRS-1 was significantly lower in muscles of R-mice than M-mice. The expression of TNF-alpha mRNA in intra-peritoneal fat tissues was significantly greater in R-mice than in M-mice, but there was no difference between the two groups with regard to subcutaneous fat tissues. The concentration of TNF-alpha in plasma was positively correlated with resistin levels in R-mice.


CONCLUSIONS
Resistin, when actually secreted from cells in mature mice, causes disturbed glucose metabolism, possibly based on decreased insulin sensitivity in muscle. The in vivo effects of resistin on insulin sensitivity might be in part mediated by increased TNF-alpha expression in visceral fat tissues.
Kitagawa
Y
Y
Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Bujo
H
H
Takahashi
K
K
Shibasaki
M
M
Ishikawa
K
K
Yagui
K
K
Hashimoto
N
N
Noda
K
K
Nakamura
T
T
Yano
S
S
Saito
Y
Y
D016475:3T3 Cells; D017667:Adipocytes / Q000637:transplantation; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006729:Hormones, Ectopic / Q000097:blood / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008819:Mice, Nude; D052243:Resistin; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D001786:Blood Glucose; D006729:Hormones, Ectopic; D007328:Insulin; D052243:Resistin; C499623:Retn protein, mouse; D014409:Tumor Necrosis Factor-alpha