학술논문
Long-Term Inhibition of GIP Signaling Reverses Insulin Resistance Through Body Composition Changes.
Document Type
Article
Author
Source
Subject
*PEPTIDE hormones
*GLUCAGON-like peptide 1
*INSULIN resistance
*MAMMAL body composition
*AGING
*LOW-calorie diet
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Language
ISSN
0012-1797
Abstract
We investigated the effect of decreased incretin signalling on aging-associated changes in fat accumulation and insulin resistance using young (10-week-old) and aged (50-week-old) mice lacking gastric inhibitory polypeptide (GIP) or glucagon-like peptide-1 (GLP-1) receptor on normal ad libitum diet, because reduced insulin signalling in adipocytes has been associated with extended longevity as observed in calorie-restricted animals. Wild-type, GIP receptor knockout (GIPR[sup -/-]) and GLP-1 receptor knockout (GLP-1[sup -/-]) mice showed similar body weight and food intake during the 50-week observation period. We first found by computed tomography (CT)-based body composition analyses that aged GIPR[sup -/-]) mice showed reduced body fat mass (0.74 ± 0.13 g) and increased lean body mass (12.2 ± 0.4 g) compared with aged wild-type and GLP1[-/-] mice (fat mass 3.48 ± 0.51 g and 2.87 ± 0.48 g, lean body mass 10.0 ±0.9 g and 10.9 ± 0.2 g, respectively). Aged GIPR[sup -/-] mice showed higher plasma adiponectin and lower plasma leptin levels, and lower body temperature and heart rate despite increased voluntary activity, which are also characteristic phenotypes of long-lived calorie-restricted animals. We assessed insulin sensitivity by insulin tolerance tests and found that insulin resistance was increased associated with aging in wild-type and GLP-1[sup -/-] mice, but not in GIPR[sup -/-] mice. Moreover, glucose tolerance was improved in aged GIPR[sup -/-] mice compared with young GIPR[sup -/-] mice, although no significant changes were observed in wild-type and GLP-1[sup -/-] mice. Our findings suggest that insulinotropic action of incretin had little effects on aging-associated fat accumulation, as shown by difference in adiposity between GIPR[sup -/-] and GLP-1[sup -/-] mice. However, long-term inhibition of extrapancreatic effects of GIP reverses aging-associated deterioration in insulin resistance through body composition changes, like calorie restriction, but without restricting caloric intake. [ABSTRACT FROM AUTHOR]