GLUCAGON-LIKE PEPTIDE 1 RECEPTOR (GLP-1R) ANTAGONIST IMPAIRS BONE TURNOVER IN HYPERCALORIC DIET-INDUCED OBESITY

抄録

Background: Exenatide (EXE), a prototypical GLP-1R agonist, has been reported as beneficial to the balance of bone turnover in hyperlipidic and hyperglucidic diet-induced obesity in rats (DIO). Objective: To identify the mediation by GLP-1R of insulin (INS), leptin (LEP), osteocalcin (OCN), calcitonin (CT), carboxy-terminal telopeptide of type 1 collagen (CTX-1), procollagen type 1 amino-terminal propeptide (P1NP) and bone mineral density of femur (BMDF) in DIO. Methods: 72-75-day-old male rats had access only to (i) hyperlipidic food (5.2 kcal/g) and 30% sucrose solution for drinking (1.2 kcal/mL), or (ii) received normocaloric diet (3 kcal/g) and were allowed to feed and to drink water ad libitum. 122-125-day-old rats with 20% overweight were selected from i as obese and those with normal weight were selected from ii as control (C) animals. Thus, obese animals remained untreated (DIO) or were treated sc with 100μg of the competitive antagonist of GLP-1R, exendin (9-39) (E9) per kg (DIO-E9) daily, for 20 days. Plasma INS, LEP, OCN, CTX-1 (ng/mL), CT and P1NP (pg/mL) were measured by ELISA. BMDF (g/cm³) was measured by X-rays. Results: DIO exhibited similar INS (12.90±1.83, n=4) and CT (2.80±1.05, n=4), higher LEP (0.33±0.04, n=5) and lower CTX-1 (0.48±0.22, n=3) than C. The treatment of DIO with E9 decreased CTX-1 (4.44±0.63, n=3) and increased P1NP (163.40±39.80, n=3). DIO-E9 decreased INS (5.75±1.50, n=3) in relation to DIO, at the same level than C (10.58±1.49, n=4). LEP level in DIO-E (0.23±0.02, n=3) was intermediate in relation to DIO and C (0.16±0.05, n=5). OCN, CT and BMDF were similar among C, DIO and DIO-E9. Conclusions: Decreased CTX-1 and normal OCN, P1NP and BMDF reflect a relative normal balance in bone turnover in DIO. Since E9 decreases CTX-1, a known effect of EXE in DIO, this alteration on CTX-1 extrapolates the GLP-1R binding and/or EXE and E9 act as selective modulators with different actions in different targets. Furthermore, E9 increases P1NP (not affected by EXE) and does not affect CT (increased by EXE). E9 effects in DIO imply in increased osteoblastic and decreased osteoclastic activities, which promote an imbalance of bone turnover.

Supported by FAPESP, CNPq and CAPES