Effects of CGRP receptor antagonism on glucose and bone metabolism in mice with diet-induced obesity
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Effects of CGRP receptor antagonism on glucose and bone metabolism in mice with diet-induced obesity. / Köhli, Paul; Appelt, Jessika; Otto, Ellen; Jahn, Denise; Baranowsky, Anke; Bahn, Alina; Erdmann, Cordula; Müchler, Judith; Mülleder, Michael; Tsitsilonis, Serafeim; Keller, Johannes.
In: BONE, Vol. 143, 115646, 02.2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Effects of CGRP receptor antagonism on glucose and bone metabolism in mice with diet-induced obesity
AU - Köhli, Paul
AU - Appelt, Jessika
AU - Otto, Ellen
AU - Jahn, Denise
AU - Baranowsky, Anke
AU - Bahn, Alina
AU - Erdmann, Cordula
AU - Müchler, Judith
AU - Mülleder, Michael
AU - Tsitsilonis, Serafeim
AU - Keller, Johannes
N1 - Copyright © 2020 Elsevier Inc. All rights reserved.
PY - 2021/2
Y1 - 2021/2
N2 - The neuropeptide calcitonin gene-related peptide (CGRP) and its receptor, calcitonin receptor-like receptor (CLR) complexing with receptor activity-modifiying protein 1 (RAMP1), have been shown to be crucially involved in the pathogenesis of migraine. However, CGRP also plays a pivotal role in regulating bone turnover and was suggested to contribute to the development of the metabolic syndrome. Therefore, our study was designed to characterize the effects of CGRP antagonism on bone and glucose metabolism in a murine model of diet-induced obesity (DIO). A subcutaneous pellet releasing the CGRP receptor antagonist BIBN 4096 (BIBN; olcegepant) was implanted in WT mice with DIO. Metabolic effects were assessed through body- and organ-weights, oral glucose tolerance (oGT), serum lipids, and gene-expression studies. Bone turnover was assessed through histomorphometry of non-decalcified bone sections and analyses of bone turnover markers in serum samples. BIBN treatment did not alter body weight gain or the levels of serum lipids including triacylglycerol and cholesterol during DIO. BIBN led to a moderate improvement of oGT which was accompanied by an increased expression of stearoyl-CoA desaturase in the liver. In skeletal tissue, BIBN treatment resulted in reduced bone volume. This was explained by decreased parameters of bone formation whereas bone resorption was not affected. Our results indicate that inhibition of CGRP signaling only moderately affects glucose metabolism during DIO but significantly impairs bone formation. As novel agents blocking CGRP or its receptor are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone metabolism requires further clinical studies.
AB - The neuropeptide calcitonin gene-related peptide (CGRP) and its receptor, calcitonin receptor-like receptor (CLR) complexing with receptor activity-modifiying protein 1 (RAMP1), have been shown to be crucially involved in the pathogenesis of migraine. However, CGRP also plays a pivotal role in regulating bone turnover and was suggested to contribute to the development of the metabolic syndrome. Therefore, our study was designed to characterize the effects of CGRP antagonism on bone and glucose metabolism in a murine model of diet-induced obesity (DIO). A subcutaneous pellet releasing the CGRP receptor antagonist BIBN 4096 (BIBN; olcegepant) was implanted in WT mice with DIO. Metabolic effects were assessed through body- and organ-weights, oral glucose tolerance (oGT), serum lipids, and gene-expression studies. Bone turnover was assessed through histomorphometry of non-decalcified bone sections and analyses of bone turnover markers in serum samples. BIBN treatment did not alter body weight gain or the levels of serum lipids including triacylglycerol and cholesterol during DIO. BIBN led to a moderate improvement of oGT which was accompanied by an increased expression of stearoyl-CoA desaturase in the liver. In skeletal tissue, BIBN treatment resulted in reduced bone volume. This was explained by decreased parameters of bone formation whereas bone resorption was not affected. Our results indicate that inhibition of CGRP signaling only moderately affects glucose metabolism during DIO but significantly impairs bone formation. As novel agents blocking CGRP or its receptor are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone metabolism requires further clinical studies.
U2 - 10.1016/j.bone.2020.115646
DO - 10.1016/j.bone.2020.115646
M3 - SCORING: Journal article
C2 - 32942062
VL - 143
JO - BONE
JF - BONE
SN - 8756-3282
M1 - 115646
ER -