The Murine Glucagon-Like Peptide-1 Receptor Is Essential for Control of Bone Resorption

Yamada, Chizumi; Yamada, Yoshio; Tsukiyama, Katsushi; Yamada, Kotaro; Udagawa, Nobuyuki; Takahashi, Naoyuki; Tanaka, Kiyoshi; Drucker, Daniel J.; Seino, Yutaka; Inagaki, Nobuya

doi:10.1210/en.2007-1292

Cited by 254 publications

(240 citation statements)

References 37 publications

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“…It has been shown that GLP1-R is also expressed in C cells of the thyroid gland and exerts, when activated by GLP-1 or its stable analogues, a stimulating effect on calcitonin secretion in rodents (63,64), a potent inhibitor of bone resorption. As proposed by Yamada et al (29), GLP-1 agonist effects on bone might be indirect rather than direct, acting mainly by targeting calcitonin secretion from the thyroid to modulate bone turnover. Our data indicate that Ex-4 stimulates calcitonin secretion and thus can induce an inhibition of resorption.…”

Section: Discussionmentioning

confidence: 96%

“…Mice with homozygous deletion of the pancreatic GLP-1 receptor develop cortical osteopenia and bone fragility as well as increased osteoclastic bone resorption that might be due to a reduction in thyroid calcitonin secretion (29). Despite a few studies showing a beneficial effect of GLP-1 agonists on bone architecture, the mechanisms by which GLP-1 regulates bone turnover are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…While previous in vivo studies indicate indirect effects of GLP-1 on the skeleton via a calcitonin-dependent pathway (29), it has recently been shown that mouse osteoblast-like MC3T3-E1 cells express a functional receptor for GLP-1, different from the cAMP-linked GLP-1R expressed in the pancreas, suggesting a possible direct skeletal action of GLP-1 (38,39). In contrast, expression of the pancreatic-type GLP-1R mRNA was identified in human osteoblastic cell lines, although its expression varied between them (40).…”

Section: Introductionmentioning

confidence: 87%

“…GLP-1 has been shown to indirectly inhibit bone resorption via stimulation of calcitonin production induced by its binding to the GLP-1 receptor (GLP-1R) in thyroid C cells (28). Accordingly, mice with deletion of pancreatic GLP-1R develop cortical osteopenia and show increased bone resorption through a calcitonindependent pathway (29). Another study showed a similar positive effect of GLP-1R activation on bone strength and quality, as mice lacking GLP-1R showed significantly impaired mechanical properties, a decrease in cortical thickness and bone outer diameter and a reduction in the maturity of the collagen matrix (30).…”

Section: Introductionmentioning

confidence: 99%

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Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Pereira

Jeyabalan

Jorgensen

et al. 2015

Bone

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Pereira

Jeyabalan

Jorgensen

et al. 2015

Bone

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“…Using a model of GLP1 signaling deficiency, Yamada et al (2008) reported that Glp1r knockout mice exhibit a trend for lower trabecular bone mass in the proximal metaphysis of the tibia. These authors also reported reduction in cortical bone mineral density (BMD) as evidenced by an experimental computed tomography (CT)-based densitometry.…”

mentioning

confidence: 99%

Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor

Mabilleau¹,

Mieczkowska²,

Irwin³

et al. 2013

Journal of Endocrinology

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Bone is permanently remodeled by a complex network of local, hormonal, and neuronal factors that affect osteoclast and osteoblast biology. Among these factors, a role for gastrointestinal hormones has been proposed based on the evidence that bone resorption dramatically falls after a meal. Glucagon-like peptide-1 (GLP1) is one of these gut hormones, and despite several reports suggesting an anabolic effect of GLP1, or its stable analogs, on bone mass, little is known about the effects of GLP1/GLP1 receptor on bone strength. In this study, we investigated by three-point bending, quantitative X-ray microradiography, microcomputed tomography, qBEI, and FTIRI bone strength and bone quality in male Glp1r knockout (Glp1r KO) mice when compared with control WT animals. Animals with a deletion of Glp1r presented with a significant reduction in ultimate load, yield load, stiffness, and total absorbed and post-yield energies when compared with WT animals. Furthermore, cortical thickness and bone outer diameter were significantly decreased in deficient animals. The mineral quantity and quality were not significantly different between Glp1r KO and WT animals. On the other hand, the maturity of the collagen matrix was significantly reduced in deficient animals and associated with lowered material properties. Taken together, these data support a positive effect of GLP1R on bone strength and quality. Key Words" bone quality " glucagon-like peptide-1 " bone strength " bone matrix " bone mineral

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Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

Jensen,

Sørensen,

Sandsdal

et al. 2024

JAMA Netw Open

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ImportanceA major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss.ObjectiveTo investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined.Design, Setting, and ParticipantsThis study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision.InterventionsAfter an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo.Main Outcomes and MeasuresThe primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population.ResultsIn total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, −0.006 g/cm2; 95% CI, −0.017 to 0.004 g/cm2; P = .24) and lumbar spine (−0.010 g/cm2; 95% CI, −0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, −0.013 g/cm2; 95% CI, −0.024 to −0.001 g/cm2; P = .03) and spine (mean change, −0.016 g/cm2; 95% CI, −0.032 to −0.001 g/cm2; P = .04).Conclusions and RelevanceIn this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss.Trial RegistrationEudraCT: 2015-005585-32

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The Murine Glucagon-Like Peptide-1 Receptor Is Essential for Control of Bone Resorption

Cited by 254 publications

References 37 publications

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Chronic administration of Glucagon-like peptide-1 receptor agonists improves trabecular bone mass and architecture in ovariectomised mice

Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor

Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment

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