The osteogenic effect of liraglutide involves enhanced mitochondrial biogenesis in osteoblasts

Abstract

Liraglutide (Lira), a long-acting glucagon-like peptide 1 receptor (GLP1R) agonist reduces glycosylated hemoglobin in type 2 diabetes mellitus patients. Lira is reported to have bone conserving effect in ovariectomized (OVX) rats. Here, we investigated the osteoanabolic effect of Lira and studied the underlying mechanism. In established osteopenic OVX rats, Lira completely restored bone mass and strength comparable to parathyroid hormone (PTH 1-34). Body mass index normalized bone mineral density of Lira was higher than PTH. The serum levels of osteogenic surrogate pro-collagen type 1 N-terminal pro-peptide (P1NP) and surface referent bone formation parameters were comparable between Lira and PTH. GLP1R, adiponectin receptor 1 (AdipoR1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) levels in bones were down-regulated in the OVX group but restored in the Lira group whereas PTH had no effect. In cultured osteoblasts, Lira time-dependently increased GLP1R, AdipoR1 and PGC1α expression. In osteoblasts, Lira rapidly phosphorylated AMP-dependent protein kinase (AMPK), the cellular energy sensor. Exendin 3, a selective GLP1R antagonist and PKA inhibitor H89 blocked Lira-induced increases in osteoblast differentiation, and expression levels of AdipoR1 and PGC1α. Furthermore, H89 inhibited Lira-induced phosphorylation of AMPK and dorsomorphin, an AMPK inhibitor blocked the Lira-induced increases in osteoblast differentiation and AdipoR1 and PGC1α levels. Lira increased mitochondrial number, respiratory proteins and respiration in osteoblasts in vitro and in vivo, and blocking mitochondrial respiration mitigated *

Sex-specific effects of metformin and liraglutide on renal pathology and expression of connexin 45 and pannexin 1 following long-term high-fat high-sugar diet

“…Besides, we found an increase of approximately 50% in mitochondria in proximal tubules of both the metformin-and liraglutide-treated HFHSD fed rats. These results are in agreement with numerous studies that relate both metformin and liraglutide with biogenesis, function and reduction of oxidative stress in mitochondria of different organs (Pintana et al, 2013;Sa-Nguanmoo et al, 2017;Karise et al, 2019;Pal et al, 2019;Vial et al, 2019;Wu et al, 2019). However, we found that these effects were not sex-specific.…”

Octanoic acid a major component of widely consumed medium-chain triglyceride ketogenic diet is detrimental to bone

“…The bone mineral density (BMD, g/cm 2 ) was also determined from which bone mineral content (BMC) was calculated using the formula BMC = BMD X bone volume (BV) 24 . The analysis was performed and reported according to the guidelines provided by the American Society for Bone and Mineral Research 25 .…”

A butanolic fraction from the standardized stem extract of Cassia occidentalis L delivered by a self-emulsifying drug delivery system protects rats from glucocorticoid-induced osteopenia and muscle atrophy

“…CTAn software were used for micro architectural parameter measurement. Bone mineral density (BMD) was measured by using hydroxyapatite phantom rods of 4 mm diameter with known BMD (0.25 g/cm 3 and 0.75 g/cm 3 ) as calibrator 14,51 .…”

“…Specific assay was designed based on published sequence using Thermo Fisher miRNA assay design tool. Assay ID of different miRNA was; hsa-miR-29a (OO2112), hsa-miR-17 (OO2308), hsa-miR-20a (OOO580) and U6 snRNA (OO1973) 54 .…”