Folic Acid Attenuates High-Fat Diet-Induced Osteoporosis Through the AMPK Signaling Pathway

Abstract

Objective: Obesity caused by a high-fat diet (HFD) will expand adipose tissue and cause chronic low-grade systemic inflammation, leading to osteoporosis. Folic acid (FA) is a water-soluble vitamin that plays an essential role in regulating blood lipids and antioxidants. However, the effects and underlying mechanisms of FA in osteoporosis induced by an HFD remain poorly understood. This study aimed to investigate the effect of FA on bone health by using HFD-induced osteoporosis mice.Materials and Methods: Mice were fed a normal diet, HFD or an HFD supplemented with FA (20 μg/ml in drinking water) for 16 weeks. Throughout the 16 weeks study period, the rats were weighed once every week. GTT, ITT and lipid indexes were detected to evaluate the effects of FA on lipid metabolism in the HFD-fed mice. Morphological and structural changes of the femur and tibial bone were observed using micro-CT, HE staining and bone conversion parameters. The expression of MDA, SOD and inflammatory factors were detected to evaluate the effects of FA on oxidative stress and inflammatory response in the HFD-fed mice. Quantitative real-time PCR and Western blot (WB) were used to investigate the AMPK signaling pathway.Results: After the intervention of FA, the body fat rate of obese mice was reduced, and related metabolic disorders such as insulin resistance, hyperlipidemia, and systemic inflammation were alleviated. In correlation with those modifications, FA attenuated bone loss and improved bone microarchitecture, accompanied the number of osteoclasts and adipocytes decreased. Furthermore, FA promoted the phosphorylation of AMPK, thereby promoting the expression of Carnitine palmitoyltransferase 1 (CPT1), nuclear factor erythroid-2 related factor 2 (Nrf2) and antioxidant enzymes.Conclusion: These findings suggest that FA may modulate lipid metabolism and oxidative stress responses activating the AMPK signaling pathway, thereby alleviating HFD-induced osteoporosis. The results from our study provide experimental evidence to prevent HFD-induced osteoporosis.

Chondroitin sulfate alleviates osteoporosis caused by calcium deficiency by regulating lipid metabolism

“…Folic acid is a water-soluble vitamin that helps maintain bone density by maintaining optimal nitric oxide synthase activity in bone cells [ 62 ]. It also significantly improves bone mineral density and bone microstructure, enriches AMPK signaling pathway, and promotes the expression of lipid oxidation-related and antioxidant enzymes [ 63 ]. Folic acid is also involved in inflammation, homocysteine metabolism, and bone turnover, acting directly and indirectly on bone.…”

Calcium carbonate alleviates calcium deficiency through changes in the gut microbiota and metabolites

“…Moreover, there is increasing evidence that lysosomal acid lipase hydrolyzes neutral lipids in osteoblasts, and thus participates in lipid metabolism, such as that of essential cellular components, free cholesterol, and high energy fatty acids, which are assumed to remain in lysosomes as cholesterol esters (CE), leading to severe metabolic imbalances [42]. Synthesis of pantothenic acid, coA, and AMPK also plays a crucial role in lipid metabolism regulation [43]. When calcium carbonate was administered to the low-calcium diet group, it affected the folate resistance of fecal metabolites, olfactory transduction, production and secretion of cortisol, Cushing's syndrome, and the CWMP-PKG signaling pathway, as well as the longevity regulation pathways of plasma metabolites-worm nicotinamide and platelet-activated ADP.…”

“…Folic acid (FA) is a water-soluble vitamin that helps maintain bone density by maintaining optimal nitric oxide synthase activity in bone cells [38]. It also signi cantly improves bone mineral density and bone microstructure, enriches AMPK signaling pathway, and promotes the expression of lipid oxidation-related and antioxidant enzymes [43]. Folic acid is also involved in in ammation, Hcy metabolism, and bone turnover, acting directly and indirectly on bone.…”

Dietary tea seed saponin combined with aerobic exercise attenuated lipid metabolism and oxidative stress in mice fed a high‐fat diet (HFD)

“…Activation of AMPK can inhibit processes such as lipid synthesis by inhibiting lipid accumulation and promoting fatty acid (FA) oxidation and catabolism (He et al, 2021). Peroxisome proliferatoractivated receptor gamma coactivator (PGC) 1α is a main regulator of mitochondrial function, oxygen consumption, and oxidative phosphorylation and is able to regulate the energy metabolism (Singh et al, 2016).…”

“…The nicotinamide adenine dinucleotide (NAD + )‐dependent protein deacetylase (Sirtuin1 (SIRT1))/AMPK pathway is a crucial energy metabolic pathway that modulates lipid and glucose metabolism in the liver, and promoting AMPK/SIRT1 may inhibit lipid accumulation and nonalcoholic fatty liver disease (NAFLD) in obese mice (Chyau et al, 2020; Liou et al, 2019; Li, Dun, et al, 2021). Activation of AMPK can inhibit processes such as lipid synthesis by inhibiting lipid accumulation and promoting fatty acid (FA) oxidation and catabolism (He et al, 2021). Peroxisome proliferator‐activated receptor gamma coactivator (PGC) 1‐α is a main regulator of mitochondrial function, oxygen consumption, and oxidative phosphorylation and is able to regulate the energy metabolism (Singh et al, 2016).…”