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

Haiting He,Jingjing Xu,Yaxi Zhang,Jihua Chen,Yuzhen Yang,Yue Sun,Yanwei Zhang

doi:10.3389/fcell.2021.791880

Haiting He, Jingjing Xu + Show 5 more

Open Access

https://doi.org/10.3389/fcell.2021.791880

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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.

Highlights

Obesity caused by an HFD will dilate adipose tissue and lead to chronic low-grade systemic inflammation
Alanine aminotransferase (ALT, C009-2-1), aspartate aminotransferase (AST, C010-2-1), triacylglycerol (TG, A110-1-1), total cholesterol (TC, A111-1-1), high-density lipoprotein cholesterol (HDL-C, A112-1-1), low-density lipoprotein cholesterol (LDL-C, A113-1-1), superoxide dismutase (SOD, A001-3-2) and malondialdehyde (MDA, A003-1-2) assay kits were obtained from Jiancheng Bioengineering Institute (Nanjing, China)
The results demonstrated that HFD induced obesity in mice, while FA intervention did not affect the weight gain of mice (Figures 1A,B), but could reduce the body fat ratio of mice fed with HFD (Figure 1C)

Summary

Introduction

Obesity caused by an HFD will dilate adipose tissue and lead to chronic low-grade systemic inflammation. Ectopic adipose cells accumulate in the bone marrow cavity, impair bone regeneration and lead to osteoporosis (Halade et al, 2010). Studies have found that osteoporosis or bone mass loss often coexists with lipid metabolism disorders (Tian and Yu, 2015). When the number and volume of adipocytes in the bone marrow continue to increase, the microenvironment in the bone marrow cavity changes, causing the bone marrow lipid metabolism disorder, the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts decreases, the formation and function activation of osteoclasts increase, and the total amount of excessive bone loss, eventually leading to osteoporosis (Hu et al, 2018). Abnormal production of adipokines and activation of some pro-inflammatory signaling pathways in obese patients can induce accelerated inflammation. Inflammation activates various immune cells to produce many free radicals, aggravating oxidative stress, and oxidative stress (OS) plays a crucial role in the pathogenesis of osteoporosis (Saltiel and Olefsky, 2017; Geng et al, 2019)

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