Exercise Promotes Bone Marrow Microenvironment by Inhibiting Adipsin in Diet-Induced Male Obese Mice

Abstract

Obesity is a growing global epidemic linked to many diseases, including diabetes, cardiovascular diseases, and musculoskeletal disorders. Exercise can improve bone density and decrease excess bone marrow adipose tissue (BMAT) in obese individuals. However, the mechanism of exercise regulating bone marrow microenvironment remains unclear. This study examines how exercise induces bone marrow remodeling in diet-induced obesity. We employed unbiased RNA-Seq to investigate the effect of exercise on the bone marrow of diet-induced obese male mice. Bone mesenchymal stem cells (BMSCs) were isolated to explore the regulatory effects of exercise in vitro. Our data demonstrated that exercise could slow down the progression of obesity and improve trabecular bone density. RNA-seq data revealed that exercise inhibited secreted phosphoprotein 1 (Spp1), which was shown to mediate bone resorption through mechanosensing mechanisms. Interactome analysis of Spp1 using the HINT database showed that Spp1 interacted with the adipokine adipsin. Moreover, exercise decreased BMAT, which induced osteoclast differentiation and promoted bone loss. Our study reveals that exercise improves the bone marrow microenvironment by at least partially inhibiting the adipsin–Spp1 signaling pathway so as to inhibit the alternative complement system from activating osteoclasts in diet-induced obese mice.

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“…This immunosuppressive effect could theoretically allow for the proliferation of pre-leukemic cells. PA impacts bone turnover and the bone marrow microenvironment [182]. Alterations in this microenvironment due to intense exercise might influence hematopoietic stem cells and potentially lead to leukemogenesis.…”

CHIP: a clonal odyssey of the bone marrow niche

“…Of note, while the capacity of exercise to reduce adipose tissue deposits in humans is well known ( 130 ), a murine study showed that aerobic exercise can also decrease dietary-induced BM adipose tissue accumulation ( 131 ). Aging and obesity increased BM adipose tissue, which altered HSC polarization, diminished granulocyte and erythroid differentiation ( 132 ), reduced bone density, and profoundly remodeled the hematopoietic niche by altering expression of extracellular matrix signaling pathways associated with proliferation and differentiation ( 133 ). In this mouse study, a 12-week treadmill regimen delayed high-fat diet–induced obesity, increased trabecular bone mass, and improved the BM microenvironment by partially inhibiting adipokine signaling ( 131 ).…”

“…Reduced bone mineral density of older mice diminishes MSC proliferation and response to osteogenic growth factors ( 139 ), resulting in decreased niche factors such as Netrin 1 ( 140 ) and POT1A ( 141 ), leading in turn to DDR defects, BM ROS, and adipose tissue accumulation ( 141 ), which can alter HSC polarization, differentiation ( 132 ), and long-term function ( 133 ). Furthermore, aging increases central marrow LepR + MSC, which, in addition to having a deleterious effect on the sinusoidal vasculature, is associated with decreased osteoprogenitor function ( 142 ).…”