Osteoporosis, a condition of skeletal decline that undermines quality of life, is treated with pharmacological interventions that are associated with poor adherence and adverse effects. Complicating efforts to improve clinical outcomes, the incidence of obesity is increasing, predisposing the population to a range of musculoskeletal complications and metabolic disorders. Pharmacological management of obesity has yet to deliver notable reductions in weight and debilitating complications are rarely avoided. By contrast, exercise shows promise as a non-invasive and non-pharmacological method of regulating both osteoporosis and obesity. The principal components of exercise — mechanical signals — promote bone and muscle anabolism while limiting formation and expansion of fat mass. Mechanical regulation of bone and marrow fat might be achieved by regulating functions of differentiated cells in the skeletal tissue while biasing lineage selection of their common progenitors — mesenchymal stem cells. An inverse relationship between adipocyte versus osteoblast fate selection from stem cells is implicated in clinical conditions such as childhood obesity and increased marrow adiposity in type 2 diabetes mellitus, as well as contributing to skeletal frailty. Understanding how exercise-induced mechanical signals can be used to improve bone quality while decreasing fat mass and metabolic dysfunction should lead to new strategies to treat chronic diseases such as osteoporosis and obesity.

ObjectiveTo determine whether inclusion of a refractory period between bouts of low magnitude mechanical stimulation (LMMS) can curb obesity-induced adipose tissue dysfunction and sequelae in adult mice.MethodsA diet-induced obesity model with 45kcal% fat diet was employed with intention-to-treat. C57BL/6J mice were weight-matched into four groups: low fat diet (LFD, n=8), high fat diet (HF, n=8), high fat diet with one bout of 30min LMMS (HFv, n=9), and high fat diet with two bouts of 15min LMMS with 5-hour separation (refractory period, RHFv, n=9). 2-week of diet was followed by 6-week of diet+LMMS.ResultsHF and HFv continued gaining body weight and visceral adiposity throughout the experiment, which was mitigated in RHFv. HF and HFv had increased adipocyte hypertrophy, immune cell infiltration (B-cells, T cells, and macrophages) into adipose tissue, adipose tissue inflammation (TNF-α gene expression), and decreased proportion of mesenchymal stem cells in adipose tissue, as compared to LFD, all of which was rescued in RHFv. Glucose intolerance, sequelae of adipose tissue dysfunction, were elevated in HF and HFv, but not in RHFv, as compared to LFD.ConclusionIncorporating a 5-hour refractory period between bouts of LMMS attenuates obesity-induced adipose tissue dysfunction and mitigates glucose intolerance.

While bone marrow hematopoietic stem cells (HSC) are increased in frequency and myeloid-biased with age, the effect of obesity on HSC proliferation and differentiation remains controversial. HSC from both aged and obese environment have reduced hematopoietic reconstitution capacity following bone marrow transplant. Increased marrow adiposity affects HSC function, causing upregulation of myelopoiesis and downregulation of lymphopoiesis. Exercise, in contrast, can reduce marrow adiposity and restore hematopoiesis. The impact of marrow adiposity on hematopoiesis is determined mainly through correlations. Mechanistic studies are needed to determine a causative relationship between marrow adiposity and declines in hematopoiesis, which could aid in developing treatments for conditions that arise from disruptions in the marrow microenvironment.

The incidence of obesity is rapidly rising, increasing morbidity and mortality rates worldwide. Associated comorbidities include type 2 diabetes, heart disease, fatty liver disease, and cancer. The impact of excess fat on musculoskeletal health is still unclear, although it is associated with increased fracture risk and a decline in muscular function. The complexity of obesity makes understanding the etiology of bone and muscle abnormalities difficult. Exercise is an effective and commonly prescribed non-pharmacological treatment option, but it can be difficult or unsafe for the frail, elderly, and morbidly obese. Exercise alternatives, such as low-intensity vibration (LIV), have potential for improving musculoskeletal health, particularly in conditions with excess fat. LIV has been shown to influence bone marrow mesenchymal stem cell differentiation toward higher-order tissues (i.e., bone) and away from fat. While the exact mechanisms are not fully understood, recent studies utilizing LIV both at the bench and in the clinic have demonstrated its efficacy. Here, we discuss the current literature investigating the effects of obesity on bone, muscle, and bone marrow and how exercise and LIV can be used as effective treatments for combating the negative effects in the presence of excess fat.

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