Elsevier

Bone

Volume 64, July 2014, Pages 39-46
Bone

Original Full Length Article
Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise

https://doi.org/10.1016/j.bone.2014.03.044Get rights and content

Highlights

  • High fat diet (HFD) increases marrow adipose tissue (MAT) similar to diet effect on visceral white fat depots.

  • Running exercise significantly prevents MAT accumulation in regular diet and HFD-fed mice.

  • Exercise limitation of MAT is associated with an increase in bone quantity.

  • Reliable quantification and visualization of MAT in the mouse femur is demonstrated via osmium stain and volumetric micro-CT image analysis.

Abstract

Marrow adipose tissue (MAT), associated with skeletal fragility and hematologic insufficiency, remains poorly understood and difficult to quantify. We tested the response of MAT to high fat diet (HFD) and exercise using a novel volumetric analysis, and compared it to measures of bone quantity. We hypothesized that HFD would increase MAT and diminish bone quantity, while exercise would slow MAT acquisition and promote bone formation. Eight week-old female C57BL/6 mice were fed a regular (RD) or HFD, and exercise groups were provided voluntary access to running wheels (RD-E, HFD-E). Femoral MAT was assessed by μCT (lipid binder osmium) using a semi-automated approach employing rigid co-alignment, regional bone masks and was normalized for total femoral volume (TV) of the bone compartment. MAT was 2.6-fold higher in HFD relative to RD mice. Exercise suppressed MAT in RD-E mice by more than half compared with RD. Running similarly inhibited MAT acquisition in HFD mice. Exercise significantly increased bone quantity in both diet groups. Thus, HFD caused significant accumulation of MAT; importantly running exercise limited MAT acquisition while promoting bone formation during both diets. That MAT is exquisitely responsive to diet and exercise, and its regulation by exercise appears to be inversely proportional to effects on exercise induced bone formation, is relevant for an aging and sedentary population.

Introduction

As obesity and its associated metabolic sequelae reach epidemic proportions globally, considerable effort has been invested in understanding the distinct roles of specific adipose depots in contributing to disease states. Besides the fat accumulating in visceral and subcutaneous depots, adipose tissue found in the bone marrow space (marrow adipose tissue; MAT) is of clinical interest. The adipocytes that form MAT are generated in the bone marrow from mesenchymal stem cells (MSC), and are more closely related to osteoblasts than other cells of mesenchymal origin [1]. Both mouse and human studies indicate that conditions of increased bone formation are associated with decreased marrow fat [2], [3], an inverse relationship thought to be due to the preferential allocation of MSC into bone forming osteoblasts rather than adipocytes [4].

Human data supports a clinical relationship between increased MAT and low bone mass; this has been demonstrated in anorexia nervosa [5], paraplegia [6] and post-menopausal osteoporosis [7]. In a study of young adults, marrow fat was inversely correlated with measures of vertebral bone density and femoral cortical bone area [8]. Further, as precursors for MAT are critical components of the hematopoietic-MSC niche, an alteration in MAT is likely to influence MSC function, either through local autocrine effects, or through physical encroachment [9], which could compromise the ability to regenerate damaged connective tissues.

The physiology of MAT is poorly understood, both in terms of its dependence and effect on MSC lineage allocation and as a potential storage depot for excess calories [10]. Importantly, whether excess calories or calorie expenditure during exercise can regulate the quantity of MAT, as it does in non-marrow adipose depots, is unknown. A recent positive correlation between bone marrow fat and intrahepatic lipid, intramyocellular lipid, and serum triglyceride level suggests that MAT might serve as a storage depot for excess calories [11]. MAT has a unique composition of lipid species [1] and recently has been shown to have a gene expression profile that overlaps with brown adipose tissue as well as white adipose tissue [12]. Interestingly, starvation diets appear to increase MAT depots [13], [14] but how high fat diet affects this lipid compartment is unclear.

Exercise is universally recognized as a means of suppressing obesity-associated white adipose tissue depots as well as enhancing bone density and muscle mass [15], [16], [17], [18]. Skeletal loading stimulates bone formation as has been widely shown in humans [19] and animals [20], [21], [22]. Our laboratory has demonstrated that mechanical input, analogous to exercise, promotes cytoskeletal complexity and activation of β-catenin in-vitro, signals associated with osteoblastogenesis [23], [24], [25], [26], [27], [28], [29], [30], [31]. These effects translate to the in-vivo physiology as well, as MSC extracted from exercising mice have increased βcatenin and a reduced capacity for adipogenesis [20].

The present study was designed to test the effects of diet and exercise on MAT and bone. We hypothesized that a high fat diet would increase MAT analogous to increases expected in white adipose tissue, and thus MAT might, besides representing a pathologic diversion of MSC into adipocytes, function as an energy storage depot. Further, we asked if changes in MAT would correlate with measures of bone quantity. To answer whether diet and exercise affect MAT, we applied a quantitative, volumetric method for measuring and localizing marrow adiposity [32]. This method identified the presence of lipid by its ability to bind osmium, a method widely used to identify adipose tissue [33], [34]. As osmium signal can be separated from both marrow and bone by a high CT density [35], we were able to analyze μCT images to obtain volumetric assessment of marrow fat.

Here we quantified MAT in mice fed regular or high-fat diets and provided access to voluntary wheel running in exercise groups. We show that diet and exercise strongly influence MAT quantity in opposite directions. While the exercise reduction in MAT was associated with increased bone quality, the increased MAT due to six weeks of high fat diet did not adversely affect bone. Our results are the first to quantify an increase in MAT in response to diet, and a reduced accumulation of MAT in response to running exercise, changes that were inversely correlated to bone quantity.

Section snippets

Animals and diet

The UNC IACUC approved the use and care of animals in the study. Eight-week old female C57BL/6 mice (n = 20) were randomly assigned to one of two diets for a period of 6 weeks: 1) regular diet, RD, low in fat (PicoLab Mouse Diet 20, Item #5058) or 2) a high-fat diet, HFD diet comprised of 45% fat, 35% carbohydrate and 20% protein, with the majority of fat calories derived from lard (Research diets, DIO Series Diets Item #12541). Mice were fed ad libitum; the grams of food consumed were weighed and

Running distance, time and speed were similar in mice on HFD and regular chow diet

Mice began running within 48 h of exposure to running wheels, with the majority of running hours during the night cycle. Daily running times and distances were consistent with previously published studies on voluntary wheel based running [36]. There was little variability between individual mice in use of the running wheel; mice ran at least 5 h for each 24-hour period, and every single day (Table 1). Mice eating the regular diet (RD) ran a daily average of 358 ± 65 min, a time that was not

Discussion

Growing consensus links bone marrow adiposity with bone fragility [1] as exemplified in clinical settings including skeletal unloading [46], [47], aging [48], postmenopausal osteoporosis [49], and anorexia nervosa [13]. Imprecise quantification has previously limited assessment of changes in MAT in response to potential regulators. Here we have used a sensitive volumetric measure of marrow adiposity to demonstrate that MAT quantity is sensitive to regulation by both diet and exercise. MAT rises

References (63)

  • G.M. Pagnotti et al.

    Low magnitude mechanical signals mitigate osteopenia without compromising longevity in an aged murine model of spontaneous granulosa cell ovarian cancer

    Bone

    (2012)
  • A. Bartelt et al.

    Apolipoprotein E-dependent inverse regulation of vertebral bone and adipose tissue mass in C57Bl/6 mice: modulation by diet-induced obesity

    Bone

    (2010)
  • P.K. Fazeli et al.

    Marrow fat and bone—new perspectives

    J Clin Endocrinol Metabol

    (2013)
  • W. Qiu et al.

    Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells

    J Bone Miner Res

    (2007)
  • L. Song et al.

    Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes

    J Bone Miner Res

    (2012)
  • M. Kawai et al.

    Fat targets for skeletal health

    Nat Rev Rheumatol

    (2009)
  • M.A. Bredella et al.

    Increased bone marrow fat in anorexia nervosa

    J Clin Endocrinol Metabol

    (2009)
  • W. Qin et al.

    Bone and muscle loss after spinal cord injury: organ interactions

    Ann N Y Acad Sci

    (2010)
  • X. Li et al.

    Quantification of vertebral bone marrow fat content using 3 Tesla MR spectroscopy: reproducibility, vertebral variation, and applications in osteoporosis

    J Magn Reson Imaging

    (2011)
  • N. Di Iorgi et al.

    Reciprocal relation between marrow adiposity and the amount of bone in the axial and appendicular skeleton of young adults

    J Clin Endocrinol Metabol

    (2008)
  • O. Naveiras et al.

    Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment

    Nature

    (2009)
  • S. Baglioni et al.

    Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell

    PLoS One

    (2012)
  • M.A. Bredella et al.

    Ectopic and serum lipid levels are positively associated with bone marrow fat in obesity

    Radiology

    (2013)
  • P.K. Fazeli et al.

    Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa

    J Bone Miner Res

    (2012)
  • M.J. Devlin et al.

    Caloric restriction leads to high marrow adiposity and low bone mass in growing mice

    J Bone Miner Res

    (2010)
  • E. Ozcivici et al.

    Mechanical signals as anabolic agents in bone

    Nat Rev Rheumatol

    (2010)
  • J.P. Walhin et al.

    Exercise counteracts the effects of short-term overfeeding and reduced physical activity independent of energy imbalance in healthy young men

    J Physiol

    (2013)
  • D. Thompson et al.

    Physical activity and exercise in the regulation of human adipose tissue physiology

    Physiol Rev

    (2012)
  • S.J. Warden et al.

    Exercise when young provides lifelong benefits to bone structure and strength

    J Bone Miner Res

    (2007)
  • G. Trudel et al.

    Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men

    J Appl Physiol

    (2012)
  • V. David et al.

    Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis

    Endocrinology

    (2007)
  • Cited by (116)

    • Bone marrow adipose tissue

      2022, Visceral and Ectopic Fat: Risk Factors for Type 2 Diabetes, Atherosclerosis, and Cardiovascular Disease
    • Suppression of cancer-associated bone loss through dynamic mechanical loading

      2021, Bone
      Citation Excerpt :

      From the standpoint of treatment, exercise can mitigate the destructive effects of disuse [44] on bone in humans and high-fat diet [45] and diabetic drugs [46] on bone in rodents. Exercise also suppresses the accumulation of systemic fat and marrow adipose [47–49], extending healthier benefits to multiple organ systems. This fundamental property is also exemplified by prolonged absence of mechanical input.

    View all citing articles on Scopus

    Funding: MS: AR062097, JR: AR042360, AR056655, CR: AR 43598, EB 14351, MH: DK092759.

    View full text