Original Full Length ArticleBone marrow fat accumulation accelerated by high fat diet is suppressed by exercise☆
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
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2021, BoneCitation 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.
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Funding: MS: AR062097, JR: AR042360, AR056655, CR: AR 43598, EB 14351, MH: DK092759.