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Bone and fat: A relationship of different shades
Archives of Biochemistry and Biophysics 561 (2014) 124–129
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Review
Bone and fat: A relationship of different shades Beata Lecka-Czernik a,b,c,⇑, Lance A. Stechschulte a,c a
Department of Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, OH 43614, United States c Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, OH 43614, United States b
a r t i c l e
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Article history: Received 31 March 2014 and in revised form 10 June 2014 Available online 20 June 2014 Keywords: Bone marrow Adipocyte WAT BAT Beige adipocytes Bone remodeling Energy homeostasis
a b s t r a c t Environmental and behavioral changes which occurred over the last century led simultaneously to a remarkable increase in human lifespan and to the development of health problems associated with functional impairment of organs either regulating or dependent on balanced energy metabolism. Diseases such as diabetes, obesity and osteoporosis are prevalent in our society and pose major challenges with respect to the overall health and economy. Therefore, better understanding of regulatory axes between bone and fat may provide the basis for development of strategies which will treat these diseases simultaneously and improve health and life quality of elderly. Ó 2014 Elsevier Inc. All rights reserved.
Introduction In recent years we are witnessing a remarkable explosion of research illuminating a relationship between bone and energy metabolism. Although central and sympathetic nervous systems as well as gastrointestinal and pancreatic axes play an essential role in systemic regulation of energy metabolism, the role of fat tissue in thia regulation is the most prominent due to its fundamental function in storing and dissipating energy. In the last two decades significant progress has been made in understanding fat tissue origin, its diverse functions, and pathophysiological consequences of its impairment. These advances lead to the finding that fat tissue metabolism is linked to bone homeostasis. Obesity, diabetes and osteoporosis are major public health concerns. Current estimates indicate that the US population consists of 25% obese, 30% diabetic and prediabetic, and 50% of elderly are osteoporotic individuals. Mechanistically these pathologies share several features including common regulators of bone homeostasis and energy metabolism. Peroxisome proliferator-activated ⇑ Corresponding author at: University of Toledo Health Science Campus, 3000 Arlington Ave, Mail Stop 1008, Toledo, OH 43614, United States. Fax: +1 419 383 2871. E-mail address: [email protected] (B. Lecka-Czernik). 1 Abbreviations used: PPARc, peroxisome proliferator-activated receptor gamma; WAT, white adipose tissue; BAT, brown adipose tissue; UCP1, uncoupling protein 1; Dio2, deiodinase 2; T4, thyroxine; T3, triiodothyronine; BMAT, bone marrow adipose tissue; MSCs, mesenchymal stem cells; FoxC2, forkhead box C2. http://dx.doi.org/10.1016/j.abb.2014.06.010 0003-9861/Ó 2014 Elsevier Inc. All rights reserved.
receptor gamma (PPARc1) plays a prominent role in these processes since it controls both energy turnover in adipose tissue and bone turnover [1,2]. In the light of evidence suggesting that bone is an organ integrated with energy metabolism system in respect to energy storage and regulation of energy balance, PPARc nuclear receptor may be considered as a factor facilitating this integration. This review is summarizing clinical and translational research findings on the association between fat metabolic status and bone mass. It also attempts to bring a perspective on the role of bone marrow fat in regulation of local milieu supporting bone homeostasis.
Color shades of fat reflect its metabolic function Fat tissue stores and releases energy under conditions of feeding and fasting, and regulates energy balance in peripheral tissues through its endocrine activities. Adipocytes accumulate energy in the form of lipids and burn it in the process of fatty acid b-oxidation. In addition, fat cells produce adipokines, among them leptin and adiponectin, which in endocrine manner regulate calorie intake and insulin sensitivity. The multiplex of fat functions is sequestered throughout different fat depots. A role of mitochondria-sparse white adipose tissue (WAT), which is represented by visceral and subcutaneous fat, is to store energy in the form of lipids and endocrinal regulation of insulin sensitivity and glucose metabolism in liver and muscle. In contrast, a role of mitochondria-enriched brown adipose tissue (BAT), which is distributed in
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adult humans as discrete deposits located in the neck, supraclavicular, paravertebral, and suprarenal regions [3], is to dissipate energy to support adaptive thermogenesis [4]. This is mediated by uncoupling protein 1 (UCP1), which stimulates proton leak from the mitochondrial membrane to uncouple respiration from ATP synthesis to produce heat. BAT thermogenic activity is controlled by the central nervous system via catecholamines and b-adrenergic signaling, and deiodinase 2 (Dio2)-mediated thyroid hormone conversion from thyroxine (T4) to triiodothyronine (T3). Along with its role in adaptive thermogenesis, BAT also functions in protecting against obesity, insulin resistance and diabetes [5–8]. Genetic ablation of BAT in rodents results in diet-induced obesity, diabetes and hyperlipidemia [9]. In humans, BAT activity correlates negatively with impairment in energy metabolism seen with aging, diabetes and obesity [10]. In conclusion, BAT plays an important role in systemic regulation of glucose metabolism. It has been recognized that BAT may come from two different origins. The classical preformed BAT originates from Myf5-positive dermomyotomal progenitors, which also give rise to skin and muscle, and functions in non-shivering thermogenesis [11]. In contrast, the Myf5-negative progenitors can differentiate to white adipocytes with function in energy storage or to BAT-like or ‘‘beige’’ adipocytes, which have characteristics of both brown and white fat cells [12]. The BAT-like phenotype can be induced in WAT-type adipocytes by several mechanisms comprising either cold exposure, endocrine action of FGF21 [13], irisin [14], or transcriptional regulators including FoxC2 [15], PRDM16 [16], and PPARc that is activated with specific agonists [17] which cause SirT1-mediated deacetylation of PPARc protein [18]. Beige fat possesses strong anti-obesity and anti-diabetic activity. An overexpression of BATspecific transcription factors, either FoxC2 or PRDM16 in WAT adipocytes, protects mice from diet-induced obesity and metabolic dysfunction [16]. On the other hand, an ablation of beige adipocytes by adipocyte-specific deletion of the transcriptional regulator PRDM16 leads to animals prone to development of diet-induced obesity and severe insulin resistance [19]. Since the beige phenotype can be induced in differentiated WAT depots, it suggests a local function of beige adipocytes within the WAT, perhaps associated with energy dissipation and thermogenesis [16,20,21]. Although beige adipocytes have been identified in human subcutaneous fat, an extent of their contribution to the regulation of energy metabolism is still debatable [12,22]. Improvement in detection of beige adipocytes using specific biomarkers will allow for quantitative assessment of their occurrence and correlation with conditions of altered energy metabolism. Up to date, several gene biomarkers have been suggested based on their relative expression in all three types of adipocytes. Thus, gene transcripts for UCP1 and Zic1 seem to be specific for brown, Tbx1 and TMEM26 for beige, and LEP for white adipocytes [12,22–25]. Bone marrow adipose tissue (BMAT) accumulates in long bones and vertebrae, and fills almost entire marrow cavity by the 3rd decade of human life [26]. In C57BL/6 mice, marrow fat is not detectable up to approximately 4 mo of age, after which it accumulates in long bones progressively with age [27]. BMAT has been historically known as yellow adipose tissue due to a moderate number of mitochondria that gives it a yellowish appearance. It is still unclear whether BMAT constitutes of a distinct population of adipocytes with mixed WAT and BAT phenotype or a heterogeneous population of both WAT- and BAT-type of fat cells. A gene expression profile of epididymal and bone marrow adipocytes shows significant difference in the expression of genes controlling biological processes and molecular functions including adipocyte differentiation, and lipid and carbohydrate metabolism. Interestingly, genes associated with brown adipocyte phenotype were over-represented in the bone marrow as compared to epididymal adipocytes [28]. Indeed, BMAT profile for white and brown
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adipocyte gene markers showed elevated expression of several BAT markers including PRDM16, FoxC2, PGC1a and Dio2. However, this profiling also showed low levels of UCP1 and b3AR, known BAT markers, and low levels of WAT markers including adiponectin and leptin (Fig. 1) [29]. Activation of PPARc in bone marrow cells with a high affinity agonist rosiglitazone increased expression of Prdm16 and UCP1 indicating that progenitors of either brown or beige lineage are present in the bone marrow and can be mobilized in specific conditions [29]. Strong evidence suggests that at least some marrow adipocytes originate from the same Myf5 negative mesenchymal stem cells (MSCs) which can differentiate to osteoblasts and white adipocytes [30,31]. Indeed, the role of the transcriptional regulator and tumor suppressor retinoblastoma protein pRb in regulation of MSCs allocation to either osteoblast, brown, or white adipocyte lineages confirms a close relationship between all three types of cells and the possibility of interconversion between phenotypes [31,32]. Thus, a presence of pRb in early mesenchymal progenitors directs their differentiation towards osteoblasts, while an absence of pRb allows for commitment of the same progenitors to the beige adipocyte lineage and their further differentiation under the control of PRDM16. More interestingly, re-expression of pRb in cells already committed to the beige lineage converts them into adipocytes of white phenotype suggesting interconversion between white and beige phenotypes [31,32]. Perhaps an indication for metabolic type and function of marrow adipocytes may be suggested by their distribution in the marrow cavity. Studies on mice showed that BMAT may form two distinctive depots in the mice tibia (Fig. 2). One depot is juxtaposed to the trabeculae in proximal part of tibia bone, where active bone turnover takes place. Adipocytes in this location are randomly dispersed throughout the area. In contrast, fat in the distal part of tibia, where bone remodeling is practically absent, occurs as a very dense depot of adipocytes which form a ring adjacent to the bone endosteal surface (Fig. 2C). This distinctive pattern of fat accumulation may suggest a specific function for the adipocytes. One can speculate that adipocytes in proximal tibia may support bone remodeling by providing energy and cytokines, whereas fat accumulated in the distal part of tibia may consist of adipocytes that are rather metabolically inert or even have a negative effect on bone turnover. Marrow fat may participate in lipid metabolism by clearing and storing circulating triglycerides, thereby providing a localized
Fig. 1. Relative expression of adipocyte-specific gene markers in BAT and BMAT as compared to WAT [29]. RNA was isolated from epididymal WAT, interscapular BAT and bone marrow isolated from femora of 6 mo old C57BL/6 male mice (n = 4). Gene expression was analyzed using real time PCR and normalized to the level of 18S RNA in each sample. The values from bone marrow analysis were further normalized to the levels of FABP4/aP2 expression in WAT and BAT. ⁄p < 0.05 vs. WAT; ^p < 0.05 BMAT vs. BAT.
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Fig. 2. MicroCT renderings of tibia bone and bone marrow fat. (A) Longitudinal cross section trough mineralized tissue. (B) Visualization of fat using osmium staining [83]. Fat appears as yellow stain. (C) Coronal cross section of proximal (upper panel) and distal (lower panel) tibia. Fat appears as white dots in proximal and white ring in distal part of tibia bone.
energy reservoir for emergency situations affecting, for example, osteogenesis (e.g., bone fracture healing) [33]. BMAT responds to systemic changes in energy metabolism, which is demonstrated by changes in its volume with aging, estrogen deficiency, diabetes, TZD anti-diabetic therapy, caloric restriction and wasting diseases such as anorexia nervosa [34–39]. Although in small quantities relatively to WAT, marrow adipocytes produce leptin and adiponectin (Fig. 1). Cells of osteoblastic lineage express receptors for both adipokines and their role in controlling osteoblast differentiation and function has been demonstrated [40,41]. Interestingly, with aging and other metabolic diseases, changes in cytokines expression in bone resemble changes in extramedullary fat depots [42,43]. Thus, it is reasonable to believe that bone fat has a local endocrine/paracrine function modulating marrow environment supporting bone remodeling and that this function is under similar regulatory axes as in peripheral fat. Impairment in fat function correlates with low bone mass and increased fractures Alterations in the efficiency of energy metabolism system during aging, and in conditions of overnutrition, malnutrition, or diabetes correlate negatively with changes in bone mass. Aging is associated with decreased efficiency of energy utilization partially due to functional impairment of fat tissue [42]. A decline in peripheral fat depots size and function is associated with increased fat accumulation in bone and decrease in bone mass. It is hypothesized that aging causes redistribution of lipids to cells of other organs, like bone marrow, muscle and liver, which may acquire fat-like phenotype without functioning as bona fide adipocytes and can lead to lipotoxicity in these organs [44]. In this respect, it is possible that marrow adipocytes function as a sink for circulating triglycerides which levels is increased due to impairment in function of extramedullar fat. Indeed, a decrease in WAT and BAT function with aging, obesity and diabetes is accompanied with an increase in fat volume in the bone marrow cavity (reviewed in [45]). An increased fat content in bone correlates negatively with decreased bone acquisition during growth and decreased bone mass during aging [34,46–48].
However, the question remains whether accumulation of BMAT has a negative effect on bone mass or whether low bone mass stimulates accumulation of BMAT. Historically BMAT was considered as an inert type of fat which accumulates in the bone marrow to fill empty space after involution of hematopoietic tissue and its correlation with low bone mass was believed to be circumstantial. However, the breadth of new evidence indicating that marrow adipogenesis is a process closely related to osteoblastogenesis, because it shares common precursor cells and is under control of the same signaling cues albeit acting with an opposite outcome, and a positive correlation with systemic lipid metabolism suggest that BMAT actively contributes to the loss of bone mass and its quality. Overnutrition and malnutrition are two examples of systemic changes in energy metabolism, which affect both, bone fat volume and bone mass. Although in general heavier individuals have higher BMD, however obese individuals, as determined not only by weight but also a ratio between fat and lean mass, have relatively lower BMD. In obese older individuals, high percentage of body fat and low percentage of lean mass correlates with decreased BMD and increased frailty [49]. Obese postmenopausal women and older men have increased fracture risk [50]. Contributing factors may include increased production by fat tissue of adiponectin and proinflammatory cytokines, while decreased leptin and IGF-1, and lower serum levels of 25-hydroxyvitamin D and higher serum parathyroid hormone levels [50]. In obese premenopausal women, visceral fat positively correlates with fat content in vertebra and independently of BMD, however increased fat in vertebra correlates independently of obesity with decreased BMD [51]. Other studies confirmed that the inverse relationship between BMAT and BMD exists independently of sex, ethnicity and amount of subcutaneous and visceral fat [52]. BMAT volume positively correlates with levels of serum lipids and ectopic lipids in liver and muscle in obese individuals [53]. While supporting an inverse relationship between BMAT and bone mass, these studies also indicate that lipid metabolism in obesity and bone marrow fat accumulation are linked through the same mechanism, which is responsible for handling increased calorie intake and accumulation of energy in the form of fat. Surprisingly, in conditions of decreased calorie intake and decrease in the amount of peripheral fat, the content of fat in bone is increased [38,51]. Patients with anorexia nervosa have elevated marrow fat mass in vertebra and femur, which is associated with low mineral density and elevated levels of circulating Pref-1, a negative regulator of both osteoblast and adipocyte differentiation [39]. Similarly, caloric restriction increases fat content in murine bone [38]. The 30% reduction in daily caloric intake had a deleterious effect on growing murine bone reflected by a decrease in cortical and trabecular bone mass. Bone loss was accompanied by increased fat accumulation in the marrow independent of a decrease in peripheral fat mass. Leptin and IGF-1 levels were also decreased suggesting a possible role of these signaling pathways for lipids accumulation in bone [38]. Diabetes is a disease of impaired glucose and fatty acids metabolism due to deficiency in insulin signaling in fat, liver and muscle. Both types of diabetes, insulin-dependent Type 1 and insulin-independent Type 2, are associated with increase in fat volume in bone and increased fractures. In Type 1, characterized by pancreatic bcell failure to produce insulin, increased quantities of fat in bone correlate with low bone mass and low levels of circulating IGF-1 and deficiency in vitamin D [36,54,55]. In contrast, in Type 2, which is associated with high levels of serum insulin but inability of peripheral tissue to respond to it, fat mass in bone is increased but this increase is associated with rather higher bone mass. However, bone turnover is low and correlates with high levels of circulating sclerostin, low numbers of circulating osteoprogenitors, and
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high levels of advanced glycation products which contribute to decreased bone quality [56–60]. In support to these clinical observations, a murine model of hyperinsulinemia due to impaired insulin clearance in the liver is characterized by high bone mass, increased marrow adiposity, and very low bone turnover due to compromised bone formation and bone resorption [61]. Interestingly, in this model the number of monocytic osteoclast progenitor cells was significantly decreased, perhaps and in part due to insulin negative effect on expression of c-fos and RANK, two proteins essential for osteoclastogenesis [61]. These observations suggest that energy metabolism regulates bone turnover. Indeed, bone homeostasis and remodeling are closely linked to the osteoblastic response to insulin [62,63]. In normoglycemic and normoinsulinemic animals insulin induces osteoblastogenesis and RANKL production leading to high bone mass which is associated with increased bone turnover [62,63], whereas loss of insulin signaling in osteoblasts or high fat dietinduced insulin resistance decreases bone turnover [64]. As showed in mice, a rate of bone turnover regulates global energy balance by controlling production and release to circulation of undercarboxylated osteocalcin which in the endocrine fashion regulates insulin production and action [62–64]. A support for an existence of a similar regulatory circuit in humans is provided by recent studies showing that an increased glucose metabolism and insulin sensitivity as a result of acute exercise is accompanied with increased serum levels of undercarboxylated osteocalcin with no change in total osteocalcin levels [65]. However, not only volume of BMAT but also quality may affect an overall milieu of bone marrow environment. The qualitative analysis of marrow fat in lumbar vertebra using nuclear magnetic resonance showed that bone loss with aging correlates with a relative decrease in the content of unsaturated fatty acids [66]. With aging and in metabolic diseases similar changes occur in visceral fat and lead to accumulation of monocytes, production of inflammatory cytokines and development of insulin resistance in fat tissue [1]. Moreover, unsaturated fatty acids are primary substrates for energy production through b-oxidation. This together with the observation that with aging and diabetes a relative expression of brown fat gene markers including UCP1, Dio2, PGC1a and b3AR, is decreased may suggest that BMAT undergoes changes toward lower efficiency in energy production which in turn may affect bone remodeling [29]. This data also suggest that marrow fat metabolism may be subjected and is responding to the same factors which modulate extramedullar BAT metabolism, which loses its function with aging and diabetes [29] [10]. The underlying mechanism of inverse relationship between bone mass and fat mass in bone includes changes in the signaling and transcriptional control of MSCs differentiation leading to their preferential differentiation toward adipocytes at the expense of osteoblast formation [67,68]. However, it is also possible that changes in bone fat metabolism leads to lipotoxicity, which may contribute to the bone loss. Indeed, an increase in oxidative stress and accumulation of oxidized lipids in bone is associated with increased local inflammatory responses, resistance to anabolic effects of PTH and Wnt signaling, and osteoporotic bone loss [43,69–71].
Brown/Beige fat activity associates with higher bone mass With identification of functional BAT and existence of beige adipocytes in adult humans, the evidence is growing for a positive correlation of these fat types with bone mass. Increased BAT activity correlates with increased bone mineral density in young women, but not in men [72], children and adolescents [73]. In addition, the bone mass in women recovering from anorexia
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nervosa is higher in those who possess cold-induced BAT foci as compared with those who lost BAT function [72]. Moreover, BAT activity in these patients was in an inverse relationship to circulating levels of Pref-1, a marker of impaired osteoblast differentiation, indicating that BAT activity has a positive association with bone formation [72]. Recently, it has been shown that BAT volume is a positive predictor of femoral bone structure including total and cortical cross section area and correlates positively with thigh muscle and subcutaneous fat [74]. With respect to rodents, there are several models indicating a positive function of BAT on bone. Recently, an association of functional BAT with bone mass has been demonstrated in a model of Misty mice. In this model, a mutation in DOCK7 causes impairment of BAT activity. Misty mice have low bone mass and accelerated bone loss with aging [75]. Interestingly, bone loss can be partially prevented by b-blocker propranolol suggesting involvement of sympathetic nervous system and adrenergic signaling in control of bone mass in this model. Conversely, heterotopic bone formation induced by BMP2 injection to muscle provides evidence that brown adipocytes may have a positive effect on bone formation [76]. As demonstrated, an accumulation of adipocytes expressing UCP1 at the early stages of heterotopic bone formation is prerequisite for this process perhaps by providing an environment supporting angiogenesis, innervation, and chondrogenesis. Because evidence of a presence of brown/beige adipocytes in bone [29] and evidence of WAT-derived beige adipocytes contribution to the systemic energy metabolism [19], it is plausible to expect that beige fat may positively contribute to the regulation of bone mass. Indeed, mice with targeted expression of forkhead box C2 (FoxC2) in adipocytes, which converts white-type adipocytes to beige-type, have high bone mass [77]. Closer examination revealed that FoxC2+/Tg AD mice have increased bone formation associated with high bone turnover, lower expression of Sost, and higher expression of RANKL in osteocytes [77]. It has been shown that FoxC2-expressing beige adipocytes secrete factors that increase alkaline phosphatase activity, increase expression of osteoblast-specific gene markers in cells of osteoblast lineage, and reduce expression of Sost in cells of osteocytic lineage. It has been identified that FoxC2-expressing beige adipocytes produce bone anabolic factors including IGF-1, IGFBP2, Wnt10b and BMP4. Interestingly, besides bone remodeling, these factors also control energy metabolism in adipocytes, providing additional evidence for close association between bone and energy metabolism. Although the above findings demonstrated that beige adipocytes expressing FoxC2 have beneficial effect on bone formation through endocrine/paracrine axes, it has to be proved that in physiologic state beige adipocytes contribute to the regulation of bone remodeling.
Exercise decrease BMAT volume and increase bone mass Exercise alter fat metabolism from storing to providing energy in the process of lipolysis and b-oxidation of fatty acids. They also increase levels of circulating FGF21, a cytokine inducing beginning of fat [78]. Bone response to exercise includes changes in the marrow composition which may contribute to the exercise beneficial effect on bone mass. Studies on the effect of long-term bone strength-enhancing exercise in young female athletes showed a reduction in tibial marrow fat and that this reduction is an independent predictor of bone strength [79]. Similarly, resistive exercise prevents marrow fat accumulation in vertebra of individuals with prolonged immobility [80]. Exercise also prevent marrow fat accumulation and increase bone mass in animals on high fat diet [81]. These and other studies suggest that the beneficial effect
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of exercise on bone is mediated via reduced bone marrow adiposity and consequently increased osteoblastogenesis. Exercise-induced osteoblastogenesis may results from either a direct effect on MSC lineage allocation [82] and/or indirect and resulting from marrow adipocytes acquiring beige phenotype secreting bone anabolic factors. Although this possibility is realistic based on similarities between BMAT and peripheral fat response to environmental cues, however up-to-date there is no evidence that exercise cause beiging of marrow fat. Conclusion The close association between bone and fat leads to the conclusion that fat metabolic status has the ability to regulate bone homeostasis by modulating bone remodeling either directly at the level of MSCs differentiation, or indirectly by providing a milieu in bone marrow environment controlling bone remodeling. If beneficial effect of marrow fat on bone is confirmed, one can expect a possibility to develop bone therapies which will target fat metabolic status instead of bone cells. Acknowledgments This work was supported to BL-C by grant from the American Diabetes Association Award 7-13-BS-089. References [1] P. Tontonoz, B.M. Spiegelman, Annu. Rev. Biochem. 77 (2008) 289–312. [2] B. Lecka-Czernik, Curr. Osteoporos. Rep. 8 (2010) 84–90. [3] K.A. Virtanen, M.E. Lidell, J. Orava, M. Heglind, R. Westergren, T. Niemi, M. Taittonen, J. Laine, N.J. Savisto, S. Enerback, et al., N. Engl. J. Med. 360 (2009) 1518–1525. [4] S. Gesta, Y.H. Tseng, C.R. Kahn, Cell 131 (2007) 242–256. [5] S. Enerback, Cell Metab. 11 (2010) 248–252. [6] J. Nedergaard, B. Cannon, Cell Metab. 11 (2010) 268–272. [7] Y. Kontani, Y. Wang, K. Kimura, K.I. Inokuma, M. Saito, T. Suzuki-Miura, Z. Wang, Y. Sato, N. Mori, H. Yamashita, Aging Cell 4 (2005) 147–155. [8] J. Kopecky, G. Clarke, S. Enerback, B. Spiegelman, L.P. Kozak, J. Clin. Invest. 96 (1995) 2914–2923. [9] B.B. Lowell, V. S-Susulic, A. Hamann, J.A. Lawitts, J. Himms-Hagen, B.B. Boyer, L.P. Kozak, J.S. Flier, Nature 366 (1993) 740–742. [10] V. Ouellet, A. Routhier-Labadie, W. Bellemare, L. Lakhal-Chaieb, E. Turcotte, A.C. Carpentier, D. Richard, J. Clin. Endocrinol. Metab. 96 (2010) 192–199. [11] P. Seale, B. Bjork, W. Yang, S. Kajimura, S. Chin, S. Kuang, A. Scime, S. Devarakonda, H.M. Conroe, H. Erdjument-Bromage, et al., Nature 454 (2008) 961–967. [12] J. Wu, P. Bostrom, L.M. Sparks, L. Ye, J.H. Choi, A.H. Giang, M. Khandekar, K.A. Virtanen, P. Nuutila, G. Schaart, et al., Cell 150 (2012) 366–376. [13] F.M. Fisher, S. Kleiner, N. Douris, E.C. Fox, R.J. Mepani, F. Verdeguer, J. Wu, A. Kharitonenkov, J.S. Flier, E. Maratos-Flier, et al., Genes Dev. 26 (2012) 271–281. [14] P. Bostrom, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, K.A. Rasbach, E.A. Bostrom, J.H. Choi, J.Z. Long, et al., Nature 481 (2012) 463–468. [15] A. Cederberg, L.M. Gronning, B. Ahren, K. Tasken, P. Carlsson, S. Enerback, Cell 106 (2001) 563–573. [16] P. Seale, H.M. Conroe, J. Estall, S. Kajimura, A. Frontini, J. Ishibashi, P. Cohen, S. Cinti, B.M. Spiegelman, J. Clin. Invest. 121 (2011) 96–105. [17] H. Ohno, K. Shinoda, B.M. Spiegelman, S. Kajimura, Cell Metab. 15 (2012) 395– 404. [18] L. Qiang, L. Wang, N. Kon, W. Zhao, S. Lee, Y. Zhang, M. Rosenbaum, Y. Zhao, W. Gu, S.R. Farmer, et al., Cell 150 (2012) 620–632. [19] P. Cohen, J.D. Levy, Y. Zhang, A. Frontini, D.P. Kolodin, K.J. Svensson, J.C. Lo, X. Zeng, L. Ye, M.J. Khandekar, et al., Cell 156 (2014) 304–316. [20] C. Vernochet, S.B. Peres, K.E. Davis, M.E. McDonald, L. Qiang, H. Wang, P.E. Scherer, S.R. Farmer, Mol. Cell. Biol. 29 (2009) 4714–4728. [21] T.J. Schulz, T.L. Huang, T.T. Tran, H. Zhang, K.L. Townsend, J.L. Shadrach, M. Cerletti, L.E. McDougall, N. Giorgadze, T. Tchkonia, et al., Proc. Natl. Acad. Sci. U.S.A. 108 (2011) 143–148. [22] M.E. Lidell, M.J. Betz, O. Dahlqvist Leinhard, M. Heglind, L. Elander, M. Slawik, T. Mussack, D. Nilsson, T. Romu, P. Nuutila, et al., Nat. Med. 19 (2013) 631–634. [23] T.B. Walden, I.R. Hansen, J.A. Timmons, B. Cannon, J. Nedergaard, Am. J. Physiol. Endocrinol. Metab. 302 (2012) E19–E31. [24] N.Z. Jespersen, T.J. Larsen, L. Peijs, S. Daugaard, P. Homoe, A. Loft, J. de Jong, N. Mathur, B. Cannon, J. Nedergaard, et al., Cell Metab. 17 (2013) 798–805. [25] A.M. Cypess, A.P. White, C. Vernochet, T.J. Schulz, R. Xue, C.A. Sass, T.L. Huang, C. Roberts-Toler, L.S. Weiner, C. Sze, et al., Nat. Med. 19 (2013) 635–639. [26] S.G. Moore, K.L. Dawson, Radiology 175 (1990) 219–223.
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Review
Bone and fat: A relationship of different shades Beata Lecka-Czernik a,b,c,⇑, Lance A. Stechschulte a,c a
Department of Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States Department of Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, OH 43614, United States c Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, OH 43614, United States b
a r t i c l e
i n f o
Article history: Received 31 March 2014 and in revised form 10 June 2014 Available online 20 June 2014 Keywords: Bone marrow Adipocyte WAT BAT Beige adipocytes Bone remodeling Energy homeostasis
a b s t r a c t Environmental and behavioral changes which occurred over the last century led simultaneously to a remarkable increase in human lifespan and to the development of health problems associated with functional impairment of organs either regulating or dependent on balanced energy metabolism. Diseases such as diabetes, obesity and osteoporosis are prevalent in our society and pose major challenges with respect to the overall health and economy. Therefore, better understanding of regulatory axes between bone and fat may provide the basis for development of strategies which will treat these diseases simultaneously and improve health and life quality of elderly. Ó 2014 Elsevier Inc. All rights reserved.
Introduction In recent years we are witnessing a remarkable explosion of research illuminating a relationship between bone and energy metabolism. Although central and sympathetic nervous systems as well as gastrointestinal and pancreatic axes play an essential role in systemic regulation of energy metabolism, the role of fat tissue in thia regulation is the most prominent due to its fundamental function in storing and dissipating energy. In the last two decades significant progress has been made in understanding fat tissue origin, its diverse functions, and pathophysiological consequences of its impairment. These advances lead to the finding that fat tissue metabolism is linked to bone homeostasis. Obesity, diabetes and osteoporosis are major public health concerns. Current estimates indicate that the US population consists of 25% obese, 30% diabetic and prediabetic, and 50% of elderly are osteoporotic individuals. Mechanistically these pathologies share several features including common regulators of bone homeostasis and energy metabolism. Peroxisome proliferator-activated ⇑ Corresponding author at: University of Toledo Health Science Campus, 3000 Arlington Ave, Mail Stop 1008, Toledo, OH 43614, United States. Fax: +1 419 383 2871. E-mail address: [email protected] (B. Lecka-Czernik). 1 Abbreviations used: PPARc, peroxisome proliferator-activated receptor gamma; WAT, white adipose tissue; BAT, brown adipose tissue; UCP1, uncoupling protein 1; Dio2, deiodinase 2; T4, thyroxine; T3, triiodothyronine; BMAT, bone marrow adipose tissue; MSCs, mesenchymal stem cells; FoxC2, forkhead box C2. http://dx.doi.org/10.1016/j.abb.2014.06.010 0003-9861/Ó 2014 Elsevier Inc. All rights reserved.
receptor gamma (PPARc1) plays a prominent role in these processes since it controls both energy turnover in adipose tissue and bone turnover [1,2]. In the light of evidence suggesting that bone is an organ integrated with energy metabolism system in respect to energy storage and regulation of energy balance, PPARc nuclear receptor may be considered as a factor facilitating this integration. This review is summarizing clinical and translational research findings on the association between fat metabolic status and bone mass. It also attempts to bring a perspective on the role of bone marrow fat in regulation of local milieu supporting bone homeostasis.
Color shades of fat reflect its metabolic function Fat tissue stores and releases energy under conditions of feeding and fasting, and regulates energy balance in peripheral tissues through its endocrine activities. Adipocytes accumulate energy in the form of lipids and burn it in the process of fatty acid b-oxidation. In addition, fat cells produce adipokines, among them leptin and adiponectin, which in endocrine manner regulate calorie intake and insulin sensitivity. The multiplex of fat functions is sequestered throughout different fat depots. A role of mitochondria-sparse white adipose tissue (WAT), which is represented by visceral and subcutaneous fat, is to store energy in the form of lipids and endocrinal regulation of insulin sensitivity and glucose metabolism in liver and muscle. In contrast, a role of mitochondria-enriched brown adipose tissue (BAT), which is distributed in
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adult humans as discrete deposits located in the neck, supraclavicular, paravertebral, and suprarenal regions [3], is to dissipate energy to support adaptive thermogenesis [4]. This is mediated by uncoupling protein 1 (UCP1), which stimulates proton leak from the mitochondrial membrane to uncouple respiration from ATP synthesis to produce heat. BAT thermogenic activity is controlled by the central nervous system via catecholamines and b-adrenergic signaling, and deiodinase 2 (Dio2)-mediated thyroid hormone conversion from thyroxine (T4) to triiodothyronine (T3). Along with its role in adaptive thermogenesis, BAT also functions in protecting against obesity, insulin resistance and diabetes [5–8]. Genetic ablation of BAT in rodents results in diet-induced obesity, diabetes and hyperlipidemia [9]. In humans, BAT activity correlates negatively with impairment in energy metabolism seen with aging, diabetes and obesity [10]. In conclusion, BAT plays an important role in systemic regulation of glucose metabolism. It has been recognized that BAT may come from two different origins. The classical preformed BAT originates from Myf5-positive dermomyotomal progenitors, which also give rise to skin and muscle, and functions in non-shivering thermogenesis [11]. In contrast, the Myf5-negative progenitors can differentiate to white adipocytes with function in energy storage or to BAT-like or ‘‘beige’’ adipocytes, which have characteristics of both brown and white fat cells [12]. The BAT-like phenotype can be induced in WAT-type adipocytes by several mechanisms comprising either cold exposure, endocrine action of FGF21 [13], irisin [14], or transcriptional regulators including FoxC2 [15], PRDM16 [16], and PPARc that is activated with specific agonists [17] which cause SirT1-mediated deacetylation of PPARc protein [18]. Beige fat possesses strong anti-obesity and anti-diabetic activity. An overexpression of BATspecific transcription factors, either FoxC2 or PRDM16 in WAT adipocytes, protects mice from diet-induced obesity and metabolic dysfunction [16]. On the other hand, an ablation of beige adipocytes by adipocyte-specific deletion of the transcriptional regulator PRDM16 leads to animals prone to development of diet-induced obesity and severe insulin resistance [19]. Since the beige phenotype can be induced in differentiated WAT depots, it suggests a local function of beige adipocytes within the WAT, perhaps associated with energy dissipation and thermogenesis [16,20,21]. Although beige adipocytes have been identified in human subcutaneous fat, an extent of their contribution to the regulation of energy metabolism is still debatable [12,22]. Improvement in detection of beige adipocytes using specific biomarkers will allow for quantitative assessment of their occurrence and correlation with conditions of altered energy metabolism. Up to date, several gene biomarkers have been suggested based on their relative expression in all three types of adipocytes. Thus, gene transcripts for UCP1 and Zic1 seem to be specific for brown, Tbx1 and TMEM26 for beige, and LEP for white adipocytes [12,22–25]. Bone marrow adipose tissue (BMAT) accumulates in long bones and vertebrae, and fills almost entire marrow cavity by the 3rd decade of human life [26]. In C57BL/6 mice, marrow fat is not detectable up to approximately 4 mo of age, after which it accumulates in long bones progressively with age [27]. BMAT has been historically known as yellow adipose tissue due to a moderate number of mitochondria that gives it a yellowish appearance. It is still unclear whether BMAT constitutes of a distinct population of adipocytes with mixed WAT and BAT phenotype or a heterogeneous population of both WAT- and BAT-type of fat cells. A gene expression profile of epididymal and bone marrow adipocytes shows significant difference in the expression of genes controlling biological processes and molecular functions including adipocyte differentiation, and lipid and carbohydrate metabolism. Interestingly, genes associated with brown adipocyte phenotype were over-represented in the bone marrow as compared to epididymal adipocytes [28]. Indeed, BMAT profile for white and brown
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adipocyte gene markers showed elevated expression of several BAT markers including PRDM16, FoxC2, PGC1a and Dio2. However, this profiling also showed low levels of UCP1 and b3AR, known BAT markers, and low levels of WAT markers including adiponectin and leptin (Fig. 1) [29]. Activation of PPARc in bone marrow cells with a high affinity agonist rosiglitazone increased expression of Prdm16 and UCP1 indicating that progenitors of either brown or beige lineage are present in the bone marrow and can be mobilized in specific conditions [29]. Strong evidence suggests that at least some marrow adipocytes originate from the same Myf5 negative mesenchymal stem cells (MSCs) which can differentiate to osteoblasts and white adipocytes [30,31]. Indeed, the role of the transcriptional regulator and tumor suppressor retinoblastoma protein pRb in regulation of MSCs allocation to either osteoblast, brown, or white adipocyte lineages confirms a close relationship between all three types of cells and the possibility of interconversion between phenotypes [31,32]. Thus, a presence of pRb in early mesenchymal progenitors directs their differentiation towards osteoblasts, while an absence of pRb allows for commitment of the same progenitors to the beige adipocyte lineage and their further differentiation under the control of PRDM16. More interestingly, re-expression of pRb in cells already committed to the beige lineage converts them into adipocytes of white phenotype suggesting interconversion between white and beige phenotypes [31,32]. Perhaps an indication for metabolic type and function of marrow adipocytes may be suggested by their distribution in the marrow cavity. Studies on mice showed that BMAT may form two distinctive depots in the mice tibia (Fig. 2). One depot is juxtaposed to the trabeculae in proximal part of tibia bone, where active bone turnover takes place. Adipocytes in this location are randomly dispersed throughout the area. In contrast, fat in the distal part of tibia, where bone remodeling is practically absent, occurs as a very dense depot of adipocytes which form a ring adjacent to the bone endosteal surface (Fig. 2C). This distinctive pattern of fat accumulation may suggest a specific function for the adipocytes. One can speculate that adipocytes in proximal tibia may support bone remodeling by providing energy and cytokines, whereas fat accumulated in the distal part of tibia may consist of adipocytes that are rather metabolically inert or even have a negative effect on bone turnover. Marrow fat may participate in lipid metabolism by clearing and storing circulating triglycerides, thereby providing a localized
Fig. 1. Relative expression of adipocyte-specific gene markers in BAT and BMAT as compared to WAT [29]. RNA was isolated from epididymal WAT, interscapular BAT and bone marrow isolated from femora of 6 mo old C57BL/6 male mice (n = 4). Gene expression was analyzed using real time PCR and normalized to the level of 18S RNA in each sample. The values from bone marrow analysis were further normalized to the levels of FABP4/aP2 expression in WAT and BAT. ⁄p < 0.05 vs. WAT; ^p < 0.05 BMAT vs. BAT.
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Fig. 2. MicroCT renderings of tibia bone and bone marrow fat. (A) Longitudinal cross section trough mineralized tissue. (B) Visualization of fat using osmium staining [83]. Fat appears as yellow stain. (C) Coronal cross section of proximal (upper panel) and distal (lower panel) tibia. Fat appears as white dots in proximal and white ring in distal part of tibia bone.
energy reservoir for emergency situations affecting, for example, osteogenesis (e.g., bone fracture healing) [33]. BMAT responds to systemic changes in energy metabolism, which is demonstrated by changes in its volume with aging, estrogen deficiency, diabetes, TZD anti-diabetic therapy, caloric restriction and wasting diseases such as anorexia nervosa [34–39]. Although in small quantities relatively to WAT, marrow adipocytes produce leptin and adiponectin (Fig. 1). Cells of osteoblastic lineage express receptors for both adipokines and their role in controlling osteoblast differentiation and function has been demonstrated [40,41]. Interestingly, with aging and other metabolic diseases, changes in cytokines expression in bone resemble changes in extramedullary fat depots [42,43]. Thus, it is reasonable to believe that bone fat has a local endocrine/paracrine function modulating marrow environment supporting bone remodeling and that this function is under similar regulatory axes as in peripheral fat. Impairment in fat function correlates with low bone mass and increased fractures Alterations in the efficiency of energy metabolism system during aging, and in conditions of overnutrition, malnutrition, or diabetes correlate negatively with changes in bone mass. Aging is associated with decreased efficiency of energy utilization partially due to functional impairment of fat tissue [42]. A decline in peripheral fat depots size and function is associated with increased fat accumulation in bone and decrease in bone mass. It is hypothesized that aging causes redistribution of lipids to cells of other organs, like bone marrow, muscle and liver, which may acquire fat-like phenotype without functioning as bona fide adipocytes and can lead to lipotoxicity in these organs [44]. In this respect, it is possible that marrow adipocytes function as a sink for circulating triglycerides which levels is increased due to impairment in function of extramedullar fat. Indeed, a decrease in WAT and BAT function with aging, obesity and diabetes is accompanied with an increase in fat volume in the bone marrow cavity (reviewed in [45]). An increased fat content in bone correlates negatively with decreased bone acquisition during growth and decreased bone mass during aging [34,46–48].
However, the question remains whether accumulation of BMAT has a negative effect on bone mass or whether low bone mass stimulates accumulation of BMAT. Historically BMAT was considered as an inert type of fat which accumulates in the bone marrow to fill empty space after involution of hematopoietic tissue and its correlation with low bone mass was believed to be circumstantial. However, the breadth of new evidence indicating that marrow adipogenesis is a process closely related to osteoblastogenesis, because it shares common precursor cells and is under control of the same signaling cues albeit acting with an opposite outcome, and a positive correlation with systemic lipid metabolism suggest that BMAT actively contributes to the loss of bone mass and its quality. Overnutrition and malnutrition are two examples of systemic changes in energy metabolism, which affect both, bone fat volume and bone mass. Although in general heavier individuals have higher BMD, however obese individuals, as determined not only by weight but also a ratio between fat and lean mass, have relatively lower BMD. In obese older individuals, high percentage of body fat and low percentage of lean mass correlates with decreased BMD and increased frailty [49]. Obese postmenopausal women and older men have increased fracture risk [50]. Contributing factors may include increased production by fat tissue of adiponectin and proinflammatory cytokines, while decreased leptin and IGF-1, and lower serum levels of 25-hydroxyvitamin D and higher serum parathyroid hormone levels [50]. In obese premenopausal women, visceral fat positively correlates with fat content in vertebra and independently of BMD, however increased fat in vertebra correlates independently of obesity with decreased BMD [51]. Other studies confirmed that the inverse relationship between BMAT and BMD exists independently of sex, ethnicity and amount of subcutaneous and visceral fat [52]. BMAT volume positively correlates with levels of serum lipids and ectopic lipids in liver and muscle in obese individuals [53]. While supporting an inverse relationship between BMAT and bone mass, these studies also indicate that lipid metabolism in obesity and bone marrow fat accumulation are linked through the same mechanism, which is responsible for handling increased calorie intake and accumulation of energy in the form of fat. Surprisingly, in conditions of decreased calorie intake and decrease in the amount of peripheral fat, the content of fat in bone is increased [38,51]. Patients with anorexia nervosa have elevated marrow fat mass in vertebra and femur, which is associated with low mineral density and elevated levels of circulating Pref-1, a negative regulator of both osteoblast and adipocyte differentiation [39]. Similarly, caloric restriction increases fat content in murine bone [38]. The 30% reduction in daily caloric intake had a deleterious effect on growing murine bone reflected by a decrease in cortical and trabecular bone mass. Bone loss was accompanied by increased fat accumulation in the marrow independent of a decrease in peripheral fat mass. Leptin and IGF-1 levels were also decreased suggesting a possible role of these signaling pathways for lipids accumulation in bone [38]. Diabetes is a disease of impaired glucose and fatty acids metabolism due to deficiency in insulin signaling in fat, liver and muscle. Both types of diabetes, insulin-dependent Type 1 and insulin-independent Type 2, are associated with increase in fat volume in bone and increased fractures. In Type 1, characterized by pancreatic bcell failure to produce insulin, increased quantities of fat in bone correlate with low bone mass and low levels of circulating IGF-1 and deficiency in vitamin D [36,54,55]. In contrast, in Type 2, which is associated with high levels of serum insulin but inability of peripheral tissue to respond to it, fat mass in bone is increased but this increase is associated with rather higher bone mass. However, bone turnover is low and correlates with high levels of circulating sclerostin, low numbers of circulating osteoprogenitors, and
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high levels of advanced glycation products which contribute to decreased bone quality [56–60]. In support to these clinical observations, a murine model of hyperinsulinemia due to impaired insulin clearance in the liver is characterized by high bone mass, increased marrow adiposity, and very low bone turnover due to compromised bone formation and bone resorption [61]. Interestingly, in this model the number of monocytic osteoclast progenitor cells was significantly decreased, perhaps and in part due to insulin negative effect on expression of c-fos and RANK, two proteins essential for osteoclastogenesis [61]. These observations suggest that energy metabolism regulates bone turnover. Indeed, bone homeostasis and remodeling are closely linked to the osteoblastic response to insulin [62,63]. In normoglycemic and normoinsulinemic animals insulin induces osteoblastogenesis and RANKL production leading to high bone mass which is associated with increased bone turnover [62,63], whereas loss of insulin signaling in osteoblasts or high fat dietinduced insulin resistance decreases bone turnover [64]. As showed in mice, a rate of bone turnover regulates global energy balance by controlling production and release to circulation of undercarboxylated osteocalcin which in the endocrine fashion regulates insulin production and action [62–64]. A support for an existence of a similar regulatory circuit in humans is provided by recent studies showing that an increased glucose metabolism and insulin sensitivity as a result of acute exercise is accompanied with increased serum levels of undercarboxylated osteocalcin with no change in total osteocalcin levels [65]. However, not only volume of BMAT but also quality may affect an overall milieu of bone marrow environment. The qualitative analysis of marrow fat in lumbar vertebra using nuclear magnetic resonance showed that bone loss with aging correlates with a relative decrease in the content of unsaturated fatty acids [66]. With aging and in metabolic diseases similar changes occur in visceral fat and lead to accumulation of monocytes, production of inflammatory cytokines and development of insulin resistance in fat tissue [1]. Moreover, unsaturated fatty acids are primary substrates for energy production through b-oxidation. This together with the observation that with aging and diabetes a relative expression of brown fat gene markers including UCP1, Dio2, PGC1a and b3AR, is decreased may suggest that BMAT undergoes changes toward lower efficiency in energy production which in turn may affect bone remodeling [29]. This data also suggest that marrow fat metabolism may be subjected and is responding to the same factors which modulate extramedullar BAT metabolism, which loses its function with aging and diabetes [29] [10]. The underlying mechanism of inverse relationship between bone mass and fat mass in bone includes changes in the signaling and transcriptional control of MSCs differentiation leading to their preferential differentiation toward adipocytes at the expense of osteoblast formation [67,68]. However, it is also possible that changes in bone fat metabolism leads to lipotoxicity, which may contribute to the bone loss. Indeed, an increase in oxidative stress and accumulation of oxidized lipids in bone is associated with increased local inflammatory responses, resistance to anabolic effects of PTH and Wnt signaling, and osteoporotic bone loss [43,69–71].
Brown/Beige fat activity associates with higher bone mass With identification of functional BAT and existence of beige adipocytes in adult humans, the evidence is growing for a positive correlation of these fat types with bone mass. Increased BAT activity correlates with increased bone mineral density in young women, but not in men [72], children and adolescents [73]. In addition, the bone mass in women recovering from anorexia
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nervosa is higher in those who possess cold-induced BAT foci as compared with those who lost BAT function [72]. Moreover, BAT activity in these patients was in an inverse relationship to circulating levels of Pref-1, a marker of impaired osteoblast differentiation, indicating that BAT activity has a positive association with bone formation [72]. Recently, it has been shown that BAT volume is a positive predictor of femoral bone structure including total and cortical cross section area and correlates positively with thigh muscle and subcutaneous fat [74]. With respect to rodents, there are several models indicating a positive function of BAT on bone. Recently, an association of functional BAT with bone mass has been demonstrated in a model of Misty mice. In this model, a mutation in DOCK7 causes impairment of BAT activity. Misty mice have low bone mass and accelerated bone loss with aging [75]. Interestingly, bone loss can be partially prevented by b-blocker propranolol suggesting involvement of sympathetic nervous system and adrenergic signaling in control of bone mass in this model. Conversely, heterotopic bone formation induced by BMP2 injection to muscle provides evidence that brown adipocytes may have a positive effect on bone formation [76]. As demonstrated, an accumulation of adipocytes expressing UCP1 at the early stages of heterotopic bone formation is prerequisite for this process perhaps by providing an environment supporting angiogenesis, innervation, and chondrogenesis. Because evidence of a presence of brown/beige adipocytes in bone [29] and evidence of WAT-derived beige adipocytes contribution to the systemic energy metabolism [19], it is plausible to expect that beige fat may positively contribute to the regulation of bone mass. Indeed, mice with targeted expression of forkhead box C2 (FoxC2) in adipocytes, which converts white-type adipocytes to beige-type, have high bone mass [77]. Closer examination revealed that FoxC2+/Tg AD mice have increased bone formation associated with high bone turnover, lower expression of Sost, and higher expression of RANKL in osteocytes [77]. It has been shown that FoxC2-expressing beige adipocytes secrete factors that increase alkaline phosphatase activity, increase expression of osteoblast-specific gene markers in cells of osteoblast lineage, and reduce expression of Sost in cells of osteocytic lineage. It has been identified that FoxC2-expressing beige adipocytes produce bone anabolic factors including IGF-1, IGFBP2, Wnt10b and BMP4. Interestingly, besides bone remodeling, these factors also control energy metabolism in adipocytes, providing additional evidence for close association between bone and energy metabolism. Although the above findings demonstrated that beige adipocytes expressing FoxC2 have beneficial effect on bone formation through endocrine/paracrine axes, it has to be proved that in physiologic state beige adipocytes contribute to the regulation of bone remodeling.
Exercise decrease BMAT volume and increase bone mass Exercise alter fat metabolism from storing to providing energy in the process of lipolysis and b-oxidation of fatty acids. They also increase levels of circulating FGF21, a cytokine inducing beginning of fat [78]. Bone response to exercise includes changes in the marrow composition which may contribute to the exercise beneficial effect on bone mass. Studies on the effect of long-term bone strength-enhancing exercise in young female athletes showed a reduction in tibial marrow fat and that this reduction is an independent predictor of bone strength [79]. Similarly, resistive exercise prevents marrow fat accumulation in vertebra of individuals with prolonged immobility [80]. Exercise also prevent marrow fat accumulation and increase bone mass in animals on high fat diet [81]. These and other studies suggest that the beneficial effect
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of exercise on bone is mediated via reduced bone marrow adiposity and consequently increased osteoblastogenesis. Exercise-induced osteoblastogenesis may results from either a direct effect on MSC lineage allocation [82] and/or indirect and resulting from marrow adipocytes acquiring beige phenotype secreting bone anabolic factors. Although this possibility is realistic based on similarities between BMAT and peripheral fat response to environmental cues, however up-to-date there is no evidence that exercise cause beiging of marrow fat. Conclusion The close association between bone and fat leads to the conclusion that fat metabolic status has the ability to regulate bone homeostasis by modulating bone remodeling either directly at the level of MSCs differentiation, or indirectly by providing a milieu in bone marrow environment controlling bone remodeling. If beneficial effect of marrow fat on bone is confirmed, one can expect a possibility to develop bone therapies which will target fat metabolic status instead of bone cells. Acknowledgments This work was supported to BL-C by grant from the American Diabetes Association Award 7-13-BS-089. References [1] P. Tontonoz, B.M. Spiegelman, Annu. Rev. Biochem. 77 (2008) 289–312. [2] B. Lecka-Czernik, Curr. Osteoporos. Rep. 8 (2010) 84–90. [3] K.A. Virtanen, M.E. Lidell, J. Orava, M. Heglind, R. Westergren, T. Niemi, M. Taittonen, J. Laine, N.J. Savisto, S. Enerback, et al., N. Engl. J. Med. 360 (2009) 1518–1525. [4] S. Gesta, Y.H. Tseng, C.R. Kahn, Cell 131 (2007) 242–256. [5] S. Enerback, Cell Metab. 11 (2010) 248–252. [6] J. Nedergaard, B. Cannon, Cell Metab. 11 (2010) 268–272. [7] Y. Kontani, Y. Wang, K. Kimura, K.I. Inokuma, M. Saito, T. Suzuki-Miura, Z. Wang, Y. Sato, N. Mori, H. Yamashita, Aging Cell 4 (2005) 147–155. [8] J. Kopecky, G. Clarke, S. Enerback, B. Spiegelman, L.P. Kozak, J. Clin. Invest. 96 (1995) 2914–2923. [9] B.B. Lowell, V. S-Susulic, A. Hamann, J.A. Lawitts, J. Himms-Hagen, B.B. Boyer, L.P. Kozak, J.S. Flier, Nature 366 (1993) 740–742. [10] V. Ouellet, A. Routhier-Labadie, W. Bellemare, L. Lakhal-Chaieb, E. Turcotte, A.C. Carpentier, D. Richard, J. Clin. Endocrinol. Metab. 96 (2010) 192–199. [11] P. Seale, B. Bjork, W. Yang, S. Kajimura, S. Chin, S. Kuang, A. Scime, S. Devarakonda, H.M. Conroe, H. Erdjument-Bromage, et al., Nature 454 (2008) 961–967. [12] J. Wu, P. Bostrom, L.M. Sparks, L. Ye, J.H. Choi, A.H. Giang, M. Khandekar, K.A. Virtanen, P. Nuutila, G. Schaart, et al., Cell 150 (2012) 366–376. [13] F.M. Fisher, S. Kleiner, N. Douris, E.C. Fox, R.J. Mepani, F. Verdeguer, J. Wu, A. Kharitonenkov, J.S. Flier, E. Maratos-Flier, et al., Genes Dev. 26 (2012) 271–281. [14] P. Bostrom, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, K.A. Rasbach, E.A. Bostrom, J.H. Choi, J.Z. Long, et al., Nature 481 (2012) 463–468. [15] A. Cederberg, L.M. Gronning, B. Ahren, K. Tasken, P. Carlsson, S. Enerback, Cell 106 (2001) 563–573. [16] P. Seale, H.M. Conroe, J. Estall, S. Kajimura, A. Frontini, J. Ishibashi, P. Cohen, S. Cinti, B.M. Spiegelman, J. Clin. Invest. 121 (2011) 96–105. [17] H. Ohno, K. Shinoda, B.M. Spiegelman, S. Kajimura, Cell Metab. 15 (2012) 395– 404. [18] L. Qiang, L. Wang, N. Kon, W. Zhao, S. Lee, Y. Zhang, M. Rosenbaum, Y. Zhao, W. Gu, S.R. Farmer, et al., Cell 150 (2012) 620–632. [19] P. Cohen, J.D. Levy, Y. Zhang, A. Frontini, D.P. Kolodin, K.J. Svensson, J.C. Lo, X. Zeng, L. Ye, M.J. Khandekar, et al., Cell 156 (2014) 304–316. [20] C. Vernochet, S.B. Peres, K.E. Davis, M.E. McDonald, L. Qiang, H. Wang, P.E. Scherer, S.R. Farmer, Mol. Cell. Biol. 29 (2009) 4714–4728. [21] T.J. Schulz, T.L. Huang, T.T. Tran, H. Zhang, K.L. Townsend, J.L. Shadrach, M. Cerletti, L.E. McDougall, N. Giorgadze, T. Tchkonia, et al., Proc. Natl. Acad. Sci. U.S.A. 108 (2011) 143–148. [22] M.E. Lidell, M.J. Betz, O. Dahlqvist Leinhard, M. Heglind, L. Elander, M. Slawik, T. Mussack, D. Nilsson, T. Romu, P. Nuutila, et al., Nat. Med. 19 (2013) 631–634. [23] T.B. Walden, I.R. Hansen, J.A. Timmons, B. Cannon, J. Nedergaard, Am. J. Physiol. Endocrinol. Metab. 302 (2012) E19–E31. [24] N.Z. Jespersen, T.J. Larsen, L. Peijs, S. Daugaard, P. Homoe, A. Loft, J. de Jong, N. Mathur, B. Cannon, J. Nedergaard, et al., Cell Metab. 17 (2013) 798–805. [25] A.M. Cypess, A.P. White, C. Vernochet, T.J. Schulz, R. Xue, C.A. Sass, T.L. Huang, C. Roberts-Toler, L.S. Weiner, C. Sze, et al., Nat. Med. 19 (2013) 635–639. [26] S.G. Moore, K.L. Dawson, Radiology 175 (1990) 219–223.
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