INFORMATIVE NOTE

An opinion on the regulation of bone marrow adipose tissue by dietary fatty acids

S. Lopeza, A. Lemus-Conejob, M.A. Rosillob, F.J.G. Murianab and R. Abiab,*

aDepartment of Cell Biology, School of Biology, University of Seville, Seville, Spain.

bLaboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, Seville, Spain.

*Corresponding author: abia@ig.csic.es

 

SUMMARY

Obesity has a significant impact on predisposition to various diseases and also affects the viability and choice of haematopoietic stem cells (HSCs) to favour myeloid cell production and/or turnover, all of which are extremely important for the functioning of immune system. As the production of blood cells and mobilization of HSCs and their progeny are regulated, at least in part, by multifaceted interactions through signals that come from the bone marrow (BM) microenvironment, it does not seem astonishing to assume that circumstances that cause alterations in BM structure will unavoidably cause alterations in mesenchymal cells such as adipocytes and lineages from HSCs. The existence of adipose tissue in BM or marrow fat (BMAT) is well known, although its origin, expansion, and functions are poorly understood. Inspired by other studies showing the potential role for olive oil and omega-3 long chain polyunsaturated fatty acids (omega-3 PUFAs) on BM health, and by our own preliminary findings showing the effects of monounsaturated (olive oil) but not saturated (milk cream) dietary fats to contain neutrophils and CD14high monocytes in BM during postprandial periods in healthy volunteers, herein we asked whether dietary fats (saturated fatty acids, SFAs, monounsaturated fatty acids, MUFAs, and omega-3 PUFAs) may be a candidate lifestyle factor to modulate the expansion, composition, and function of BMAT, the infiltration of adipose tissue macrophages (ATMs) in BMAT and the mobilization of HSCs and mature myeloid cells from BM during high-fat-induced obesity in mice. This is the first time that the interplay between different dietary fatty acids, obesity, and BM is addressed.

 

RESUMEN

Una opinión sobre la regulación del tejido adiposo de médula ósea por los ácidos grasos de la dieta. La obesidad aumenta de forma significativa la susceptibilidad a diversas enfermedades y también afecta a la viabilidad y elección del destino de las células madre hematopoyéticas (HSCs) y las cinéticas de producción de los leucocitos que provienen de ellas, todo ello de extrema importancia para el funcionamiento del sistema inmune. Considerando que la producción de células sanguíneas y movilización de HSCs y su progenie están reguladas, al menos en parte, por interacciones complejas a través de señales que provienen del microambiente de la médula ósea (BM), no parece sorprendente suponer que condiciones que causen alteraciones en la estructura de BM inevitablemente causarán alteraciones en las células mesenquimales como los adipocitos y los linajes procedentes de las HSCs. Es bien conocida la existencia de tejido adiposo en BM (BMAT), aunque su origen, desarrollo, y sus funciones son muy poco conocidas. Basándonos en los resultados de otros autores, quienes han descrito que el aceite de oliva y los ácidos grasos poliinsaturados omega-3 de cadena larga (omega-3 PUFAs) pueden tener efectos beneficiosos en la salud ósea, y no en menor medida en nuestros estudios previos que sugieren la capacidad del aceite de oliva, al contrario que las grasas saturadas, de inducir la retención de neutrófilos y monocitos con CD14 en BM de voluntarios sanos durante periodos postprandiales, en esta propuesta se pretende evaluar si las grasas de la dieta (ácidos grasos saturados, SFAs, ácidos grasos monoinsaturados, MUFAs, y omega-3 PUFAs) tienen relevancia en la expansión, composición, y funcionalidad de BMAT, en la infiltración de macrófagos de tejido adiposo (ATMs) en BMAT, y en la movilización de HSCs y células maduras mieloides de BM durante la obesidad inducida por dietas ricas en grasas en animales de experimentación. Es la primera vez que se aborda la posible interacción entre diferentes ácidos grasos de la dieta, la obesidad, y BM.

 

ORCID ID: Lopez S https://orcid.org/0000-0001-5952-3568, Lemus-Conejo A https://orcid.org/0000-0002-5539-2393, Rosillo MA https://orcid.org/0000-0001-6470-4427, Muriana FJG https://orcid.org/0000-0002-9018-4792, Abia R https://orcid.org/0000-0003-2741-189X

KEYWORDS: Adipose tissue; Bone marrow; Olive oil; Omega-3 PUFAs; Saturated fats

PALABRAS CLAVE: Aceite de oliva; Ácidos grasos omega-3; Grasas saturadas; Médula ósea; Tejido adiposo

Citation/Cómo citar esta Nota Informativa: Lopez S, Lemus-Conejo A, Rosillo MA, Muriana FJG, Abia R. 2020. An opinion on the regulation of bone marrow adipose tissue by dietary fatty acids. Grasas Aceites 71 (3), e362. http://grasasyaceites.revistas.csic.es

Copyright: ©2020 CSIC. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.


 

CONTENT

In previous studies, we have identified atherosclerosis, thrombosis, and inflammatory risk factors associated to the ingestion of dietary fats during the postprandial period in humans (Lopez et al., 2018, 2011, 2010, 2008; Ortega-Gomez et al., 2017, 2012; Montserrat-de la Paz et al., 2016; Naranjo et al., 2016; Bermudez et al., 2014, 2011; Varela et al., 2011; Lopez-Miranda et al., 2010; Pacheco et al., 2008, 2006; Abia et al., 2003, 2001, 1999). Our findings included some of the putative mechanisms by which exogenous fatty acids modulate cellular and molecular targets in the aetiology and pathogenesis of cardiovascular disease (Varela et al., 2015, 2014, 2013; Lopez et al., 2013, 2007; Bermudez et al., 2012, 2008; Bellido et al., 2004; Pacheco et al., 2003, 2002, 2001). Recently, our research team has also discovered that neutrophils and monocytes/macrophages undergo phenotype/functional dynamic switch in response to the microenvironment signals during the period that follows the ingestion of dietary fats (manuscripts in preparation). We found that circulating neutrophil number was transiently increased after the ingestion of saturated (milk cream) but not of monounsaturated (refined olive oil) dietary fats. In addition, while total number of circulating monocytes was not postprandially affected, those monocytes expressing CD14 and CD16 at high density were characteristic after the ingestion of saturated and monounsaturated dietary fats, respectively. These observations are the first evidence of a potential crosstalk between exogenous fatty acids and bone marrow (BM) function, and suggest that dietary fats, in a fatty acid-dependent manner, could trigger myeloid cell mobilization in BM.

Hematopoietic stem cells (HSCs) exist in the BM and are in charge to generate all the cells necessary to refill the blood and immune systems. It is hierarchical and firmly orchestrated by a proper environment of cells and factors for controlling the fate decision of HSCs to preserve a steady platelet, erythrocyte, and leukocyte supply (Eaves, 2015; Boulais and Frenette, 2015). HSCs are rare (1 in 10000 BM cells), relatively quiescent (<5% are in cell cycle), and constitute the apex of a differentiation cascade of hematopoietic progenitor cells with gradually reduced regeneration competence while augmented ability of conversion into multiple blood cell lineages. The existence of subpopulations with different phenotypes among the progenitor cells involved in the reconstitution of haematopoiesis and able to produce the entire range of haematopoietic progeny cells has already been documented for a long time (Morrison and Scadden, 2014). According to the latest model of haematopoiesis, the multipotency of HSCs is conserved by the presence of long-term HSCs (LT-HSCs) that differentiate to yield short-term HSCs (ST-HSCs) in BM and no other population of HSCs is devoted to sustaining a certain lineage, but the potential lineage appears as the HSC grow (Adler et al., 2014). Blood and immune system have the requirement of a proper supply of red cells and mature leukocytes with a finite lifespan throughout life. It is more evident after stress situations in which both host defence and repair mechanisms are mobilized. Furthermore, intravenously injected HSCs during BM transplantation can also promote homing and engraftment of HSCs to BM and regenerate the HSC pool to meet the demand of blood and immunity (Lapidot et al., 2005). The endosteal and perivascular regions in bone are anatomical locations for HSCs within the BM. Several stromal cells, including mesenchymal stem cells (MSCs), secrete messengers [e.g. granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and stromal cell-derived factor 1 (SDF-1)/C-X-C motif chemokine ligand 12 (CXCL12)] that bind to cell-surface receptors on HSCs for modulating their survival and functional role (Morrison and Scadden, 2014; Mendelson and Frenette, 2014). In addition, HSCs are retained in restricted hematopoietic niches via adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), cadherins, annexin II, and E-selectin, where they receive and integrate extrinsic regulatory cues through the activation of transcription factors of the ETS family and partners, the main of which are crucial to divert the production to myeloid cells (Pittet et al., 2014).

Once neutrophils and monocytes are produced in mature form, they can leave the bone marrow into circulation. The release is tightly controlled by numerous signals such as C-C motif chemokine receptor 2 (CCR2) ligands [e.g. monocyte chemoattractant protein-1 (MCP-1)] and CXCL12. Migration of HPCs is limited, as only a few hundred are normally found outside BM (Massberg et al., 2007). However, proteases [neutrophil elastase (NE), cathepsin G, and metalloproteinases (MMPs)] produced by BM myeloid cells have been noticed to be involved in the cleavage and inactivation of CXCL12 and KIT ligand throughout mobilization of myeloid cells from BM in stress situations (Shen et al., 2010; Klein et al., 2015). Serine protease inhibitor α1-antitrypsin (A1AT) is expressed in BM to prevent the accidental cleavage of niche components by NE and cathepsin G, and extracellular matrix (ECM) disarrangement (Kuiperij et al., 2009). Genes encoding the small Rho guanosine triphosphatases Rac1 and Rac2 that control cell migration further promote the rapid mobilization and entry of HSCs into circulation (Gu et al., 2003). We have preliminary data showing that monounsaturated, when compared to saturated dietary fats, promote: (i) a higher content of A1AT in lipoproteins of intestinal origin, neutrophils, and monocytes (manuscript in preparation); and (ii) the activation of the phosphoinositide 3-kinase (PI3k)-Rac1-Jun N-terminal kinase (JNK) and Rac1-MMP-2 pathways in human perivascular smooth muscle cells (Varela et al., 2014). Therefore, it is tempting to speculate that dietary fats, in a fatty acid-dependent manner, may be involved on migratory capacity and release of HSCs.

In BM, cells of the osteoblast and adipocyte lineages have a common precursor, which comes from MSCs (Tian and Yu, 2015). Tracking the fate of MSCs in aged BM has revealed that close proximity between osteoblasts and adipocytes underscores the reciprocal relation of bone mass and BM adipogenesis. As a result, bone loss caused by osteoporosis is accompanied by a progressive BM adiposity, which suggests that differentiation of MSCs into adipocytes predominates over osteoblasts. To support MSC differentiation into either osteoblasts or adipocytes, it is essential that MSCs be recruited to proper density and confluence. Involved in modulating the lineage commitment, a variety of external stimuli delicately balanced include the release of growth factors [e.g. transforming growth factor-β (TGF-β) family members, bone morphogenic proteins (BMPs), and Wnt proteins] and transcription factors [e.g. peroxisome proliferator-activator gamma 2 (PPARγ2) for adipogenesis and runt-related transcription factor 2 (RUNX2) for osteogenesis]. The canonical Wnt/β-catenin pathway plays a major role in regulating these two differentiation processes (Yuan et al., 2016). Soluble Wnt proteins such as Wnt10b, Wnt1, Wnt6, Wnt7a, and Wnt10a have pro-osteogenic activity and prevent phosphorylation, and thereby degradation of β-catenin. Unphosphorylated β-catenin may then translocate into the nucleus to form transcriptional complexes along with members of the T-cell factor (Tcf)/lymphoid enhancer-binding factor (Lef) nuclear protein family and RUNX2. These processes facilitate the osteogenic differentiation of MSCs, the mineralization by increasing alkaline phosphatase (ALP) activity in pre-osteoblasts, and the expression of the anti-bone resorption osteoprotegerin (OPG). During bone formation, pro-osteogenic Wnt proteins (Wnt10b, Wnt1, Wnt6, Wnt7a, and Wnt10a) coordinate each other and bind to low-density lipoprotein receptor-related protein (LRP) family, most likely LRP5/6. This crosstalk stabilizes β-catenin and allows its translocation, promoting osteoblastogenesis whereas blocking adipogenesis (Cawthorn et al., 2012). However, other Wnt proteins (Wnt4, Wnt5a, and Wnt5b) obstruct these communications and networks, enabling degradation of β-catenin and inducing adipogenesis (Cristancho and Lazar, 2011). Previous studies noticed that MSCs are by-default programmed to differentiate into adipocytes (Lecka-Czernik, 2006; Kirkland et al., 2002). By contrast, when the nuclear envelope intermediate filament lamin A/C is overexpressed, as it occurs in the bone in youth, MSCs enter the osteogenic lineage, preventing MSCs to differentiate into adipocytes (Pajerowski et al., 2007; Bermeo et al., 2015). Disruption of nearly all of these conditions takes place with aging and therefore the balance between MSC osteogenesis and adipogenesis will move towards adipogenic differentiation. In a setting of PPARγ activation, adipogenesis in BM-MSCs is positively regulated. Through mechanisms mediated by PPARγ signalling pathways, Wnt proteins are inhibited, β-catenin is degraded, and lamin A/C expression is suppressed. Interestingly, systemic adipokynes that regulate insulin sensitivity can also influence the fate of MSCs in BM. Insulin impedes the production of OPG in osteoblasts, thus, an increased ratio of OPG to receptor activator of nuclear factor-kB ligand (RANKL) supports the release of active osteocalcin from bone ECM giving rise the release of insulin from pancreas (Chen et al., 2012). We have previously demonstrated that β-cell function and insulin sensitivity are modulated by meals enriched with refined olive oil (source of oleic acid) when compared to meals enriched with butter/milk cream (source of SFAs) (Lopez et al., 2011; Lopez et al., 2008), in agreement with a local action of meal-derived oleic and palmitic acids on pancreatic β-cells (Bermudez et al., 2014). The adipocyte/osteoblast balance is also highly regulated at the level of gene transcription by the transfer of adipogenic microRNAs from adipocytes to osteoblasts, which enhances BM adiposity (Martin et al., 2015).

Exponential accumulation of BM fat begins at birth. This happens more quickly in distal than in proximal bones, so that at 25 years old, BM is approximately 70% fat (Fazeli et al., 2013; Cawthorn et al., 2014). Apart from age, certain conditions such as metabolic diseases (type 1 and 2 diabetes) (Kurra and Siris, 2011), oestrogen withdrawal (Taxel et al., 2008), immobilization (Lau and Guo, 2011), glucocorticoid treatment (Havashi et al., 2009), Cushing’s disease (Geer et al., 2012), and caloric restriction (Devlin et al., 2010) favour fat accumulation within BM instead of bone formation. These risk factors encourage the MSCs to change into its default lineage: adipocytes. BM adipose tissue (BMAT) formation is further induced by several treatment modalities such as radiation, chemotherapy, and thiazolidinediones (Suchacki et al., 2016). Until the last few years, adipocytes were perceived by many as metabolically inactive cells in the BM niche, even as cells only intended to fill trabecular bone holes. It is now clear that the adipocyte within bone is indispensable for the normal function of other neighbouring cells in the marrow microenvironment. BM adipocytes are scattered throughout the hematopoietic tissue, instead of grouped in lobules as in other fat depots (Hardouin et al., 2014). It is relevant that subcutaneous and visceral adipose tissues (white adipose tissue, WAT) have a fatty acid composition different to that found in BM adipose tissue (BMAT), which is richer in saturated fatty acids (SFAs) and poorer in monounsaturated fatty acids (MUFAs) than subcutaneous or visceral WAT (Griffith et al., 2009). Observations from randomized controlled trials and population-based observational studies have shown that a high intake of fatty fish strongly correlates with a reduction in the burden of fragility fracture (Longo and Ward, 2016), suggesting that omega-3 long chain polyunsaturated fatty acids (omega-3 PUFAs), as demonstrated for oleic acid (Gillet et al., 2015; Garcia-Martinez et al., 2014), have potential benefits on BM cells and microenvironment. Under high levels of adipogenesis, BM adipocyte products (free fatty acids and adipokynes) may induce osteoblast apoptosis, even the fat tissue can undergo dramatic and repetitive sequences in the remodelling to allow tissue expansion and removal of dead adipocytes, which is a process mediated by adipose tissue macrophages (ATMs). This scenario causing a vicious circle is known as lipotoxicity (Ng and Duque, 2010). Conversely, when co-cultured with adipocytes having inhibited the fatty acid endogenous biosynthesis, osteoblasts increase survival and improve mineralization (Elbaz et al., 2010). There is now plenty evidence that lipotoxicity by ectopic fat accumulation in BM is common in other organs, including pancreas, muscle, and liver. In pancreas, newly arrived adipocytes (deposition of fat inside and around the pancreas) affect the function and induce the death of β-cells (Long et al., 2014). Interestingly, this fat-induced process may be orchestrated by fatty acids. For example, exposure of human islet cells to palmitic acid [the main SFA in the diet] impairs glucose-stimulated insulin secretion, reduces insulin gene transcription, and induces β-cell apoptosis, whereas oleic acid [the main MUFA in the diet] is cytoprotective for β-cells and even attenuates the pro-apoptotic effects of palmitic acid (Lopez et al., 2010). Similarly, among the adipocyte-secreted factors in BM, palmitic acid has negative effect on osteoblasts in co-culture (Gunaratnam et al., 2014; Wang et al., 2013): (i) lowering mineralization, ALP activity, and expression of osteogenic mRNA markers; (ii) increasing intracellular reactive oxygen species (ROS); and (iii) disrupting the Wnt signalling and BMP2/RUNX2/SMADs pathways. Evidence from proteomic analysis of adipocytes suggests the occurrence of changes during ageing BM from pro-osteogenic, anti-adipogenic, and anti-apoptotic phenotype in young mice to a toxic and pro-adipogenic phenotype in old mice through paracrine mechanisms involving local secretion of adipokynes particularly involved in BM function (Gasparrini et al., 2009). Recent studies have reported that secretion of leptin and adiponectin (the adipokynes whose receptors are expressed by osteoblasts and osteoclasts) is greater from BMAT than from visceral WAT (Cawthorn et al., 2014) and that adiponectin from BM adipocytes has a relevant role in mobilizing HSCs/HPCs into blood to participate in tissue repair and remodelling (Yu et al., 2015).

The link between progressively sedentary lifestyle and cumulative consumption of high-dense foods, exemplified by the “Western style” high-fat diet, has contributed to the global pandemic of obesity and related disorders. This diet-induced adiposity is generally localized in subcutaneous or visceral WAT. There are important metabolic differences between adipocytes in different anatomical compartments; therefore, the location of fat pads at any of these regions is not their only distinctive characteristic. In fact, this adipose heterogeneity is also visualized by their different roles in disease susceptibility. BMAT seems to be a special class of fat depot with unique functions. Despite a similar appearance to subcutaneous and visceral adipocytes, BM adipocytes have divergent physiological, hormonal, and metabolic responses. In the C57BL/6J and C3H/HeJ mouse strains, by using the osmium staining technique for comparative morphology, BMAT may be found in two different groups: constitutive BMAT (cBMAT) and “regulated” BMAT (rBMAT). cBMAT is formed very early after birth in distal region of tibia and in caudal vertebrae, its adipocytes look like those in WAT and are poorly responsive to systemic disturbances. On the other hand, rBMAT is developed later as smaller adipocytes scattered with other BM cells in proximal skeletal sites, being responsive to a range of environmental, metabolic, and genetic cues (Scheller et al., 2014). Strikingly, the analysis of lipids, gene expression patterns, and functions in rBMAT is different from cBMAT (Scheller et al., 2015). It is possible that the origin of BMAT, still unveiled, is dissimilar to that of other fat depots. Thus, the origin of WAT and brown adipose tissue (BAT) is even a matter of on-going debate. After body weight loss induced by caloric restriction or by starvation in an eating disorder such as anorexia nervosa, there is an increase of BMAT. This fat tissue accretion in BM is to some extent unexpected because other fat depots (for example, visceral WAT) are being mobilised to meet energy demands when excessive catabolic activities. It is unclear why this happens. Several hypotheses have been proposed to explain this apparent paradox, including the occupation by BMAT of BM cavity space in response to the eventual loss of trabecular bone, the expansion of BMAT in response to starvation-induced stress as an adaptive strategy for supporting survival of BM cells, and the adiponectin secretion by BMAT to enhance insulin sensitivity and to stimulate appetite (Scheller et al., 2014). Notwithstanding the relevance of BMAT for metabolic and hematopoietic outcomes, it remains unexplored whether dietary fatty acids are instrumental in BM adiposity and in the phenotype of BM adipocytes, which could balance the likely adverse effects of increased adipogenesis on BM organization and function.

ACKNOWLEDGMENTSTOP

This work was supported by the grant AGL2016-80852-R from The Spanish Ministry of Science, Innovation and Universities. MAR acknowledges financial support from the Spanish Research Council (CSIC)/Juan de la Cierva [FJCI-2017-33132].

 

REFERENCESTOP


Abia R, Pacheco YM, Montero E, Ruiz-Gutierrez V, Muriana FJ. 2003. Distribution of fatty acids from dietary oils into phospholipid classes of triacylglycerol-rich lipoproteins in healthy subjects. Life Sciences 72, 1643–1654.
Abia R, Pacheco YM, Perona JS, Montero E, Muriana FJ, Ruiz-Gutierrez V. 2001. The metabolic availability of dietary triacylglycerols from two high oleic oils during the postprandial period does not depend on the amount of oleic acid ingested by healthy men. The Journal of Nutrition 131, 59–65.
Abia R, Perona JS, Pacheco YM, Montero E, Muriana FJ, Ruiz-Gutierrez V. 1999. Postprandial triacylglycerols from dietary virgin olive oil are selectively cleared in humans. The Journal of Nutrition 129, 2184–2191.
Adler BJ, Kaushansky K, Rubin CT. 2014. Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nature Reviews. Endocrinology 10, 737–748. https://doi.org/10.1038/nrendo.2014.169
Bellido C, Lopez-Miranda J, Blanco-Colio LM, Perez-Martinez P, Muriana FJ, Martin-Ventura JL, Marin C, Gomez P, Fuentes F, Egido J, Perez-Jimenez F. 2004. Butter and walnuts, but not olive oil, elicit postprandial activation of nuclear transcription factor kappaB in peripheral blood mononuclear cells from healthy men. The American Journal of Clinical Nutrition 80, 1487–1491. https://doi.org/10.1093/ajcn/80.6.1487
Bermeo S, Vidal C, Zhou H, Duque G. 2015. Lamin A/C acts as an essential factor in mesenchymal stem cell differentiation through the regulation of the dynamics of the Wnt/β-catenin pathway. Journal of Cellular Biochemistry 116, 2344–2353. https://doi.org/10.1002/jcb.25185
Bermudez B, Lopez S, Ortega A, Varela LM, Pacheco YM, Abia R, Muriana FJ. 2011. Oleic acid in olive oil: from a metabolic framework toward a clinical perspective. Current Pharmaceutical Design 17, 831–843.
Bermudez B, Lopez S, Pacheco YM, Villar J, Muriana FJ, Hoheisel JD, Bauer A, Abia R. 2008. Influence of postprandial triglyceride-rich lipoproteins on lipid-mediated gene expression in smooth muscle cells of the human coronary artery. Cardiovascular Research 79, 294–303. https://doi.org/10.1093/cvr/cvn082
Bermudez B, Lopez S, Varela LM, Ortega A, Pacheco YM, Moreda W, Moreno-Luna R, Abia R, Muriana FJ. 2012. Triglyceride-rich lipoprotein regulates APOB48 receptor gene expression in human THP-1 monocytes and macrophages. The Journal of Nutrition 142, 227–232. https://doi.org/10.3945/jn.111.149963
Bermudez B, Ortega-Gomez A, Varela LM, Villar J, Abia R, Muriana FJ, Lopez S. 2014. Clustering effects on postprandial insulin secretion and sensitivity in response to meals with different fatty acid compositions. Food & Function 5, 1374–1380. https://doi.org/10.1039/c4fo00067f
Boulais PE, Frenette PS. 2015. Making sense of hematopoietic stem cell niches. Blood 125, 2621–2629. https://doi.org/10.1182/blood-2014-09-570192
Cawthorn WP, Bree AJ, Yao Y, Du B, Hemati N, Martinez-Santibañez G, MacDougald OA. 2012. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism. Bone 50, 477–489. https://doi.org/10.1016/j.bone.2011.08.010
Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, Ning X, Bree AJ, Schell B, Broome DT, Soliman SS, DelProposto JL, Lumeng CN, Mitra A, Pandit SV, Gallagher KA, Miller JD, Krishnan V, Hui SK, Bredella MA, Fazeli PK, Klibanski A, Horowitz MC, Rosen CJ, MacDougald OA. 2014. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metabolism 20, 368–375. https://doi.org/10.1016/j.cmet.2014.06.003
Chen X, Tian HM, Yu XJ. 2012. Bone delivers its energy information to fat and islets through osteocalcin. Orthopaedic Surgery 4, 114–117. https://doi.org/10.1111/j.1757-7861.2012.00180.x
Cristancho AG, Lazar MA. 2011. Forming functional fat: a growing understanding of adipocyte differentiation. Nature Reviews. Molecular Cell Biology 12, 722–734. https://doi.org/10.1038/nrm3198
Devlin MJ, Cloutier AM, Thomas NA, Panus DA, Lotinun S, Pinz I, Baron R, Rosen CJ, Bouxsein ML. 2010. Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. Journal of Bone and Mineral Research 25, 2078–2088. https://doi.org/10.1002/jbmr.82
Eaves CJ. 2015. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 125, 2605–2613. https://doi.org/10.1182/blood-2014-12-570200
Elbaz A, Wu X, Rivas D, Gimble JM, Duque G. 2010. Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro. Journal of Cellular and Molecular Medicine 14, 982-991. https://doi.org/10.1111/j.1582-4934.2009.00751.x
Fazeli PK, Horowitz MC, MacDougald OA, Scheller EL, Rodeheffer MS, Rosen CJ, Klibanski A. 2013. Marrow fat and bone--new perspectives. The Journal of Clinical Endocrinology and Metabolism 98, 935–945. https://doi.org/10.1210/jc.2012-3634
Garcia-Martinez O, Rivas A, Ramos-Torrecillas J, De Luna-Bertos E, Ruiz C. 2014. The effect of olive oil on osteoporosis prevention. International Journal of Food Sciences and Nutrition 65, 834–840. https://doi.org/10.3109/09637486.2014.931361
Gasparrini M, Rivas D, Elbaz A, Duque G. 2009. Differential expression of cytokines in subcutaneous and marrow fat of aging C57BL/6J mice. Experimental Gerontology 44, 613–618. https://doi.org/10.1016/j.exger.2009.05.009
Geer EB, Shen W, Strohmayer E, Post KD, Freda PU. 2012. Body composition and cardiovascular risk markers after remission of Cushing’s disease: a prospective study using whole-body MRI. The Journal of Clinical Endocrinology and Metabolism 97, 1702–1711. https://doi.org/10.1210/jc.2011-3123
Gillet C, Spruyt D, Rigutto S, Dalla Valle A, Berlier J, Louis C, Debier C, Gaspard N, Malaisse WJ, Gangji V, Rasschaert J. 2015. Oleate abrogates palmitate-induced lipotoxicity and proinflammatory response in human bone marrow-derived mesenchymal stem cells and osteoblastic cells. Endocrinology 156, 4081–4093. https://doi.org/10.1210/en.2015-1303
Griffith JF, Yeung DK, Ahuja AT, Choy CW, Mei WY, Lam SS, Lam TP, Chen ZY, Leung PC. 2009. A study of bone marrow and subcutaneous fatty acid composition in subjects of varying bone mineral density. Bone 44, 1092–1096. https://doi.org/10.1016/j.bone.2009.02.022
Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, Harris CE, Lee AW, Prabhakar R, Atkinson SJ, Kwiatkowski DJ, Williams DA. 2003. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302, 445–449. https://doi.org/10.1126/science.1088485
Gunaratnam K, Vidal C, Gimble JM, Duque G. 2014. Mechanisms of palmitate-induced lipotoxicity in human osteoblasts. Endocrinology 155, 108–116. https://doi.org/10.1210/en.2013-1712
Hardouin P, Pansini V, Cortet B. 2014. Bone marrow fat. Joint, Bone, Spine 81, 313–319. https://doi.org/10.1016/j.jbspin.2014.02.013
Hayashi K, Yamaguchi T, Yano S, Kanazawa I, Yamauchi M, Yamamoto M, Sugimoto T. 2009. BMP/Wnt antagonists are upregulated by dexamethasone in osteoblasts and reversed by alendronate and PTH: potential therapeutic targets for glucocorticoid-induced osteoporosis. Biochemical and Biophysical Research Communications 379, 261–266. https://doi.org/10.1016/j.bbrc.2008.12.035
Kirkland JL, Tchkonia T, Pirtskhalava T, Han J, Karagiannides I. 2002. Adipogenesis and aging: does aging make fat go MAD? Experimental Gerontology 37, 757–767.
Klein G, Schmal O, Aicher WK. 2015. Matrix metalloproteinases in stem cell mobilization. Matrix Biology 44, 175–183. https://doi.org/10.1016/j.matbio.2015.01.011
Kuiperij HB, van Pel M, de Rooij KE, Hoeben RC, Fibbe WE. 2009. Serpina1 (alpha1-AT) is synthesized in the osteoblastic stem cell niche. Experimental Hematology 37, 641–647. https://doi.org/10.1016/j.exphem.2009.02.004
Kurra S, Siris E. 2011. Diabetes and bone health: the relationship between diabetes and osteoporosis-associated fractures. Diabetes Metabolism Research and Reviews 27, 430–435. https://doi.org/10.1002/dmrr.1197
Lapidot T, Dar A, Kollet O. 2005. How do stem cells find their way home? Blood 106, 1901–1910. https://doi.org/10.1182/blood-2005-04-1417
Lau RY, Guo X. 2011. A review on current osteoporosis research: with special focus on disuse bone loss. Journal of Osteoporosis 2011, 293808. https://doi.org/10.4061/2011/293808.
Lecka-Czernik B. 2006. PPARs and bone metabolism. PPAR Research 2006, 18089. https://doi.org/10.1155/PPAR/2006/18089
Long J, Su YX, Deng HC. 2014. Lipoapoptosis pathways in pancreatic β-cells and the anti-apoptosis mechanisms of adiponectin. Hormone and Metabolic Research 46, 722–727. https://doi.org/10.1055/s-0034-1382014
Longo AB, Ward WE. 2016. PUFAs, bone mineral density, and fragility fracture: findings from human studies. Advances in Nutrition 7, 299–312. https://doi.org/10.3945/an.115.009472
Lopez S, Bermudez B, Abia R, Muriana FJ. 2010. The influence of major dietary fatty acids on insulin secretion and action. Current Opinion in Lipidology 21, 15–20. https://doi.org/10.1097/MOL.0b013e3283346d39
Lopez S, Bermudez B, Montserrat-de la Paz S, Abia R, Muriana FJG. 2018. A microRNA expression signature of the postprandial state in response to a high-saturated-fat challenge. The Journal of Nutritional Biochemistry 57, 45–55. https://doi.org/10.1016/j.jnutbio.2018.03.010
Lopez S, Bermudez B, Ortega A, Varela LM, Pacheco YM, Villar J, Abia R, Muriana FJ. 2011. Effects of meals rich in either monounsaturated or saturated fat on lipid concentrations and on insulin secretion and action in subjects with high fasting triglyceride concentrations. The American Journal of Clinical Nutrition 93, 494–499. https://doi.org/10.3945/ajcn.110.003251
Lopez S, Bermudez B, Pacheco YM, Lopez-Lluch G, Moreda W, Villar J, Abia R, Muriana FJ. 2007. Dietary oleic and palmitic acids modulate the ratio of triacylglycerols to cholesterol in postprandial triacylglycerol-rich lipoproteins in men and cell viability and cycling in human monocytes. The Journal of Nutrition 137, 1999–2005. https://doi.org/10.1093/jn/137.9.1999
Lopez S, Bermudez B, Pacheco YM, Villar J, Abia R, Muriana FJ. 2008. Distinctive postprandial modulation of beta cell function and insulin sensitivity by dietary fats: monounsaturated compared with saturated fatty acids. The American Journal of Clinical Nutrition 88, 638–644. https://doi.org/10.1093/ajcn/88.3.638
Lopez S, Jaramillo S, Varela LM, Ortega A, Bermudez B, Abia R, Muriana FJ. 2013. p38 MAPK protects human monocytes from postprandial triglyceride-rich lipoprotein-induced toxicity. The Journal of Nutrition 143, 620–626. https://doi.org/10.3945/jn.113.174656
Lopez-Miranda J, Perez-Jimenez F, Ros E, De Caterina R, Badimon L, Covas MI, Escrich E, Ordovas JM, Soriguer F, Abia R, de la Lastra CA, Battino M, Corella D, Chamorro-Quiros J, Delgado-Lista J, Giugliano D, Esposito K, Estruch R, Fernandez-Real JM, Gaforio JJ, La Vecchia C, Lairon D, Lopez-Segura F, Mata P, Menendez JA, Muriana FJ, Osada J, Panagiotakos DB, Paniagua JA, Perez-Martinez P, Perona J, Peinado MA, Pineda-Priego M, Poulsen HE, Quiles JL, Ramirez-Tortosa MC, Ruano J, Serra-Majem L, Sola R, Solanas M, Solfrizzi V, de la Torre-Fornell R, Trichopoulou A, Uceda M, Villalba-Montoro JM, Villar-Ortiz JR, Visioli F, Yiannakouris N. 2008. Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008. Nutrition, Metabolism, and Cardiovascular Diseases 20, 284–294. https://doi.org/10.1016/j.numecd.2009.12.007
Martin PJ, Haren N, Ghali O, Clabaut A, Chauveau C, Hardouin P, Broux O. 2015. Adipogenic RNAs are transferred in osteoblasts via bone marrow adipocytes-derived extracellular vesicles (EVs). BMC Cell Biology 16, 10. https://doi.org/10.1186/s12860-015-0057-5
Massberg S, Schaerli P, Knezevic-Maramica I, Köllnberger M, Tubo N, Moseman EA, Huff IV, Junt T, Wagers AJ, Mazo IB, von Andrian UH. 2007. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008. https://doi.org/10.1016/j.cell.2007.09.047
Mendelson A, Frenette PS. 2014. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nature Medicine 20, 833–846. https://doi.org/10.1038/nm.3647
Montserrat-de la Paz S, Bermudez B, Cardelo MP, Lopez S, Abia R, Muriana FJ. 2016. Olive oil and postprandial hyperlipidemia: implications for atherosclerosis and metabolic syndrome. Food & Function 7, 4734–4744. https://doi.org/10.1039/c6fo01422d
Morrison SJ, Scadden DT. 2014. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334. https://doi.org/10.1038/nature12984
Naranjo MC, Garcia I, Bermudez B, Lopez S, Cardelo MP, Abia R, Muriana FJ, Montserrat-de la Paz S. 2016. Acute effects of dietary fatty acids on osteclastogenesis via RANKL/RANK/OPG system. Molecular Nutrition & Food Research 60, 2505–2513. https://doi.org/10.1002/mnfr.201600303
Ng A, Duque G. 2010. Osteoporosis as a lipotoxic disease. IBMS BoneKEy 7, 108–123.
Ortega A, Varela LM, Bermudez B, Lopez S, Abia R, Muriana FJ. 2012. Dietary fatty acids linking postprandial metabolic response and chronic diseases. Food & Function 3, 22–27. https://doi.org/10.1039/c1fo10085h
Ortega-Gomez A, Varela LM, Lopez S, Montserrat de la Paz S, Sanchez R, Muriana FJG, Bermudez B, Abia R. 2017. Postprandial triglyceride-rich lipoproteins promote lipid accumulation and apolipoprotein B-48 receptor transcriptional activity in human circulating and murine bone marrow neutrophils in a fatty acid-dependent manner. Molecular Nutrition & Food Research 61. https://doi.org/10.1002/mnfr.201600879
Pacheco YM, Abia R, Olivera A, Spiegel S, Ruiz-Gutierrez V, Muriana FJ. 2003. Sphingosine 1-phosphate signal survival and mitogenesis are mediated by lipid-stereospecific binding of triacylglycerol-rich lipoproteins. Cellular and Molecular Life Sciences 60, 2757–2766. https://doi.org/10.1007/s00018-003-3323-1
Pacheco YM, Abia R, Perona JS, Meier KE, Montero E, Ruiz-Gutierrez V, Muriana FJ. 2002. Triacylglycerol-rich lipoproteins trigger the phosphorylation of extracellular-signal regulated kinases in vascular cells. Life Sciences 71, 1351–1360.
Pacheco YM, Abia R, Perona JS, Reina M, Ruiz-Gutierrez V, Montero E, Muriana FJ. 2001. Triacylglycerol-rich lipoproteins interact with human vascular cells in a lipid-dependent fashion. Journal of Agricultural and Food Chemistry 49, 5653–5661.
Pacheco YM, Bermudez B, Lopez S, Abia R, Villar J, Muriana FJ. 2006. Ratio of oleic to palmitic acid is a dietary determinant of thrombogenic and fibrinolytic factors during the postprandial state in men. The American Journal of Clinical Nutrition 84, 342–349. https://doi.org/10.1093/ajcn/84.1.342
Pacheco YM, Lopez S, Bermudez B, Abia R, Villar J, Muriana FJ. 2008. A meal rich in oleic acid beneficially modulates postprandial sICAM-1 and sVCAM-1 in normotensive and hypertensive hypertriglyceridemic subjects. The Journal of Nutritional Biochemistry 19, 200–205. https://doi.org/10.1016/j.jnutbio.2007.03.002
Pajerowski JD, Dahl KN, Zhong FL, Sammak PJ, Discher DE. 2007. Physical plasticity of the nucleus in stem cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 104, 15619–15624. https://doi.org/10.1073/pnas.0702576104
Pittet MJ, Nahrendorf M, Swirski FK. 2014. The journey from stem cell to macrophage. Annals of the New York Academy of Sciences 1319, 1–18. https://doi.org/10.1111/nyas.12393
Scheller EL, Doucette CR, Learman BS, Cawthorn WP, Khandaker S, Schell B, Wu B, Ding SY, Bredella MA, Fazeli PK, Khoury B, Jepsen KJ, Pilch PF, Klibanski A, Rosen CJ, MacDougald OA. 2015. Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues. Nature Communications 6, 7808. https://doi.org/10.1038/ncomms8808
Scheller EL, Rosen CJ. 2014. What’s the matter with MAT? Marrow adipose tissue, metabolism, and skeletal health. Annals of the New York Academy of Sciences 1311, 14–30. https://doi.org/10.1111/nyas.12327
Scheller EL, Troiano N, Vanhoutan JN, Bouxsein MA, Fretz JA, Xi Y, Nelson T, Katz G, Berry R, Church CD, Doucette CR, Rodeheffer MS, Macdougald OA, Rosen CJ, Horowitz MC. 2014. Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. Methods in Enzymology 537, 123–139. https://doi.org/10.1016/B978-0-12-411619-1.00007-0
Shen Y, Winkler IG, Barbier V, Sims NA, Hendy J, Levesque JP. 2010. Tissue inhibitor of metalloproteinase-3 (TIMP-3) regulates hematopoiesis and bone formation in vivo. PLoS One 5, e13086. https://doi.org/10.1371/journal.pone.0013086
Suchacki KJ, Cawthorn WP, Rosen CJ. 2016. Bone marrow adipose tissue: formation, function and regulation. Current Opinion in Pharmacology 28, 50–56. https://doi.org/10.1016/j.coph.2016.03.001
Taxel P, Kaneko H, Lee SK, Aguila HL, Raisz LG, Lorenzo JA. 2008. Estradiol rapidly inhibits osteoclastogenesis and RANKL expression in bone marrow cultures in postmenopausal women: a pilot study. Osteoporosis International 19, 193–199. https://doi.org/10.1007/s00198-007-0452-7
Tian L, Yu X. 2015. Lipid metabolism disorders and bone dysfunction--interrelated and mutually regulated (review). Molecular Medicine Reports 12, 783–794. https://doi.org/10.3892/mmr.2015.3472
Varela LM, Bermudez B, Ortega-Gomez A, Lopez S, Sanchez R, Villar J, Anguille C, Muriana FJ, Roux P, Abia R. 2014. Postprandial triglyceride-rich lipoproteins promote invasion of human coronary artery smooth muscle cells in a fatty-acid manner through PI3k-Rac1-JNK signaling. Molecular Nutrition & Food Research 58, 1349–1364. https://doi.org/10.1002/mnfr.201300749
Varela LM, Lopez S, Ortega-Gomez A, Bermudez B, Buers I, Robenek H, Muriana FJ, Abia R. 2015. Postprandial triglyceride-rich lipoproteins regulate perilipin-2 and perilipin-3 lipid-droplet-associated proteins in macrophages. The Journal of Nutritional Biochemistry 26, 327–336. https://doi.org/10.1016/j.jnutbio.2014.11.007
Varela LM, Ortega A, Bermudez B, Lopez S, Pacheco YM, Villar J, Abia R, Muriana FJ. 2011. A high-fat meal promotes lipid-load and apolipoprotein B-48 receptor transcriptional activity in circulating monocytes. The American Journal of Clinical Nutrition 93, 918–925. https://doi.org/10.3945/ajcn.110.007765
Varela LM, Ortega-Gomez A, Lopez S, Abia R, Muriana FJ, Bermudez B. 2013. The effects of dietary fatty acids on the postprandial triglyceride-rich lipoprotein/apoB48 receptor axis in human monocyte/macrophage cells. The Journal of Nutritional Biochemistry 24, 2031–2039. https://doi.org/10.1016/j.jnutbio.2013.07.004
Wang D, Haile A, Jones LC. 2013. Dexamethasone-induced lipolysis increases the adverse effect of adipocytes on osteoblasts using cells derived from human mesenchymal stem cells. Bone 53, 520–530. https://doi.org/10.1016/j.bone.2013.01.009
Yu L, Tu Q, Han Q, Zhang L, Sui L, Zheng L, Meng S, Tang Y, Xuan D, Zhang J, Murray D, Shen Q, Cheng J, Kim SH, Dong LQ, Valverde P, Cao X, Chen J. 2015. Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes. Stem Cells 33, 240–252. https://doi.org/10.1002/stem.1844
Yuan Z, Li Q, Luo S, Liu Z, Luo D, Zhang B, Zhang D, Rao P, Xiao J. 2016. PPARγ and Wnt signaling in adipogenic and osteogenic differentiation of mesenchymal stem cells. Current Stem Cell Research & Therapy 11, 216–225.



Copyright (c) 2020 Consejo Superior de Investigaciones Científicas (CSIC)

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


Contact us grasasyaceites@ig.csic.es

Technical support soporte.tecnico.revistas@csic.es