PURPOSE OF REVIEW: The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS: Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.

Department of Cellular and Molecular Medicine The Novo Nordisk Foundation Center for Stem Cell Biology Panum Institute University of Copenhagen Copenhagen Denmark

Department of Community Health Sciences College of Applied Medical Sciences King Saud University Riyadh Saudi Arabia

Department of Molecular Endocrinology KMEB University of Southern Denmark and Odense University Hospital 5000 Odense C Denmark

Department of Molecular Physiology of Bone Institute of Physiology Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Stem Cell Unit Department of Anatomy College of Medicine King Saud University Riyadh Saudi Arabia

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Tencerova M, Kassem M. The bone marrow-derived stromal cells: commitment and regulation of adipogenesis. Front Endocrinol (Lausanne). 2016;7:–127. PubMed PMC

Kim TY, Schafer AL. Diabetes and bone marrow adiposity. Curr Osteoporos Rep. 2016;14(6):337–344. doi: 10.1007/s11914-016-0336-x. PubMed DOI PMC

Bartelt Alexander, Koehne Till, Tödter Klaus, Reimer Rudolph, Müller Brigitte, Behler-Janbeck Friederike, Heeren Joerg, Scheja Ludger, Niemeier Andreas. Quantification of Bone Fatty Acid Metabolism and Its Regulation by Adipocyte Lipoprotein Lipase. International Journal of Molecular Sciences. 2017;18(6):1264. doi: 10.3390/ijms18061264. PubMed DOI PMC

Hawkes CP, Mostoufi-Moab S. Fat-bone interaction within the bone marrow milieu: impact on hematopoiesis and systemic energy metabolism. Bone. 2019;119:57–64. doi: 10.1016/j.bone.2018.03.012. PubMed DOI PMC

Li Q, Wu Y, Kang N. Marrow adipose tissue: its origin, function, and regulation in bone remodeling and regeneration. Stem Cells Int. 2018;2018:7098456. PubMed PMC

Sebo ZL, Rendina-Ruedy E, Ables GP, Lindskog DM, Rodeheffer MS, Fazeli PK, Horowitz MC. Bone marrow adiposity: basic and clinical implications. Endocr Rev. 2019;40(5):1187–1206. doi: 10.1210/er.2018-00138. PubMed DOI PMC

Yue R, Zhou BO, Shimada IS, Zhao Z, Morrison SJ. Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow. Cell Stem Cell. 2016;18(6):782–796. doi: 10.1016/j.stem.2016.02.015. PubMed DOI

Holt V, Caplan AI, Haynesworth SE. Identification of a subpopulation of marrow MSC-derived medullary adipocytes that express osteoclast-regulating molecules: marrow adipocytes express osteoclast mediators. PLoS One. 2014;9(10):e108920. doi: 10.1371/journal.pone.0108920. PubMed DOI PMC

Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20(6):771–84 e6. doi: 10.1016/j.stem.2017.02.009. PubMed DOI PMC

Pineault KM, Song JY, Kozloff KM, Lucas D, Wellik DM. Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life. Nat Commun. 2019;10(1):3168. doi: 10.1038/s41467-019-11100-4. PubMed DOI PMC

Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 2014;20(2):368–375. doi: 10.1016/j.cmet.2014.06.003. PubMed DOI PMC

Jafari A, Qanie D, Andersen TL, Zhang Y, Chen L, Postert B, Parsons S, Ditzel N, Khosla S, Johansen HT, Kjærsgaard-Andersen P, Delaisse JM, Abdallah BM, Hesselson D, Solberg R, Kassem M. Legumain regulates differentiation fate of human bone marrow stromal cells and is altered in postmenopausal osteoporosis. Stem Cell Reports. 2017;8(2):373–386. doi: 10.1016/j.stemcr.2017.01.003. PubMed DOI PMC

Abdallah BM, Kassem M. New factors controlling the balance between osteoblastogenesis and adipogenesis. Bone. 2012;50(2):540–545. doi: 10.1016/j.bone.2011.06.030. PubMed DOI

Abdallah BM, Jensen CH, Gutierrez G, Leslie RG, Jensen TG, Kassem M. Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. J Bone Miner Res. 2004;19(5):841–852. doi: 10.1359/jbmr.040118. PubMed DOI

Zhu L, Xu Z, Li G, Wang Y, Li X, Shi X, Lin H, Chang S. Marrow adiposity as an indicator for insulin resistance in postmenopausal women with newly diagnosed type 2 diabetes - an investigation by chemical shift-encoded water-fat MRI. Eur J Radiol. 2019;113:158–164. doi: 10.1016/j.ejrad.2019.02.020. PubMed DOI

Artsi H, Gurt I, El-Haj M, Muller R, Kuhn GA, Ben Shalom G, et al. Sirt1 promotes a thermogenic gene program in bone marrow adipocytes: from mice to (wo)men. Front Endocrinol (Lausanne) 2019;10:126. doi: 10.3389/fendo.2019.00126. PubMed DOI PMC

Li Y, Meng Y, Yu X. The unique metabolic characteristics of bone marrow adipose tissue. Front Endocrinol (Lausanne) 2019;10:69. doi: 10.3389/fendo.2019.00069. PubMed DOI PMC

Tencerova M, Figeac F, Ditzel N, Taipaleenmaki H, Nielsen TK, Kassem M. High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice. J Bone Miner Res. 2018;33(6):1154–1165. doi: 10.1002/jbmr.3408. PubMed DOI

Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2012;50(2):534–539. doi: 10.1016/j.bone.2011.06.032. PubMed DOI PMC

Qiang G, Whang Kong H, Xu S, Pham HA, Parlee SD, Burr AA, Gil V, Pang J, Hughes A, Gu X, Fantuzzi G, MacDougald O, Liew CW. Lipodystrophy and severe metabolic dysfunction in mice with adipose tissue-specific insulin receptor ablation. Mol Metab. 2016;5(7):480–490. doi: 10.1016/j.molmet.2016.05.005. PubMed DOI PMC

Irwin R, Lin HV, Motyl KJ, McCabe LR. Normal bone density obtained in the absence of insulin receptor expression in bone. Endocrinology. 2006;147(12):5760–5767. doi: 10.1210/en.2006-0700. PubMed DOI

Tencerova M, Frost M, Figeac F, Nielsen TK, Ali D, Lauterlein JL, et al. Obesity-associated hypermetabolism and accelerated senescence of bone marrow stromal stem cells suggest a potential mechanism for bone fragility. Cell Rep. 2019;27(7):2050–62 e6. doi: 10.1016/j.celrep.2019.04.066. PubMed DOI

Yu EW, Greenblatt L, Eajazi A, Torriani M, Bredella MA. Marrow adipose tissue composition in adults with morbid obesity. Bone. 2017;97:38–42. doi: 10.1016/j.bone.2016.12.018. PubMed DOI PMC

Wang Y, Yang L, Liu X, Hong T, Wang T, Dong A, et al. miR-431 inhibits adipogenic differentiation of human bone marrow-derived mesenchymal stem cells via targeting insulin receptor substance 2. Stem Cell Res Ther. 2018;9(1):231. doi: 10.1186/s13287-018-0980-4. PubMed DOI PMC

Wang N, Li Y, Li Z, Ma J, Wu X, Pan R, Wang Y, Gao L, Bao X, Xue P. IRS-1 targets TAZ to inhibit adipogenesis of rat bone marrow mesenchymal stem cells through PI3K-Akt and MEK-ERK pathways. Eur J Pharmacol. 2019;849:11–21. doi: 10.1016/j.ejphar.2019.01.064. PubMed DOI

Tang CY, Man XF, Guo Y, Tang HN, Tang J, Zhou CL, Tan SW, Wang M, Zhou HD. IRS-2 partially compensates for the insulin signal defects in IRS-1(−/−) mice mediated by miR-33. Mol Cells. 2017;40(2):123–132. doi: 10.14348/molcells.2017.2228. PubMed DOI PMC

Maridas DE, DeMambro VE, Le PT, Mohan S, Rosen CJ. IGFBP4 is required for adipogenesis and influences the distribution of adipose depots. Endocrinology. 2017;158(10):3488–3500. doi: 10.1210/en.2017-00248. PubMed DOI PMC

Dinchuk JE, Cao C, Huang F, Reeves KA, Wang J, Myers F, et al. Insulin receptor (IR) pathway hyperactivity in IGF-IR null cells and suppression of downstream growth signaling using the dual IGF-IR/IR inhibitor, BMS-754807. Endocrinology. 2010;151(9):4123–4132. doi: 10.1210/en.2010-0032. PubMed DOI

Slaaby R, Schaffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, et al. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem. 2006;281(36):25869–25874. doi: 10.1074/jbc.M605189200. PubMed DOI

Patel VS, Ete Chan M, Rubin J, Rubin CT. Marrow adiposity and hematopoiesis in aging and obesity: exercise as an intervention. Curr Osteoporos Rep. 2018;16(2):105–115. doi: 10.1007/s11914-018-0424-1. PubMed DOI PMC

Ghali O, Al Rassy N, Hardouin P, Chauveau C. Increased bone marrow adiposity in a context of energy deficit: the tip of the iceberg? Front Endocrinol (Lausanne) 2016;7:125. doi: 10.3389/fendo.2016.00125. PubMed DOI PMC

Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, Rosen CJ, Klibanski A, Miller KK. Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women. Obesity (Silver Spring) 2011;19(1):49–53. doi: 10.1038/oby.2010.106. PubMed DOI PMC

Menagh PJ, Turner RT, Jump DB, Wong CP, Lowry MB, Yakar S, Rosen CJ, Iwaniec UT. Growth hormone regulates the balance between bone formation and bone marrow adiposity. J Bone Miner Res. 2010;25(4):757–768. PubMed PMC

Fritton JC, Kawashima Y, Mejia W, Courtland HW, Elis S, Sun H, Wu Y, Rosen CJ, Clemmons D, Yakar S. The insulin-like growth factor-1 binding protein acid-labile subunit alters mesenchymal stromal cell fate. J Biol Chem. 2010;285(7):4709–4714. doi: 10.1074/jbc.M109.041913. PubMed DOI PMC

Kim TY, Schwartz AV, Li X, Xu K, Black DM, Petrenko DM, Stewart L, Rogers SJ, Posselt AM, Carter JT, Shoback DM, Schafer AL. Bone marrow fat changes after gastric bypass surgery are associated with loss of bone mass. J Bone Miner Res. 2017;32(11):2239–2247. doi: 10.1002/jbmr.3212. PubMed DOI PMC

Moseley KF, Doyle ME, Jan De Beur SM. Diabetic serum from older women increases adipogenic differentiation in mesenchymal stem cells. Endocr Res. 2018;43(3):155–165. doi: 10.1080/07435800.2018.1441868. PubMed DOI PMC

Baum T, Yap SP, Karampinos DC, Nardo L, Kuo D, Burghardt AJ, et al. Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus? J Magn Reson Imaging. 2012;35(1):117–124. doi: 10.1002/jmri.22757. PubMed DOI PMC

Ramasamy R, Yan SF, Schmidt AM. Receptor for AGE (RAGE): signaling mechanisms in the pathogenesis of diabetes and its complications. Ann N Y Acad Sci. 2011;1243:88–102. doi: 10.1111/j.1749-6632.2011.06320.x. PubMed DOI PMC

Chuah YK, Basir R, Talib H, Tie TH, Nordin N. Receptor for advanced glycation end products and its involvement in inflammatory diseases. Int J Inflam. 2013;2013:403460. doi: 10.1155/2013/403460. PubMed DOI PMC

Aikawa E, Fujita R, Asai M, Kaneda Y, Tamai K. Receptor for advanced glycation end products-mediated signaling impairs the maintenance of bone marrow mesenchymal stromal cells in diabetic model mice. Stem Cells Dev. 2016;25(22):1721–1732. doi: 10.1089/scd.2016.0067. PubMed DOI

Motyl KJ, McCauley LK, McCabe LR. Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. J Cell Physiol. 2012;227(4):1326–1334. doi: 10.1002/jcp.22844. PubMed DOI PMC

Yang M, Arai A, Udagawa N, Zhao L, Nishida D, Murakami K, et al. Parathyroid hormone shifts cell fate of a Leptin receptor-marked stromal population from adipogenic to osteoblastic lineage. J Bone Miner Res. 2019. PubMed

Fan Y, Hanai JI, Le PT, Bi R, Maridas D, DeMambro V, et al. Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab. 2017;25(3):661–672. doi: 10.1016/j.cmet.2017.01.001. PubMed DOI PMC

Lee HM, Joo BS, Lee CH, Kim HY, Ock JH, Lee YS. Effect of glucagon-like peptide-1 on the differentiation of adipose-derived stem cells into osteoblasts and adipocytes. J Menopausal Med. 2015;21(2):93–103. doi: 10.6118/jmm.2015.21.2.93. PubMed DOI PMC

Luciani P, Fibbi B, Mazzanti B, Deledda C, Ballerini L, Aldinucci A, et al. The effects of Exendin-4 on bone marrow-derived mesenchymal cells. Endocrine. 2018;60(3):423–434. doi: 10.1007/s12020-017-1430-2. PubMed DOI

Meng J, Ma X, Wang N, Jia M, Bi L, Wang Y, Li M, Zhang H, Xue X, Hou Z, Zhou Y, Yu Z, He G, Luo X. Activation of GLP-1 receptor promotes bone marrow stromal cell osteogenic differentiation through beta-catenin. Stem Cell Reports. 2016;6(4):579–591. doi: 10.1016/j.stemcr.2016.02.002. PubMed DOI PMC

Abdallah BM, Ditzel N, Laborda J, Karsenty G, Kassem M. DLK1 regulates whole-body glucose metabolism: a negative feedback regulation of the osteocalcin-insulin loop. Diabetes. 2015;64(9):3069–3080. doi: 10.2337/db14-1642. PubMed DOI

Thrailkill K, Bunn RC, Lumpkin C, Jr, Wahl E, Cockrell G, Morris L, et al. Loss of insulin receptor in osteoprogenitor cells impairs structural strength of bone. J Diabetes Res. 2014;2014:703589. doi: 10.1155/2014/703589. PubMed DOI PMC

Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142(2):309–319. doi: 10.1016/j.cell.2010.06.002. PubMed DOI PMC

Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142(2):296–308. doi: 10.1016/j.cell.2010.06.003. PubMed DOI PMC

Wei Jianwen, Ferron Mathieu, Clarke Christopher J., Hannun Yusuf A., Jiang Hongfeng, Blaner William S., Karsenty Gerard. Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. Journal of Clinical Investigation. 2014;124(4):1781–1793. doi: 10.1172/JCI72323. PubMed DOI PMC

Kim SP, Li Z, Zoch ML, Frey JL, Bowman CE, Kushwaha P, et al. Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. JCI Insight. 2017;2(16). PubMed PMC

Li Z, Frey JL, Wong GW, Faugere MC, Wolfgang MJ, Kim JK, Riddle RC, Clemens TL. Glucose transporter-4 facilitates insulin-stimulated glucose uptake in osteoblasts. Endocrinology. 2016;157(11):4094–4103. doi: 10.1210/en.2016-1583. PubMed DOI PMC

Ryall JG, Cliff T, Dalton S, Sartorelli V. Metabolic reprogramming of stem cell epigenetics. Cell Stem Cell. 2015;17(6):651–662. doi: 10.1016/j.stem.2015.11.012. PubMed DOI PMC

Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol. 2012;13(4):270–276. doi: 10.1038/nrm3305. PubMed DOI

Larsen KH, Frederiksen CM, Burns JS, Abdallah BM, Kassem M. Identifying a molecular phenotype for bone marrow stromal cells with in vivo bone-forming capacity. J Bone Miner Res. 2010;25(4):796–808. PubMed

Post S, Abdallah BM, Bentzon JF, Kassem M. Demonstration of the presence of independent pre-osteoblastic and pre-adipocytic cell populations in bone marrow-derived mesenchymal stem cells. Bone. 2008;43(1):32–39. doi: 10.1016/j.bone.2008.03.011. PubMed DOI

Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M, Bomze D, Elena-Herrmann B, Scherf T, Nissim-Rafinia M, Kempa S, Itskovitz-Eldor J, Meshorer E, Aberdam D, Nahmias Y. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 2015;21(3):392–402. doi: 10.1016/j.cmet.2015.02.002. PubMed DOI

Hansson J, Rafiee MR, Reiland S, Polo JM, Gehring J, Okawa S, et al. Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. Cell Rep. 2012;2(6):1579–1592. doi: 10.1016/j.celrep.2012.10.014. PubMed DOI PMC

Klimmeck D, Hansson J, Raffel S, Vakhrushev SY, Trumpp A, Krijgsveld J. Proteomic cornerstones of hematopoietic stem cell differentiation: distinct signatures of multipotent progenitors and myeloid committed cells. Mol Cell Proteomics. 2012;11(8):286–302. doi: 10.1074/mcp.M111.016790. PubMed DOI PMC

Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7(3):380–390. doi: 10.1016/j.stem.2010.07.011. PubMed DOI PMC

Guntur AR, Gerencser AA, Le PT, DeMambro VE, Bornstein SA, Mookerjee SA, et al. Osteoblast-like MC3T3-E1 cells prefer glycolysis for ATP production but adipocyte-like 3T3-L1 cells prefer oxidative phosphorylation. J Bone Miner Res. 2018;33(6):1052–1065. doi: 10.1002/jbmr.3390. PubMed DOI PMC

Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61(6):1315–1322. doi: 10.2337/db11-1300. PubMed DOI PMC

van Heemst D. Insulin, IGF-1 and longevity. Aging Dis. 2010;1(2):147–157. PubMed PMC

Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab. 2010;21(10):589–598. doi: 10.1016/j.tem.2010.06.005. PubMed DOI PMC

Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci U S A. 2003;100(13):7996–8001. doi: 10.1073/pnas.1332551100. PubMed DOI PMC

Loh K, Deng H, Fukushima A, Cai X, Boivin B, Galic S, Bruce C, Shields BJ, Skiba B, Ooms LM, Stepto N, Wu B, Mitchell CA, Tonks NK, Watt MJ, Febbraio MA, Crack PJ, Andrikopoulos S, Tiganis T. Reactive oxygen species enhance insulin sensitivity. Cell Metab. 2009;10(4):260–272. doi: 10.1016/j.cmet.2009.08.009. PubMed DOI PMC

Ristow M, Zarse K, Oberbach A, Kloting N, Birringer M, Kiehntopf M, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009;106(21):8665–8670. doi: 10.1073/pnas.0903485106. PubMed DOI PMC

Radak Z, Chung HY, Goto S. Systemic adaptation to oxidative challenge induced by regular exercise. Free Radic Biol Med. 2008;44(2):153–159. doi: 10.1016/j.freeradbiomed.2007.01.029. PubMed DOI

Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 2003;22(20):5501–5510. doi: 10.1093/emboj/cdg513. PubMed DOI PMC

Tormos KV, Anso E, Hamanaka RB, Eisenbart J, Joseph J, Kalyanaraman B, et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab. 2011;14(4):537–544. doi: 10.1016/j.cmet.2011.08.007. PubMed DOI PMC

Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21(12):1443–1455. doi: 10.1101/gad.1550907. PubMed DOI

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127(6):1109–1122. doi: 10.1016/j.cell.2006.11.013. PubMed DOI

Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008;8(5):347–358. doi: 10.1016/j.cmet.2008.08.017. PubMed DOI

Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000;14(9):1021–1026. PubMed

Sasaki T, Maier B, Bartke A, Scrable H. Progressive loss of SIRT1 with cell cycle withdrawal. Aging Cell. 2006;5(5):413–422. doi: 10.1111/j.1474-9726.2006.00235.x. PubMed DOI

Lecka-Czernik B. Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep. 2010;8(4):178–184. doi: 10.1007/s11914-010-0027-y. PubMed DOI PMC

Lee RH, Sloane R, Pieper C, Lyles KW, Adler RA, Van Houtven C, et al. Glycemic control and insulin treatment alter fracture risk in older men with type 2 diabetes mellitus. J Bone Miner Res. 2019. PubMed PMC

Vestergaard P. Diabetes and bone fracture: risk factors for old and young. Diabetologia. 2014;57(10):2007–2008. doi: 10.1007/s00125-014-3338-1. PubMed DOI

Kohler S, Kaspers S, Salsali A, Zeller C, Woerle HJ. Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride. Diabetes Care. 2018;41(8):1809–1816. doi: 10.2337/dc17-1525. PubMed DOI

Monami M, Cresci B, Colombini A, Pala L, Balzi D, Gori F, Chiasserini V, Marchionni N, Rotella CM, Mannucci E. Bone fractures and hypoglycemic treatment in type 2 diabetic patients: a case-control study. Diabetes Care. 2008;31(2):199–203. doi: 10.2337/dc07-1736. PubMed DOI

Redman Leanne M., Smith Steven R., Burton Jeffrey H., Martin Corby K., Il'yasova Dora, Ravussin Eric. Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metabolism. 2018;27(4):805-815.e4. doi: 10.1016/j.cmet.2018.02.019. PubMed DOI PMC

Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. 2018;27(6):1212–1221. doi: 10.1016/j.cmet.2018.04.010. PubMed DOI PMC

Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838–847. doi: 10.1016/j.cmet.2012.04.022. PubMed DOI PMC

Next Generation Bone Marrow Adiposity Researchers: Report From the 1st BMAS Summer School 2021