Sommerfeldt, D. W. & Rubin, C. T. Biology of bone and how it orchestrates the form and function of the skeleton. Eur. Spine J. 10, S86–S95 (2001).
Article PubMed Central PubMed Google Scholar
Bronner, F. Extracellular and intracellular regulation of calcium homeostasis. Sci. World J. 1, 919–925 (2001).
Article CAS Google Scholar
Askmyr, M., Quach, J. & Purton, L. E. Effects of the bone marrow microenvironment on hematopoietic malignancy. Bone 48, 115–120 (2011).
Article PubMed Google Scholar
Abarrategi, A. et al. Modeling the human bone marrow niche in mice: from host bone marrow engraftment to bioengineering approaches. J. Exp. Med. 215, 729–743 (2018).
Article CAS PubMed Central PubMed Google Scholar
Kajimura, D. et al. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell Metab. 17, 901–915 (2013).
Article CAS PubMed Central PubMed Google Scholar
Karsenty, G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 4, 341–348 (2006).
Article CAS PubMed Google Scholar
Lecka-Czernik, B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia 60, 1163–1169 (2017).
Article CAS PubMed Central PubMed Google Scholar
Andrukhova, O., Streicher, C., Zeitz, U. & Erben, R. G. Fgf23 and parathyroid hormone signaling interact in kidney and bone. Mol. Cell Endocrinol. 436, 224–239 (2016).
Article CAS PubMed Google Scholar
Cai, X., Xing, J., Long, C. L., Peng, Q. & Humphrey, M. B. DOK3 modulates bone remodeling by negatively regulating osteoclastogenesis and positively regulating osteoblastogenesis. J. Bone Min. Res. 32, 2207–2218 (2017).
Article CAS Google Scholar
Kalbasi Anaraki, P. et al. Urokinase receptor mediates osteoclastogenesis via M-CSF release from osteoblasts and the c-Fms/PI3K/Akt/NF-κB pathway in osteoclasts. J. Bone Min. Res. 30, 379–388 (2015).
Article CAS Google Scholar
Matsuoka, K., Park, K. A., Ito, M., Ikeda, K. & Takeshita, S. Osteoclast-derived complement component 3a stimulates osteoblast differentiation. J. Bone Min. Res. 29, 1522–1530 (2014).
Article CAS Google Scholar
Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Min. Res. 19, 429–435 (2004).
Article CAS Google Scholar
Gupte, A. A. et al. Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology 155, 4697–4705 (2014).
Article PubMed Central CAS PubMed Google Scholar
Du, J. et al. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK. Endocrine 53, 701–709 (2016).
Article CAS PubMed Google Scholar
Mizokami, A. et al. Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice. PLoS ONE 8, e57375 (2013).
Article CAS PubMed Central PubMed Google Scholar
Otani, T. et al. Signaling pathway for adiponectin expression in adipocytes by osteocalcin. Cell Signal 27, 532–544 (2015).
Article CAS PubMed Google Scholar
Booth, S. L., Centi, A., Smith, S. R. & Gundberg, C. The role of osteocalcin in human glucose metabolism: marker or mediator? Nat. Rev. Endocrinol. 9, 43–55 (2013).
Article CAS PubMed Google Scholar
Hauschka, P. V., Lian, J. B., Cole, D. E. & Gundberg, C. M. Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol. Rev. 69, 990–1047 (1989).
Article CAS PubMed Google Scholar
Ducy, P. et al. Increased bone formation in osteocalcin-deficient mice. Nature 382, 448–452 (1996).
Article CAS PubMed Google Scholar
Ishida, M. & Amano, S. Osteocalcin fragment in bone matrix enhances osteoclast maturation at a late stage of osteoclast differentiation. J. Bone Min. Metab. 22, 415–429 (2004).
Article CAS Google Scholar
Nikel, O., Poundarik, A. A., Bailey, S. & Vashishth, D. Structural role of osteocalcin and osteopontin in energy dissipation in bone. J. Biomech. 80, 45–52 (2018).
Article PubMed Central PubMed Google Scholar
Hu, C. M. et al. High glucose triggers nucleotide imbalance through O-GlcNAcylation of key enzymes and induces KRAS mutation in pancreatic cells. Cell Metab. 29, 1334–1349.e10 (2019).
Article CAS PubMed Google Scholar
Lee, N. K. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456–469 (2007).
Article CAS PubMed Central PubMed Google Scholar
Malashkevich, V. N., Almo, S. C. & Dowd, T. L. X-ray crystal structure of bovine 3 Glu-osteocalcin. Biochemistry 52, 8387–8392 (2013).
Article CAS PubMed Google Scholar
Rached, M.-T. et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J. Clin. Investig. 120, 357–368 (2010).
Article CAS PubMed Google Scholar
Guedes, J. A. C., Esteves, J. V., Morais, M. R., Zorn, T. M. & Furuya, D. T. Osteocalcin improves insulin resistance and inflammation in obese mice: Participation of white adipose tissue and bone. Bone 115, 68–82 (2018).
Article CAS PubMed Google Scholar
Levinger, I. et al. The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo. Osteoporos. Int. 27, 653–663 (2016).
Article CAS PubMed Google Scholar
Lin, X. et al. Recombinant uncarboxylated osteocalcin per se enhances mouse skeletal muscle glucose uptake in both extensor digitorum longus and soleus muscles. Front Endocrinol. 8, 330 (2017).
Article Google Scholar
Pi, M. et al. Evidence for osteocalcin binding and activation of GPRC6A in β-cells. Endocrinology 157, 1866–1880 (2016).
Article CAS PubMed Central PubMed Google Scholar
Sanchez-Gurmaches, J. et al. Brown Fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis. Cell Metab. 27, 195–209.e6 (2018).
Article CAS PubMed Google Scholar
Gao, J. et al. The PLC/PKC/Ras/MEK/Kv channel pathway is involved in uncarboxylated osteocalcin-regulated insulin secretion in rats. Peptides 86, 72–79 (2016).
Article CAS PubMed Google Scholar
Drucker, D. J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 27, 740–756 (2018).
Article CAS PubMed Google Scholar
Mizokami, A. et al. Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion. Bone 69, 68–79 (2014).
Article CAS PubMed Google Scholar
Zhou, B. et al. Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-κB signaling pathway. Endocrinology 154, 1055–1068 (2013).
Article CAS PubMed Google Scholar
Guo, Q. et al. Undercarboxylated osteocalcin reverts insulin resistance induced by endoplasmic reticulum stress in human umbilical vein endothelial cells. Sci. Rep. 7, 46 (2017).
Article PubMed Central CAS PubMed Google Scholar
Jung, C. H. et al. The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway. Metabolism 62, 1250–1257 (2013).
Article CAS PubMed Google Scholar
Kalucka, J. et al. Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis. Cell Metab. 28, 881–894.e13 (2018).
Article CAS PubMed Google Scholar
Li, X., Sun, X. & Carmeliet, P. Hallmarks of endothelial cell metabolism in health and disease. Cell Metab. 30, 414–433 (2019).
Article CAS PubMed Google Scholar
Hill, H. S. et al. Carboxylated and uncarboxylated forms of osteocalcin directly modulate the glucose transport system and inflammation in adipocytes. Horm. Metab. Res. 46, 341–347 (2014).
Article CAS PubMed Central PubMed Google Scholar
Clemens, T. L. & Karsenty, G. The osteoblast: an insulin target cell controlling glucose homeostasis. J. Bone Min. Res. 26, 677–680 (2011).
Article CAS Google Scholar
De Toni, L. et al. Osteocalcin, a bone-derived hormone with important andrological implications. Andrology 5, 664–670 (2017).
Article CAS PubMed Google Scholar
Otani, T. et al. Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes via activation of p300. Cell Death Dis. 9, 1194 (2018).
Article CAS PubMed Central PubMed Google Scholar
Li, Q. et al. T Cell factor 7 (TCF7)/TCF1 feedback controls osteocalcin signaling in brown adipocytes independent of the Wnt/β-catenin pathway. Mol. Cell Biol. 38, e00562–17 (2018).
PubMed Central PubMed Google Scholar
Mottillo, E. P., Ramseyer, V. D. & Granneman, J. G. SERCA2b cycles its way to UCP1-independent thermogenesis in beige fat. Cell Metab. 27, 7–9 (2018).
Article CAS PubMed Google Scholar
Deppermann, C. et al. Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets. J. Exp. Med. 217, e20190723 (2020).
Wellendorph, P. & Bräuner-Osborne, H. Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor. Gene 335, 37–46 (2004).
Article CAS PubMed Google Scholar
Ackerman, S. D. et al. GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. J. Exp. Med. 215, 941–961 (2018).
Article CAS PubMed Central PubMed Google Scholar
Pi, M., Wu, Y. & Quarles, L. D. GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo. J. Bone Min. Res. 26, 1680–1683 (2011).
Article CAS Google Scholar
Fu, A., Eberhard, C. E. & Screaton, R. A. Role of AMPK in pancreatic beta cell function. Mol. Cell Endocrinol. 366, 127–134 (2013).
Article CAS PubMed Google Scholar
Ardestani, A., Lupse, B., Kido, Y., Leibowitz, G. & Maedler, K. mTORC1 Signaling: A Double-Edged Sword in Diabetic β Cells. Cell Metab. 27, 314–331 (2018).
Article CAS PubMed Google Scholar
Karmaus, P. W. F. et al. Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis. J. Exp. Med. 214, 2629–2647 (2017).
Article CAS PubMed Central PubMed Google Scholar
Lin, S. C. & Hardie, D. G. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 27, 299–313 (2018).
Article CAS PubMed Google Scholar
Pi, M., Nishimoto, S. K. & Quarles, L. D. GPRC6A: Jack of all metabolism (or master of none). Mol. Metab. 6, 185–193 (2016).
Article PubMed Central CAS PubMed Google Scholar
Diegel, C. R. et al. An osteocalcin-deficient mouse strain without endocrine abnormalities. PLoS Genet. 16, e1008361 (2020).
Article CAS PubMed Central PubMed Google Scholar
Choi, H. J. et al. Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial. Diabetes Care 34, e147 (2011).
Article PubMed Central PubMed Google Scholar
Pollock, N. K. et al. Lower uncarboxylated osteocalcin concentrations in children with prediabetes is associated with beta-cell function. J. Clin. Endocrinol. Metab. 96, E1092–E1099 (2011).
Article PubMed Central PubMed Google Scholar
Choudhury, A. B., Sarkar, P. D., Sakalley, D. K. & Petkar, S. B. Role of adiponectin in mediating the association of osteocalcin with insulin resistance and type 2 diabetes: a cross sectional study in pre- and post-menopausal women. Arch. Physiol. Biochem. 120, 73–79 (2014).
Article CAS PubMed Google Scholar
Martin, T. J. & Sims, N. A. RANKL/OPG; Critical role in bone physiology. Rev. Endocr. Metab. Disord. 16, 131–139 (2015).
Article CAS PubMed Google Scholar
Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).
Article CAS PubMed Google Scholar
Boyce, B. F. & Xing, L. Biology of RANK, RANKL, and osteoprotegerin. Arthritis Res Ther. 9, S1 (2007).
Article PubMed Central CAS PubMed Google Scholar
Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).
Article CAS PubMed Google Scholar
Chen, C. et al. MiR-503 regulates osteoclastogenesis via targeting RANK. J. Bone Min. Res. 29, 338–347 (2014).
Article CAS Google Scholar
Kondegowda, N. G. et al. Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-κB ligand pathway. Cell Metab. 22, 77–85 (2015).
Article CAS PubMed Central PubMed Google Scholar
Sacco, F. et al. Phosphoproteomics reveals the GSK3-PDX1 axis as a key pathogenic signaling node in diabetic islets. Cell Metab. 29, 1422–1432.e3 (2019).
Article CAS PubMed Google Scholar
Musialik, K., Szulińska, M., Hen, K., Skrypnik, D. & Bogdański, P. The relation between osteoprotegerin, inflammatory processes, and atherosclerosis in patients with metabolic syndrome. Eur. Rev. Med Pharm. Sci. 21, 4379–4385 (2017).
CAS Google Scholar
Monseu, M. et al. Osteoprotegerin levels are associated with liver fat and liver markers in dysmetabolic adults. Diabetes Metab. 42, 364–367 (2016).
Article CAS PubMed Google Scholar
Cappel, D. A. et al. Pyruvate-carboxylase-mediated anaplerosis promotes antioxidant capacity by sustaining TCA cycle and redox metabolism in liver. Cell Metab. 29, 1291–1305.e8 (2019).
Article CAS PubMed Central PubMed Google Scholar
Bilgir, O. et al. Relationship between insulin resistance, hs-CRP, and body fat and serum osteoprotegerin/RANKL in prediabetic patients. Minerva Endocrinol. 43, 19–26 (2018).
PubMed Google Scholar
Suliburska, J. et al. The association of insulin resistance with serum osteoprotegerin in obese adolescents. J. Physiol. Biochem 69, 847–853 (2013).
Article CAS PubMed Google Scholar
Stekovic, S. et al. Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans. Cell Metab. 30, 462–476.e6 (2019).
Article CAS PubMed Google Scholar
Ou, D. et al. TNF-related apoptosis-inducing ligand death pathway-mediated human beta-cell destruction. Diabetologia 45, 1678–1688 (2002).
Article CAS PubMed Google Scholar
Chamoux, E., Houde, N., L’Eriger, K. & Roux, S. Osteoprotegerin decreases human osteoclast apoptosis by inhibiting the TRAIL pathway. J. Cell Physiol. 216, 536–542 (2008).
Article CAS PubMed Google Scholar
Vaccarezza, M., Bortul, R., Fadda, R. & Zweyer, M. Increased OPG expression and impaired OPG/TRAIL ratio in the aorta of diabetic rats. Med. Chem. 3, 387–391 (2007).
Article CAS PubMed Google Scholar
Knudsen, J. G. & Rorsman, P. β cell dysfunction in type 2 diabetes: drained of energy? Cell Metab. 29, 1–2 (2019).
Article CAS PubMed Google Scholar
Schrader, J. et al. Cytokine-induced osteoprotegerin expression protects pancreatic beta cells through p38 mitogen-activated protein kinase signalling against cell death. Diabetologia 50, 1243–1247 (2007).
Article CAS PubMed Google Scholar
Taylor, R. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery. Cell Metab. 28, 547–556.e3 (2018).
Article CAS PubMed Google Scholar
Lacombe, J., Karsenty, G. & Ferron, M. In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice. Mol. Metab. 2, 498–504 (2013).
Article CAS PubMed Central PubMed Google Scholar
Niu, Y. et al. Plasma osteoprotegerin levels are inversely associated with nonalcoholic fatty liver disease in patients with type 2 diabetes: a case-control study in China. Metabolism 65, 475–481 (2016).
Article CAS PubMed Google Scholar
Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22–41 (2018).
Article CAS PubMed Google Scholar
Ayaz, T. et al. The relation between carotid intima media thickness and serum osteoprotegerin levels in nonalcoholic fatty liver disease. Metab. Syndr. Relat. Disord. 12, 283–289 (2014).
Article CAS PubMed Google Scholar
D’Amelio, P., Isaia, G., Fau, -, Isaia, G. C. & Isaia, G. C. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. Expert Rev. Cardiovasc Ther. 4, 801–811 (2006).
Article Google Scholar
Kiechl, S. et al. Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat. Med. 19, 358–363 (2013).
Article CAS PubMed Google Scholar
Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).
Article CAS PubMed Google Scholar
Fan, Y. et al. Parathyroid hormone directs bone marrow mesenchymal cell fate. Cell Metab. 25, 661–672 (2017).
Article CAS PubMed Central PubMed Google Scholar
Franzén, A. & Heinegård, D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem. J. 232, 715–724 (1985).
Article PubMed Central PubMed Google Scholar
Gimba, E. R. & Tilli, T. M. Human osteopontin splicing isoforms: known roles, potential clinical applications and activated signaling pathways. Cancer Lett. 331, 11–17 (2013).
Article CAS PubMed Google Scholar
Luukkonen, J. et al. Osteoclasts secrete osteopontin into resorption lacunae during bone resorption. Histochem. Cell Biol. 151, 475–487 (2019).
Article CAS PubMed Central PubMed Google Scholar
Oldberg, A., Franzén, A. & Heinegård, D. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc. Natl Acad. Sci. USA 83, 8819–8823 (1986).
Article CAS PubMed PubMed Central Google Scholar
Wang, K. X. & Denhardt, D. T. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 19, 333–345 (2008).
Article CAS PubMed Google Scholar
Ge, Q. et al. Osteopontin regulates macrophage activation and osteoclast formation in hypertensive patients with vascular calcification. Sci. Rep. 7, 40253 (2017).
Article CAS PubMed Central PubMed Google Scholar
Ishijima, M. et al. Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin. J. Exp. Med. 193, 399–404 (2001).
Article CAS PubMed Central PubMed Google Scholar
Chen, Q. et al. An osteopontin-integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal. Stem Cells 32, 327–337 (2014).
Article CAS PubMed Central PubMed Google Scholar
Chapman, J. et al. Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice. PLoS ONE 5, e13959 (2010).
Article PubMed Central CAS PubMed Google Scholar
Inoue, H. et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat. Med. 10, 168–174 (2004).
Article CAS PubMed Google Scholar
Kiefer, F. W. et al. Neutralization of osteopontin inhibits obesity-induced inflammation and insulin resistance. Diabetes 59, 935–946 (2010).
Article CAS PubMed Central PubMed Google Scholar
Kon, S. et al. Syndecan-4 protects against osteopontin-mediated acute hepatic injury by masking functional domains of osteopontin. J. Exp. Med. 205, 25–33 (2008).
Article CAS PubMed Central PubMed Google Scholar
Nuñez-Garcia, M. et al. Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver. J. Lipid Res. 58, 1903–1915 (2017).
Article PubMed Central PubMed Google Scholar
Zeyda, M. et al. Osteopontin is an activator of human adipose tissue macrophages and directly affects adipocyte function. Endocrinology 152, 2219–2227 (2011).
Article CAS PubMed Google Scholar
Arafat, H. A. et al. Osteopontin protects the islets and beta-cells from interleukin-1 beta-mediated cytotoxicity through negative feedback regulation of nitric oxide. Endocrinology 148, 575–584 (2007).
Article CAS PubMed Google Scholar
Ma, D. & Leulier, F. A new transkingdom dimension to NO signaling. Cell Metab. 29, 513–515 (2019).
Article CAS PubMed Google Scholar
Wendt, A. et al. Osteopontin affects insulin vesicle localization and Ca2+ homeostasis in pancreatic beta cells from female mice. PLoS ONE 12, e0170498 (2017).
Article PubMed Central CAS PubMed Google Scholar
Ahmad, R. et al. Interaction of osteopontin with IL-18 in obese individuals: implications for insulin resistance. PLoS ONE 8, e63944 (2013).
Article CAS PubMed Central PubMed Google Scholar
Barchetta, I. et al. Increased circulating osteopontin levels in adult patients with type 1 diabetes mellitus and association with dysmetabolic profile. Eur. J. Endocrinol. 174, 187–192 (2016).
Article CAS PubMed Google Scholar
Carbone, F. et al. Serum levels of osteopontin predict diabetes remission after bariatric surgery. Diabetes Metab. 45, 356–362 (2019).
Article CAS PubMed Google Scholar
Kiefer, F. W. et al. Osteopontin expression in human and murine obesity: extensive local up-regulation in adipose tissue but minimal systemic alterations. Endocrinology 149, 1350–1357 (2008).
Article CAS PubMed Google Scholar
Talat, M. A. et al. The role of osteopontin in the pathogenesis and complications of type 1 diabetes mellitus in children. J. Clin. Res. Pediatr. Endocrinol. 8, 399–404 (2016).
Article PubMed Central PubMed Google Scholar
Lee, H. et al. Beta cell dedifferentiation induced by IRE1α deletion prevents type 1 diabetes. Cell Metab. 31, 822–836.e5 (2020).
Article CAS PubMed Central PubMed Google Scholar
Marciano, R. et al. Association of alleles at polymorphic sites in the Osteopontin encoding gene in young type 1 diabetic patients. Clin. Immunol. 131, 84–91 (2009).
Article CAS PubMed Google Scholar
Warshauer, J. T., Bluestone, J. A. & Anderson, M. S. New frontiers in the treatment of type 1 diabetes. Cell Metab. 31, 46–61 (2020).
Article CAS PubMed Google Scholar
You, J. S. et al. Serum osteopontin concentration is decreased by exercise-induced fat loss but is not correlated with body fat percentage in obese humans. Mol. Med. Rep. 8, 579–584 (2013).
Article PubMed Google Scholar
Israel, D. I. et al. Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors 13, 291–300 (1996).
Article CAS PubMed Google Scholar
Urist, M. R. Bone: formation by autoinduction. Science 150, 893–899 (1965).
Article CAS PubMed Google Scholar
Celeste, A. J. et al. Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone. Proc. Natl Acad. Sci. USA 87, 9843–9847 (1990).
Article CAS PubMed PubMed Central Google Scholar
Brazil, D. P., Church, R. H., Surae, S., Godson, C. & Martin, F. BMP signalling: agony and antagony in the family. Trends Cell Biol. 25, 249–264 (2015).
Article CAS PubMed Google Scholar
Chen, D., Zhao, M. & Mundy, G. R. Bone morphogenetic proteins. Growth Factors 22, 233–241 (2004).
Article CAS PubMed Google Scholar
Nohno, T. et al. Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J. Biol. Chem. 270, 22522–22526 (1995).
Article CAS PubMed Google Scholar
ten Dijke, P., Miyazono, K. & Heldin, C. H. Signaling via hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors. Curr. Opin. Cell Biol. 8, 139–145 (1996).
Article PubMed Google Scholar
Ebara, S. & Nakayama, K. Mechanism for the action of bone morphogenetic proteins and regulation of their activity. Spine 27, S10–S15 (2002).
Article PubMed Google Scholar
Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).
Article CAS PubMed Google Scholar
Wang, P. et al. Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells. Cell Metab. 29, 638–652.e5 (2019).
Article CAS PubMed Google Scholar
Lu, Q. et al. GDF11 inhibits bone formation by activating Smad2/3 in bone marrow mesenchymal stem cells. Calcif. Tissue Int. 99, 500–509 (2016).
Article CAS PubMed Google Scholar
Guo, X. & Wang, X.-F. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 19, 71–88 (2009).
Article CAS PubMed Google Scholar
Lowery, J. W. & Rosen, V. The BMP pathway and its inhibitors in the skeleton. Physiol. Rev. 98, 2431–2452 (2018).
Article CAS PubMed Google Scholar
Yang, M. et al. MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity. Nat. Commun. 8, 16003 (2017).
Article CAS PubMed Central PubMed Google Scholar
Maeda, Y., Tsuji, K., Nifuji, A. & Noda, M. Inhibitory helix-loop-helix transcription factors Id1/Id3 promote bone formation in vivo. J. Cell Biochem. 93, 337–344 (2004).
Article CAS PubMed Google Scholar
Peng, Y. et al. Inhibitor of DNA binding/differentiation helix-loop-helix proteins mediate bone morphogenetic protein-induced osteoblast differentiation of mesenchymal stem cells. J. Biol. Chem. 279, 32941–32949 (2004).
Article CAS PubMed Google Scholar
Elsen, M. et al. BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells. Am. J. Physiol. Cell Physiol. 306, C431–C440 (2014).
Article CAS PubMed Google Scholar
Fabbiano, S. et al. Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab. 24, 434–446 (2016).
Article CAS PubMed Google Scholar
Gustafson, B. et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes 64, 1670–1681 (2015).
Article CAS PubMed Google Scholar
Hata, K. et al. Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol. Biol. Cell 14, 545–555 (2003).
Article CAS PubMed Central PubMed Google Scholar
Hino, J. et al. Overexpression of bone morphogenetic protein-3b (BMP-3b) in adipose tissues protects against high-fat diet-induced obesity. Int J. Obes. 41, 483–488 (2017).
Article CAS Google Scholar
Hoffmann, J. M. et al. BMP4 gene therapy in mature mice reduces BAT activation but protects from obesity by browning subcutaneous adipose tissue. Cell Rep. 20, 1038–1049 (2017).
Article CAS PubMed Google Scholar
Huang, H. et al. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl Acad. Sci. USA 106, 12670–12675 (2009).
Article CAS PubMed PubMed Central Google Scholar
Kim, S., Choe, S. & Lee, D. K. BMP-9 enhances fibroblast growth factor 21 expression and suppresses obesity. Biochim. Biophys. Acta 1862, 1237–1246 (2016).
Article CAS PubMed Central PubMed Google Scholar
Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).
Article CAS PubMed Central PubMed Google Scholar
Wang, E. A., Israel, D. I., Kelly, S. & Luxenberg, D. P. Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors 9, 57–71 (1993).
Article CAS PubMed Google Scholar
Whittle, A. J. et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012).
Article CAS PubMed Central PubMed Google Scholar
Wang, Q. A. et al. Reversible de-differentiation of mature white adipocytes into preadipocyte-like precursors during lactation. Cell Metab. 28, 282–288.e3 (2018).
Article CAS PubMed Central PubMed Google Scholar
Li, C. J. et al. MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J. Clin. Investig. 125, 1509–1522 (2015).
Article PubMed PubMed Central Google Scholar
Zhang, R. et al. The role of microRNAs in adipocyte differentiation. Front. Med. 7, 223–230 (2013).
Article CAS PubMed Google Scholar
Chattopadhyay, T., Singh, R. R., Gupta, S. & Surolia, A. Bone morphogenetic protein-7 (BMP-7) augments insulin sensitivity in mice with type II diabetes mellitus by potentiating PI3K/AKT pathway. Biofactors 43, 195–209 (2017).
Article CAS PubMed Google Scholar
Luo, Y. et al. Decreased circulating BMP-9 levels in patients with Type 2 diabetes is a signature of insulin resistance. Clin. Sci. 131, 239–246 (2017).
Article CAS Google Scholar
Schreiber, I. et al. BMPs as new insulin sensitizers: enhanced glucose uptake in mature 3T3-L1 adipocytes via PPARγ and GLUT4 upregulation. Sci. Rep. 7, 17192 (2017).
Article PubMed Central CAS PubMed Google Scholar
Yang, M. et al. Role of bone morphogenetic protein-9 in the regulation of glucose and lipid metabolism. FASEB J. 33, 10077–10088 (2019).
Article CAS PubMed Google Scholar
Wang, X. et al. New association of bone morphogenetic protein 4 concentrations with fat distribution in obesity and Exenatide intervention on it. Lipids Health Dis. 16, 70 (2017).
Article PubMed Central CAS PubMed Google Scholar
Hodgson, J. et al. Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 201, 575–585 (2020).
Article CAS PubMed Central PubMed Google Scholar
Vukicevic, S., Helder, M. N. & Luyten, F. P. Developing human lung and kidney are major sites for synthesis of bone morphogenetic protein-3 (osteogenin). J. Histochem. Cytochem. 42, 869–875 (1994).
Article CAS PubMed Google Scholar
Kokubu, N., Tsujii, M., Akeda, K., Iino, T. & Sudo, A. BMP-7/Smad expression in dedifferentiated Schwann cells during axonal regeneration and upregulation of endogenous BMP-7 following administration of PTH (1–34). J. Orthop. Surg. 26, 2309499018812953 (2018).
Yamashita, K., Mikawa, S. & Sato, K. BMP3 expression in the adult rat CNS. Brain Res. 1643, 35–50 (2016).
Article CAS PubMed Google Scholar
Desroches-Castan, A. et al. Differential consequences of Bmp9 deletion on sinusoidal endothelial cell differentiation and liver fibrosis in 129/Ola and C57BL/6 mice. Cells 8, 1079 (2019).
Article CAS PubMed Central Google Scholar
Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 8, 235–253 (2009).
Article CAS PubMed Central PubMed Google Scholar
Ornitz, D. M. & Marie, P. J. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 29, 1463–1486 (2015).
Article CAS PubMed Central PubMed Google Scholar
Luo, Y., Ye, S., Li, X. & Lu, W. Emerging structure-function paradigm of endocrine FGFs in metabolic diseases. Trends Pharm. Sci. 40, 142–153 (2019).
Article CAS PubMed Google Scholar
Peng, M. et al. Developments in the study of gastrointestinal microbiome disorders affected by FGF19 in the occurrence and development of colorectal neoplasms. J. Cell Physiol. 235, 4060–4069 (2020).
Article CAS PubMed Google Scholar
Geller, S. et al. Tanycytes regulate lipid homeostasis by sensing free fatty acids and signaling to key hypothalamic neuronal populations via FGF21 secretion. Cell Metab. 30, 833–844.e7 (2019).
Article CAS PubMed Google Scholar
Nishimura, T., Nakatake, Y., Konishi, M. & Itoh, N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim. Biophys. Acta. 1492, 203–206 (2000).
Article CAS PubMed Google Scholar
Erben, R. G. Pleiotropic actions of FGF23. Toxicol. Pathol. 45, 904–910 (2017).
Article CAS PubMed Central PubMed Google Scholar
Clinkenbeard, E. L. et al. Conditional deletion of murine Fgf23: interruption of the normal skeletal responses to phosphate challenge and rescue of genetic hypophosphatemia. J. Bone Miner. Res. 31, 1247–1257 (2016).
Article CAS PubMed Google Scholar
Hu, M. C. et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 24, 3438–3450 (2010).
Article CAS PubMed Central PubMed Google Scholar
Strewler, G. J. Untangling klotho’s role in calcium homeostasis. Cell Metab. 6, 93–95 (2007).
Article CAS PubMed Google Scholar
Angelin, B., Larsson, T. E. & Rudling, M. Circulating fibroblast growth factors as metabolic regulators-a critical appraisal. Cell Metab. 16, 693–705 (2012).
Article CAS PubMed Google Scholar
Komaba, H. et al. Klotho expression in osteocytes regulates bone metabolism and controls bone formation. Kidney Int. 92, 599–611 (2017).
Article CAS PubMed Google Scholar
Rhee, Y. et al. Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo. Bone 49, 636–643 (2011).
Article CAS PubMed Central PubMed Google Scholar
Kaludjerovic, J. et al. Klotho expression in long bones regulates FGF23 production during renal failure. FASEB J. 31, 2050–2064 (2017).
Article CAS PubMed Google Scholar
Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).
Article CAS PubMed Central PubMed Google Scholar
Hesse, M., Fröhlich, L. F., Zeitz, U., Lanske, B. & Erben, R. G. Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. Matrix Biol. 26, 75–84 (2007).
Article CAS PubMed Google Scholar
López, I. et al. Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int. 80, 475–482 (2011).
Article CAS PubMed Google Scholar
Singh, S. et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 90, 985–996 (2016).
Article CAS PubMed Central PubMed Google Scholar
Ito, N. et al. Regulation of FGF23 expression in IDG-SW3 osteocytes and human bone by pro-inflammatory stimuli. Mol. Cell. Endocrinol. 399, 208–218 (2015).
Article CAS PubMed Google Scholar
Mirza, M. A. I. et al. Circulating fibroblast growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly individuals. Arterioscler Thromb. Vasc. Biol. 31, 219–227 (2011).
Article CAS PubMed Google Scholar
Aljohani, A. et al. Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α-FGF21 axis in mice. J. Biol. Chem. 294, 19475–19485 (2019).
Article CAS PubMed Central PubMed Google Scholar
Chen, Y., Lu, J., Nemati, R., Plank, L. D. & Murphy, R. Acute changes of bile acids and FGF19 after sleeve gastrectomy and Roux-en-Y gastric bypass. Obes. Surg. 29, 3605–3621 (2019).
Article PubMed Google Scholar
Lan, T. et al. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab. 26, 709–718.e3 (2017).
Article CAS PubMed Central PubMed Google Scholar
Mosialou, I. et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543, 385–390 (2017).
Article CAS PubMed Central PubMed Google Scholar
Zhang, J. et al. The role of lipocalin 2 in the regulation of inflammation in adipocytes and macrophages. Mol. Endocrinol. 22, 1416–1426 (2008).
Article CAS PubMed Central PubMed Google Scholar
Flower, D. R. Beyond the superfamily: the lipocalin receptors. Biochim Biophys. Acta 1482, 327–336 (2000).
Article CAS PubMed Google Scholar
Jha, M. K. et al. Diverse functional roles of lipocalin-2 in the central nervous system. Neurosci. Biobehav Rev. 49, 135–156 (2015).
Article CAS PubMed Google Scholar
Adriaenssens, A. E. et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30, 987–996.e6 (2019).
Article CAS PubMed Central PubMed Google Scholar
Liu, H. et al. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J. Neurosci. 23, 7143–7154 (2003).
Article CAS PubMed Central PubMed Google Scholar
Guo, H. et al. Lipocalin 2, a regulator of retinoid homeostasis and retinoid-mediated thermogenic activation in adipose tissue. J. Biol. Chem. 291, 11216–11229 (2016).
Article CAS PubMed Central PubMed Google Scholar
Guo, H. et al. Lipocalin-2 deficiency impairs thermogenesis and potentiates diet-induced insulin resistance in mice. Diabetes 59, 1376–1385 (2010).
Article CAS PubMed Central PubMed Google Scholar
Yu, B. et al. PGC-1α controls skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal aging by inducing TAZ. Cell Stem Cell 23, 193–209.e5 (2018).
Article CAS PubMed Central PubMed Google Scholar
Zhang, Y. et al. Lipocalin 2 regulates brown fat activation via a nonadrenergic activation mechanism. J. Biol. Chem. 289, 22063–22077 (2014).
Article CAS PubMed Central PubMed Google Scholar
Kamble, P. G. et al. Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue. Mol. Cell Endocrinol. 427, 124–132 (2016).
Article CAS PubMed Google Scholar
Capulli, M. et al. A complex role for lipocalin 2 in bone metabolism: global ablation in mice induces osteopenia caused by an altered energy metabolism. J. Bone Min. Res. 33, 1141–1153 (2018).
Article CAS Google Scholar
Wang, W. et al. Elevated serum lipocalin 2 levels are associated with indexes of both glucose and bone metabolism in type 2 diabetes mellitus. Endokrynol. Pol. 69, 276–282 (2018).
Article CAS PubMed Google Scholar
van Bezooijen, R. L. et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J. Exp. Med. 199, 805–814 (2004).
Article PubMed Central CAS PubMed Google Scholar
Collette, N. M. et al. Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Dev. Biol. 383, 90–105 (2013).
Article CAS PubMed Central PubMed Google Scholar
Winkler, D. G. et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 22, 6267–6276 (2003).
Article CAS PubMed Central PubMed Google Scholar
Li, C. et al. Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression. Ann. N. Y Acad. Sci. 1364, 62–73 (2016).
Article CAS PubMed Google Scholar
Bullock, W. A. et al. Lrp4 mediates bone homeostasis and mechanotransduction through interaction with sclerostin in vivo. iScience 20, 205–215 (2019).
Article CAS PubMed Central PubMed Google Scholar
Liu, W. et al. Osteocyte TSC1 promotes sclerostin secretion to restrain osteogenesis in mice. Open Biol. 9, 180262 (2019).
Article CAS PubMed Central PubMed Google Scholar
Stolina, M. et al. Temporal changes in systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats. Bone 67, 305–313 (2014).
Article CAS PubMed Google Scholar
Fijalkowski, I. et al. A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone. J. Bone Min. Res. 31, 874–881 (2016).
Article CAS Google Scholar
Haynes, K. R. et al. Treatment of a mouse model of ankylosing spondylitis with exogenous sclerostin has no effect on disease progression. BMC Musculoskelet. Disord. 16, 368 (2015).
Article PubMed Central CAS PubMed Google Scholar
Koide, M. et al. Bone formation is coupled to resorption via suppression of sclerostin expression by osteoclasts. J. Bone Min. Res. 32, 2074–2086 (2017).
Article CAS Google Scholar
Faienza, M. F. et al. High sclerostin and dickkopf-1 (DKK-1) serum levels in children and adolescents with type 1 diabetes mellitus. J. Clin. Endocrinol. Metab. 102, 1174–1181 (2017).
Article PubMed Google Scholar
Hie, M., Iitsuka, N., Otsuka, T. & Tsukamoto, I. Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation. Int J. Mol. Med. 28, 455–462 (2011).
CAS PubMed Google Scholar
Daniele, G. et al. Sclerostin and insulin resistance in prediabetes: evidence of a cross talk between bone and glucose metabolism. Diabetes Care 38, 1509–1517 (2015).
Article CAS PubMed Google Scholar
Yu, O. H. Y. et al. The association between sclerostin and incident type 2 diabetes risk: a cohort study. Clin. Endocrinol. 86, 520–525 (2017).
Article CAS Google Scholar
Kim, S. P. et al. Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc. Natl Acad. Sci. USA 114, E11238–E11247 (2017).
Article CAS PubMed PubMed Central Google Scholar
Fulzele, K. et al. Osteocyte-secreted Wnt signaling inhibitor sclerostin contributes to beige adipogenesis in peripheral fat depots. J. Bone Min. Res. 32, 373–384 (2017).
Article CAS Google Scholar
Hofmann, S., Bellmann-Sickert, K. & Beck-Sickinger, A. G. Chemical modification of neuropeptide Y for human Y1 receptor targeting in health and disease. Biol. Chem. 400, 299–311 (2019).
Article CAS PubMed Google Scholar
Kawakami, Y. Neuropeptide Y. Nihon. Rinsho. 63, S421–S424 (2005).
Google Scholar
Cedernaes, J. et al. Transcriptional basis for rhythmic control of hunger and metabolism within the AgRP neuron. Cell Metab. 29, 1078–1091.e5 (2019).
Article CAS PubMed Central PubMed Google Scholar
Ip, C. K. et al. Amygdala NPY circuits promote the development of accelerated obesity under chronic stress conditions. Cell Metab. 30, 111–128.e6 (2019).
Article CAS PubMed Google Scholar
Krashes, M. J. et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242 (2014).
Article CAS PubMed Central PubMed Google Scholar
Chen, Z. Temporal control of appetite by AgRP Clocks. Cell Metab. 29, 1022–1023 (2019).
Article CAS PubMed Central PubMed Google Scholar
Makhmutova, M., Rodriguez-Diaz, R. & Caicedo, A. A nervous breakdown that may stop autoimmune diabetes. Cell Metab. 31, 215–216 (2020).
Article CAS PubMed Central PubMed Google Scholar
Lee, D. Y. et al. Neuropeptide Y mitigates ER stress-induced neuronal cell death by activating the PI3K-XBP1 pathway. Eur. J. Cell Biol. 97, 339–348 (2018).
Article CAS PubMed Google Scholar
Fetissov, S. O., Kopp, J. & Hökfelt, T. Distribution of NPY receptors in the hypothalamus. Neuropeptides 38, 175–188 (2004).
Article CAS PubMed Google Scholar
Huang, L. et al. Actions of NPY, and its Y1 and Y2 receptors on pulsatile growth hormone secretion during the fed and fasted state. J. Neurosci. 34, 16309–16319 (2014).
Article PubMed Central CAS PubMed Google Scholar
Park, M. H. et al. Neuropeptide Y induces hematopoietic stem/progenitor cell mobilization by regulating matrix metalloproteinase-9 activity through Y1 receptor in osteoblasts. Stem Cells 34, 2145–2156 (2016).
Article CAS PubMed Google Scholar
Shin, M. K. et al. Elevated pentraxin 3 in obese adipose tissue promotes adipogenic differentiation by activating neuropeptide Y signaling. Front. Immunol. 9, 1790 (2018).
Article PubMed Central CAS PubMed Google Scholar
Yang, K., Guan, H., Arany, E., Hill, D. J. & Cao, X. Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor. FASEB J. 22, 2452–2464 (2008).
Article CAS PubMed Google Scholar
Franklin, Z. J. et al. Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass. Diabetes Obes. Metab. 20, 599–609 (2018).
Article CAS PubMed Google Scholar
Khan, D., Vasu, S., Moffett, R. C., Irwin, N. & Flatt, P. R. Influence of neuropeptide Y and pancreatic polypeptide on islet function and beta-cell survival. Biochim. Biophys. Acta Gen. Subj. 1861, 749–758 (2017).
Article CAS PubMed Google Scholar
Loh, K., Herzog, H. & Shi, Y. C. Regulation of energy homeostasis by the NPY system. Trends Endocrinol. Metab. 26, 125–135 (2015).
Article CAS PubMed Google Scholar
Igwe, J. C. et al. Neuropeptide Y is expressed by osteocytes and can inhibit osteoblastic activity. J. Cell Biochem. 108, 621–630 (2009).
Article CAS PubMed Central PubMed Google Scholar
Wee, N. K. Y. et al. Diet-induced obesity suppresses cortical bone accrual by a neuropeptide Y-dependent mechanism. Int J. Obes. 42, 1925–1938 (2018).
Article CAS Google Scholar
Wu, J. et al. Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/β-catenin pathway in vitro. Stem Cell Res 21, 74–84 (2017).
Article CAS PubMed Google Scholar
Wee, N. K. Y. et al. Skeletal phenotype of the neuropeptide Y knockout mouse. Neuropeptides 73, 78–88 (2019).
Article CAS PubMed Google Scholar
Lee, N. J. et al. NPY signalling in early osteoblasts controls glucose homeostasis. Mol. Metab. 4, 164–174 (2015).
Article CAS PubMed Central PubMed Google Scholar
Kronenberg, H. M. PTHrP and skeletal development. Ann. N. Y Acad. Sci. 1068, 1–13 (2006).
Article CAS PubMed Google Scholar
Wysolmerski, J. J. Parathyroid hormone-related protein: an update. J. Clin. Endocrinol. Metab. 97, 2947–2956 (2012).
Article CAS PubMed Central PubMed Google Scholar
Dudeck, J. et al. Mast cells acquire MHCII from dendritic cells during skin inflammation. J. Exp. Med. 214, 3791–3811 (2017).
Article CAS PubMed Central PubMed Google Scholar
Miao, D. et al. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J. Clin. Investig. 115, 2402–2411 (2005).
Article CAS PubMed PubMed Central Google Scholar
Zhang, X., Cheng, Q., Wang, Y., Leung, P. S. & Mak, K. K. Hedgehog signaling in bone regulates whole-body energy metabolism through a bone-adipose endocrine relay mediated by PTHrP and adiponectin. Cell Death Differ. 24, 225–237 (2017).
Article CAS PubMed Google Scholar
Guthalu Kondegowda, N. et al. Parathyroid hormone-related protein enhances human ß-cell proliferation and function with associated induction of cyclin-dependent kinase 2 and cyclin E expression. Diabetes 59, 3131–3138 (2010).
Article PubMed Central CAS PubMed Google Scholar
Horwitz, M. J. et al. Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose. J. Clin. Endocrinol. Metab. 95, 1279–1287 (2010).
Article CAS PubMed Central PubMed Google Scholar
Bukowska, J. et al. Bone marrow adipocyte developmental origin and biology. Curr. Osteoporos. Rep. 16, 312–319 (2018).
Article PubMed Central PubMed Google Scholar
Bhansali, S. et al. Effect of mesenchymal stem cells transplantation on glycaemic profile & their localization in streptozotocin induced diabetic Wistar rats. Indian J. Med. Res. 142, 63–71 (2015).
Article PubMed Central CAS PubMed Google Scholar
Bhansali, S. et al. Efficacy of autologous bone marrow-derived mesenchymal stem cell and mononuclear cell transplantation in type 2 diabetes mellitus: a randomized, placebo-controlled comparative study. Stem Cells Dev. 26, 471–481 (2017).
Article CAS PubMed Google Scholar
Rydén, M. et al. Transplanted bone marrow-derived cells contribute to human adipogenesis. Cell Metab. 22, 408–417 (2015).
Article CAS PubMed Google Scholar
Goldberg, E. L. & Dixit, V. D. Bone marrow: an immunometabolic refuge during energy depletion. Cell Metab. 30, 621–623 (2019).
Article CAS PubMed Google Scholar
Zhang, J. et al. Metabolism in pluripotent stem cells and early mammalian development. Cell Metab. 27, 332–338 (2018).
Article CAS PubMed Google Scholar
Liu, J. et al. Bone-derived exosomes. Curr. Opin. Pharm. 34, 64–69 (2017).
Article CAS Google Scholar
Kita, S., Maeda, N. & Shimomura, I. Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome. J. Clin. Investig. 129, 4041–4049 (2019).
Article PubMed PubMed Central Google Scholar
Raposo, G. & Stoorvogel, W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383 (2013).
Article CAS PubMed Central PubMed Google Scholar
Guay, C. et al. Lymphocyte-derived exosomal micrornas promote pancreatic β cell death and may contribute to type 1 diabetes development. Cell Metab. 29, 348–361.e6 (2019).
Article CAS PubMed Google Scholar
Whitham, M. et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 27, 237–251.e4 (2018).
Article CAS PubMed Google Scholar
Deng, L. et al. Osteoblast-derived microvesicles: a novel mechanism for communication between osteoblasts and osteoclasts. Bone 79, 37–42 (2015).
Article CAS PubMed Google Scholar
Lyu, H., Xiao, Y., Guo, Q., Huang, Y. & Luo, X. The role of bone-derived exosomes in regulating skeletal metabolism and extraosseous diseases. Front. Cell Dev. Biol. 8, 89 (2020).
Article PubMed Central PubMed Google Scholar
Sun, W. et al. Osteoclast-derived microRNA-containing exosomes selectively inhibit osteoblast activity. Cell Discov. 2, 16015 (2016).
Article CAS PubMed Central PubMed Google Scholar
Yeo, R. W. Y. et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv. Drug Deliv. Rev. 65, 336–341 (2013).
Article CAS PubMed Google Scholar
Huynh, N. et al. Characterization of regulatory extracellular vesicles from osteoclasts. J. Dent. Res 95, 673–679 (2016).
Article CAS PubMed Central PubMed Google Scholar
Li, D. et al. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat. Commun. 7, 10872 (2016).
Article CAS PubMed Central PubMed Google Scholar
Mori, M. A., Ludwig, R. G., Garcia-Martin, R., Brandão, B. B. & Kahn, C. R. Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab. 30, 656–673 (2019).
Article CAS PubMed Central PubMed Google Scholar
Baglio, S. R. et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 6, 127 (2015).
Article PubMed Central CAS PubMed Google Scholar
Su, T. et al. Bone marrow mesenchymal stem cells-derived exosomal MiR-29b-3p regulates aging-associated insulin resistance. ACS Nano 13, 2450–2462 (2019).
Article CAS PubMed Google Scholar
Rong, X. et al. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway. Stem Cell Res. Ther. 10, 98 (2019).
Article CAS PubMed Central PubMed Google Scholar
AbuBakr, N., Haggag, T., Sabry, D. & Salem, Z. A. Functional and histological evaluation of bone marrow stem cell-derived exosomes therapy on the submandibular salivary gland of diabetic Albino rats through TGFβ/ Smad3 signaling pathway. Heliyon 6, e03789 (2020).
Article PubMed Central PubMed Google Scholar
Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
Article CAS PubMed Google Scholar
Malle, E. K. et al. Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity. J. Exp. Med. 212, 1239–1254 (2015).
Article CAS PubMed Central PubMed Google Scholar
Lee, A. & Dixit, V. D. Energy sparing orexigenic inflammation of obesity. Cell Metab. 26, 10–12 (2017).
Article CAS PubMed Google Scholar
Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Investig. 127, 1–4 (2017).
Article PubMed PubMed Central Google Scholar
Laharrague, P. et al. Inflammatory/haematopoietic cytokine production by human bone marrow adipocytes. Eur. Cytokine Netw. 11, 634–639 (2000).
CAS PubMed Google Scholar
Sanchez-Lopez, E. et al. Choline uptake and metabolism modulate macrophage IL-1β and IL-18 production. Cell Metab. 29, 1350–1362.e7 (2019).
Article CAS PubMed Central PubMed Google Scholar
Romas, E. et al. The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J. Exp. Med. 183, 2581–2591 (1996).
Article CAS PubMed Google Scholar
Ishimi, Y. et al. IL-6 is produced by osteoblasts and induces bone resorption. J. Immunol. 145, 3297–3303 (1990).
CAS PubMed Google Scholar
Hardaway, A. L., Herroon, M. K., Rajagurubandara, E. & Podgorski, I. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin. Exp. Metastasis 32, 353–368 (2015).
Article CAS PubMed Central PubMed Google Scholar
Cereijo, R. et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab. 28, 750–763.e6 (2018).
Article CAS PubMed Google Scholar
Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).
Article CAS PubMed Google Scholar
Saraiva, M., Vieira, P. & O’Garra, A. Biology and therapeutic potential of interleukin-10. J. Exp. Med. 217, e20190418 (2020).
Article CAS PubMed Google Scholar
Li, P. et al. Hematopoietic-derived galectin-3 causes cellular and systemic insulin resistance. Cell 167, 973–984.e12 (2016).
Article CAS PubMed Central PubMed Google Scholar
Lyons, J. J. et al. ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans. J. Exp. Med. 214, 669–680 (2017).
Article CAS PubMed Central PubMed Google Scholar
Rajbhandari, P. et al. IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172, 218–233.e17 (2018).
Article CAS PubMed Google Scholar
Corre, J. et al. Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors. J. Cell Physiol. 208, 282–288 (2006).
Article CAS PubMed Google Scholar
Cawthorn, W. P. et al. Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab. 20, 368–375 (2014).
Article CAS PubMed Central PubMed Google Scholar
Rendina-Ruedy, E. & Rosen, C. J. Lipids in the bone marrow: an evolving perspective. Cell Metab. 31, 219–231 (2020).
Article CAS PubMed Google Scholar
Kricun, M. E. Red-yellow marrow conversion: its effect on the location of some solitary bone lesions. Skelet. Radio. 14, 10–19 (1985).
Article CAS Google Scholar
Tavassoli, M. Marrow adipose cells. Histochemical identification of labile and stable components. Arch. Pathol. Lab Med 100, 16–18 (1976).
CAS PubMed Google Scholar
Nishio, M. et al. Production of functional classical brown adipocytes from human pluripotent stem cells using specific hemopoietin cocktail without gene transfer. Cell Metab. 16, 394–406 (2012).
Article CAS PubMed Google Scholar
Wang, Z. V. & Scherer, P. E. Adiponectin, the past two decades. J. Mol. Cell Biol. 8, 93–100 (2016).
Article CAS PubMed Central PubMed Google Scholar
Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).
Article CAS PubMed Google Scholar
Scheller, E. L., Burr, A. A., MacDougald, O. A. & Cawthorn, W. P. Inside out: bone marrow adipose tissue as a source of circulating adiponectin. Adipocyte 5, 251–269 (2016).
Article CAS PubMed Central PubMed Google Scholar
Gil-Campos, M., Cañete, R. R. & Gil, A. Adiponectin, the missing link in insulin resistance and obesity. Clin. Nutr. 23, 963–974 (2004).
Article CAS PubMed Google Scholar
Yamauchi, T. & Kadowaki, T. Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. Cell Metab. 17, 185–196 (2013).
Article CAS PubMed Google Scholar
Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003).
Article CAS PubMed Google Scholar
Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7, 941–946 (2001).
Article CAS PubMed Google Scholar
Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e3 (2018).
Article CAS PubMed Central PubMed Google Scholar
Manieri, E. et al. Adiponectin accounts for gender differences in hepatocellular carcinoma incidence. J. Exp. Med. 216, 1108–1119 (2019).
Article CAS PubMed Central PubMed Google Scholar
González, A., Hall, M. N., Lin, S. C. & Hardie, D. G. AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. Cell Metab. 31, 472–492 (2020).
Article CAS PubMed Google Scholar
Qi, Y. et al. Adiponectin acts in the brain to decrease body weight. Nat. Med. 10, 524–529 (2004).
Article CAS PubMed Google Scholar
Uchihashi, K. et al. Organotypic culture of human bone marrow adipose tissue. Pathol. Int. 60, 259–267 (2010).
Article CAS PubMed Google Scholar
Berner, H. S. et al. Adiponectin and its receptors are expressed in bone-forming cells. Bone 35, 842–849 (2004).
Article CAS PubMed Google Scholar
Dalamaga, M. et al. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab. 18, 29–42 (2013).
Article CAS PubMed Google Scholar
Hoggard, N. et al. Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization. Biochem. Biophys. Res. Commun. 232, 383–387 (1997).
Article CAS PubMed Google Scholar
Harris, R. B. S. Direct and indirect effects of leptin on adipocyte metabolism. Biochim. Biophys. Acta. 1842, 414–423 (2014).
Article CAS PubMed Google Scholar
Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. & Goldstein, J. L. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 (1999).
Article CAS PubMed Google Scholar
Alfa, R. W. et al. Suppression of insulin production and secretion by a decretin hormone. Cell Metab. 27, 479 (2018).
Article CAS PubMed Google Scholar
Zhao, S. et al. Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab. 30, 706–719.e6 (2019).
Article CAS PubMed Central PubMed Google Scholar
Müller, G., Ertl, J., Gerl, M. & Preibisch, G. Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J. Biol. Chem. 272, 10585–10593 (1997).
Article PubMed Google Scholar
Laharrague, P. et al. High expression of leptin by human bone marrow adipocytes in primary culture. FASEB J. 12, 747–752 (1998).
Article CAS PubMed Google Scholar
Krings, A. et al. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone 50, 546–552 (2012).
Article CAS PubMed Google Scholar
Laharrague, P. et al. Regulation by cytokines of leptin expression in human bone marrow adipocytes. Horm. Metab. Res. 32, 381–385 (2000).
Article CAS PubMed Google Scholar
Münzberg, H. & Heymsfield, S. B. New insights into the regulation of leptin gene expression. Cell Metab. 29, 1013–1014 (2019).
Article PubMed Central CAS PubMed Google Scholar
Upadhyay, J., Farr, O. M. & Mantzoros, C. S. The role of leptin in regulating bone metabolism. Metabolism 64, 105–113 (2015).
Article CAS PubMed Google Scholar
Haeusler, R. A., McGraw, T. E. & Accili, D. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol. 19, 31–44 (2018).
Article CAS PubMed Google Scholar
Pramojanee, S. N., Phimphilai, M., Chattipakorn, N. & Chattipakorn, S. C. Possible roles of insulin signaling in osteoblasts. Endocr. Res. 39, 144–151 (2014).
Article CAS PubMed Google Scholar
Fulzele, K. et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142, 309–319 (2010).
Article CAS PubMed Central PubMed Google Scholar
Fulzele, K. et al. Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action. J. Biol. Chem. 282, 25649–25658 (2007).
Article CAS PubMed Google Scholar
Oh, J. H. & Lee, N. K. Up-regulation of RANK expression via ERK1/2 by insulin contributes to the enhancement of osteoclast differentiation. Mol. Cells 40, 371–377 (2017).
CAS PubMed Central PubMed Google Scholar
Shimoaka, T. et al. Impairment of bone healing by insulin receptor substrate-1 deficiency. J. Biol. Chem. 279, 15314–15322 (2004).
Article CAS PubMed Google Scholar
Conte, C., Epstein, S. & Napoli, N. Insulin resistance and bone: a biological partnership. Acta Diabetol. 55, 305–314 (2018).
Article CAS PubMed Google Scholar
Li, Z. et al. Glucose transporter-4 facilitates insulin-stimulated glucose uptake in osteoblasts. Endocrinology 157, 4094–4103 (2016).
Article CAS PubMed Central PubMed Google Scholar
Ferron, M. et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142, 296–308 (2010).
Article CAS PubMed Central PubMed Google Scholar
Mera, P. et al. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab. 25, 218 (2017).
Article CAS PubMed Google Scholar
Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L. & Carmeliet, G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev. 96, 365–408 (2016).
Article CAS PubMed Google Scholar
Hochberg, Z., Tiosano, D. & Even, L. Calcium therapy for calcitriol-resistant rickets. J. Pediatr. 121, 803–808 (1992).
Article CAS PubMed Google Scholar
Erben, R. G. et al. Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D. Mol. Endocrinol. 16, 1524–1537 (2002).
Article CAS PubMed Google Scholar
Nakamichi, Y. et al. VDR in osteoblast-lineage cells primarily mediates vitamin D treatment-induced increase in bone mass by suppressing bone resorption. J. Bone Min. Res. 32, 1297–1308 (2017).
Article CAS Google Scholar
Matthews, D. G., D’Angelo, J., Drelich, J. & Welsh, J. Adipose-specific Vdr deletion alters body fat and enhances mammary epithelial density. J. Steroid Biochem. Mol. Biol. 164, 299–308 (2016).
Article CAS PubMed Google Scholar
Rosenstreich, S. J., Rich, C. & Volwiler, W. Deposition in and release of vitamin D3 from body fat: evidence for a storage site in the rat. J. Clin. Investig. 50, 679–687 (1971).
Article CAS PubMed PubMed Central Google Scholar
Abbas, M. A. Physiological functions of Vitamin D in adipose tissue. J. Steroid Biochem Mol. Biol. 165, 369–381 (2017).
Article CAS PubMed Google Scholar
Blumberg, J. M. et al. Complex role of the vitamin D receptor and its ligand in adipogenesis in 3T3-L1 cells. J. Biol. Chem. 281, 11205–11213 (2006).
Article CAS PubMed Google Scholar
Ricciardi, C. J. et al. 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration. Eur. J. Nutr. 54, 1001–1012 (2015).
Article CAS PubMed Google Scholar
Sun, X. & Zemel, M. B. Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. FASEB J. 18, 1430–1432 (2004).
Article CAS PubMed Google Scholar
Eshraghian, A. Bone metabolism in non-alcoholic fatty liver disease: vitamin D status and bone mineral density. Minerva Endocrinol. 42, 164–172 (2017).
PubMed Google Scholar
Pittas, A. G., Harris, S. S., Stark, P. C. & Dawson-Hughes, B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 30, 980–986 (2007).
Article CAS PubMed Google Scholar
Liu, S. et al. Bovine parathyroid hormone enhances osteoclast bone resorption by modulating V-ATPase through PTH1R. Int J. Mol. Med. 37, 284–292 (2016).
Article CAS PubMed Google Scholar
Guo, J. et al. Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab. 11, 161–171 (2010).
Article CAS PubMed Central PubMed Google Scholar
Vrahnas, C. et al. Anabolic action of parathyroid hormone (PTH) does not compromise bone matrix mineral composition or maturation. Bone 93, 146–154 (2016).
Article CAS PubMed Google Scholar
Jilka, R. L. et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J. Clin. Investig. 104, 439–446 (1999).
Article CAS PubMed PubMed Central Google Scholar
Keller, H. & Kneissel, M. SOST is a target gene for PTH in bone. Bone 37, 148–158 (2005).
Article CAS PubMed Google Scholar
Boucher, D. et al. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J. Exp. Med. 215, 827–840 (2018).
Article CAS PubMed Central PubMed Google Scholar
Esen, E., Lee, S.-Y., Wice, B. M. & Long, F. PTH promotes bone anabolism by stimulating aerobic glycolysis via IGF signaling. J. Bone Min. Res. 30, 1959–1968 (2015).
Article CAS Google Scholar
Yamaguchi, M. Effect of parathyroid hormone on the increase in serum glucose and insulin levels after a glucose load to thyroparathyroidectomized rats. Endocrinol. Jpn 26, 353–358 (1979).
Article CAS PubMed Google Scholar
Kimura, S., Sasase, T., Ohta, T., Sato, E. & Matsushita, M. Parathyroid hormone (1-34) improves bone mineral density and glucose metabolism in Spontaneously Diabetic Torii-Lepr(fa) rats. J. Vet. Med. Sci. 74, 103–105 (2012).
Article CAS PubMed Google Scholar
Chiu, K. C. et al. Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism 49, 1501–1505 (2000).
Article CAS PubMed Google Scholar
Heuck, C. C. & Ritz, E. Does parathyroid hormone play a role in lipid metabolism? Contrib. Nephrol. 20, 118–128 (1980).
Article CAS PubMed Google Scholar
Lacour, B., Basile, C., Drüeke, T. & Funck-Brentano, J. L. Parathyroid function and lipid metabolism in the rat. Min. Electrolyte Metab. 7, 157–165 (1982).
CAS Google Scholar
Larsson, S., Jones, H. A., Göransson, O., Degerman, E. & Holm, C. Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase. Cell Signal 28, 204–213 (2016).
Article CAS PubMed Google Scholar
LeBlanc, M. E. et al. Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy. J. Exp. Med. 214, 1029–1047 (2017).
Article CAS PubMed Central PubMed Google Scholar
Mauvais-Jarvis, F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol. Metab. 22, 24–33 (2011).
Article CAS PubMed Google Scholar
Jia, M., Dahlman-Wright, K. & Gustafsson, J.-Å. Estrogen receptor alpha and beta in health and disease. Best. Pr. Res Clin. Endocrinol. Metab. 29, 557–568 (2015).
Article CAS Google Scholar
Brown, L. M., Gent, L., Davis, K. & Clegg, D. J. Metabolic impact of sex hormones on obesity. Brain Res. 1350, 77–85 (2010).
Article CAS PubMed Central PubMed Google Scholar
Voisin, D. L., Simonian, S. X. & Herbison, A. E. Identification of estrogen receptor-containing neurons projecting to the rat supraoptic nucleus. Neuroscience 78, 215–228 (1997).
Article CAS PubMed Google Scholar
Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 29, 1232 (2019).
Article CAS PubMed Central PubMed Google Scholar
Eckel, R. H. Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N. Engl. J. Med. 320, 1060–1068 (1989).
Article CAS PubMed Google Scholar
Cooke, P. S. & Naaz, A. Role of estrogens in adipocyte development and function. Exp. Biol. Med. 229, 1127–1135 (2004).
Article CAS Google Scholar
Gorres, B. K., Bomhoff, G. L., Morris, J. K. & Geiger, P. C. In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake. J. Physiol. 589, 2041–2054 (2011).
Article CAS PubMed Central PubMed Google Scholar
Hayashi, M. et al. Autoregulation of osteocyte Sema3A orchestrates estrogen action and counteracts bone aging. Cell Metab. 29, 627–637.e5 (2019).
Article CAS PubMed Google Scholar
Kondoh, S. et al. Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice. Bone 60, 68–77 (2014).
Article CAS PubMed Google Scholar
Novack, D. V. Estrogen and bone: osteoclasts take center stage. Cell Metab. 6, 254–256 (2007).
Article CAS PubMed Google Scholar
Streicher, C. et al. Estrogen regulates bone turnover by targeting RANKL expression in bone lining cells. Sci. Rep. 7, 6460 (2017).
Article PubMed Central CAS PubMed Google Scholar
Janghorbani, M., Van Dam, R. M., Willett, W. C. & Hu, F. B. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am. J. Epidemiol. 166, 495–505 (2007).
Article PubMed Google Scholar
Schwartz, A. V. et al. Older women with diabetes have an increased risk of fracture: a prospective study. J. Clin. Endocrinol. Metab. 86, 32–38 (2001).
Article CAS PubMed Google Scholar
Evans, A. L., Paggiosi, M. A., Eastell, R. & Walsh, J. S. Bone density, microstructure and strength in obese and normal weight men and women in younger and older adulthood. J. Bone Min. Res 30, 920–928 (2015).
Article Google Scholar
Sornay-Rendu, E., Boutroy, S., Vilayphiou, N., Claustrat, B. & Chapurlat, R. D. In obese postmenopausal women, bone microarchitecture and strength are not commensurate to greater body weight: the Os des Femmes de Lyon (OFELY) study. J. Bone Min. Res 28, 1679–1687 (2013).
Article CAS Google Scholar
Driessler, F. & Baldock, P. A. Hypothalamic regulation of bone. J. Mol. Endocrinol. 45, 175–181 (2010).
Article CAS PubMed Google Scholar
Lin, Y. Y. et al. Adiponectin receptor 1 regulates bone formation and osteoblast differentiation by GSK-3β/β-catenin signaling in mice. Bone 64, 147–154 (2014).
Article CAS PubMed Google Scholar
Boskey, A. L. & Coleman, R. Aging and bone. J. Dent. Res 89, 1333–1348 (2010).
Article CAS PubMed Central PubMed Google Scholar
Grandl, G. & Wolfrum, C. Adipocytes at the core of bone function. Cell Stem Cell 20, 739–740 (2017).
Article CAS PubMed Google Scholar
Benedetti, M. G., Furlini, G., Zati, A. & Letizia Mauro, G. The effectiveness of physical exercise on bone density in osteoporotic patients. Biomed. Res. Int. 2018, 4840531 (2018).
Article PubMed Central PubMed Google Scholar
Contrepois, K. et al. Molecular choreography of acute exercise. Cell 181, 1112–1130.e16 (2020).
Article CAS PubMed PubMed Central Google Scholar
Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020).
Article CAS PubMed Central PubMed Google Scholar
Duan, P., Yang, M., Wei, M., Liu, J. & Tu, P. Serum osteoprotegerin is a potential biomarker of insulin resistance in chinese postmenopausal women with prediabetes and type 2 diabetes. Int J. Endocrinol. 2017, 8724869 (2017).
Article PubMed Central CAS PubMed Google Scholar
Ndip, A., Wilkinson, F. L., Jude, E. B., Boulton, A. J. M. & Alexander, M. Y. RANKL-OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy. Diabetologia 57, 2251–2260 (2014).
Article CAS PubMed Google Scholar
Cypess, A. M., Haft, C. R., Laughlin, M. R. & Hu, H. H. Brown fat in humans: consensus points and experimental guidelines. Cell Metab. 20, 408–415 (2014).
Article CAS PubMed Central PubMed Google Scholar
Yao, Q. et al. Wnt/β-catenin signaling in osteoblasts regulates global energy metabolism. Bone 97, 175–183 (2017).
Article CAS PubMed Google Scholar
Wang, P. et al. Osthole promotes bone fracture healing through activation of BMP signaling in chondrocytes. Int J. Biol. Sci. 13, 996–1007 (2017).
Article CAS PubMed Central PubMed Google Scholar
Yee, C. S. et al. Conditional deletion of Sost in MSC-derived lineages identifies specific cell-type contributions to bone mass and B-cell development. J. Bone Min. Res 33, 1748–1759 (2018).
Article CAS Google Scholar