KIAA1199 (CEMIP) regulates adipogenesis and whole-body energy metabolism

Abstract

An increasing number of studies have characterized the bone as an endocrine organ, and that bone secreted factors may not only regulate local bone remodeling, but also other tissues and whole-body metabolic functions. The precise nature of these regulatory factors and their roles at bridging the bone, bone marrow adipose tissue, extramedullary body fat and whole-body energy homeostasis are being explored. In this study, we report that KIAA1199, a secreted factor produced from bone and bone marrow, previously described as an inhibitor of bone formation, also plays a role at promoting adipogenesis. KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue, subcutaneous and visceral fat tissue mass, blood cholesterol, triglycerides, free fatty acids and glycerol, as well as improved insulin sensitivity in skeletal muscle, liver and fat. Moreover, these mice are protected from the detrimental effects of high-fat diet feeding, with decreased obesity, lower blood glucose and glucose tolerance, as well as decreased adipose tissue inflammation, insulin resistance and hepatic steatosis. In human studies, plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol, triglycerides, free fatty acids, glycerol, fasting glucose and HOMA-IR. Mechanistically, KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT / ERK signaling. These findings provide evidence for the role of bone secreted factors on coupling bone, fat and whole-body energy homeostasis.

Keywords

Medical and Health Sciences / Clinical Sciences / Biological Sciences / Biochemistry and Cell Biology

References

[1] KarsentyG, KhoslaS. The crosstalk between bone remodeling and energy metabolism: a translational perspective. Cell Metab., 2022, 34: 805-817.

[2] KarsentyG. Update on the biology of osteocalcin. Endocr. Pract., 2017, 23: 1270-1274.

[3] MosialouI, et al. . Corrigendum: MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature, 2017, 546: 440.

[4] AbdallahBM, DitzelN, LabordaJ, KarsentyG, KassemM. DLK1 regulates whole-body glucose metabolism: a negative feedback regulation of the osteocalcin-insulin loop. Diabetes, 2015, 64: 3069-3080.

[5] ZhangQ, RiddleRC, ClemensTL. Bone and the regulation of global energy balance. J. Intern. Med., 2015, 277: 681-689.

[6] TencerovaM, KassemM. The bone marrow-derived stromal cells: commitment and regulation of adipogenesis. Front. Endocrinol., 2016, 7: 127.

[7] KristensenLP, et al. . Temporal profiling and pulsed SILAC labeling identify novel secreted proteins during ex vivo osteoblast differentiation of human stromal stem cells. Mol. Cell Proteom., 2012, 11: 989-1007.

[8] JafariA, et al. . Legumain regulates differentiation fate of human bone marrow stromal cells and is altered in postmenopausal osteoporosis. Stem Cell Rep., 2017, 8: 373-386.

[9] AbdallahBM, et al. . DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice. J. Bone Miner. Res., 2011, 26: 1457-1471.

[10] DashDP, SilvestriG, HughesAE. Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis. Mol. Vis., 2006, 12: 499-505

[11] YoshidaH, et al. . KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc. Natl. Acad. Sci. USA, 2013, 110: 5612-5617.

[12] YoshidaH, et al. . N-Terminal signal sequence is required for cellular trafficking and hyaluronan-depolymerization of KIAA1199. FEBS Lett., 2014, 588: 111-116.

[13] YangX, et al. . KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis. Arthritis Res. Ther., 2015, 17: 140.

[14] DengF, et al. . Overexpression of KIAA1199: an independent prognostic marker in nonsmall cell lung cancer. J. Cancer Res. Ther., 2017, 13: 664-668.

[15] ChenL, ShiK, AndersenTL, QiuW, KassemM. KIAA1199 is a secreted molecule that enhances osteoblastic stem cell migration and recruitment. Cell Death Dis., 2019, 10. 126

[16] ChenL, et al. . KIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration. Nat. Commun., 2023, 14. 2016

[17] RauchA, et al. . Osteogenesis depends on commissioning of a network of stem cell transcription factors that act as repressors of adipogenesis. Nat. Genet., 2019, 51: 716-727.

[18] MadsenJGS, et al. . Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells. Nat. Genet., 2020, 52: 1227-1238.

[19] KerckhofsG, et al. . Simultaneous three-dimensional visualization of mineralized and soft skeletal tissues by a novel microCT contrast agent with polyoxometalate structure. Biomaterials, 2018, 159: 1-12.

[20] BajzovaM, et al. . Retinol-binding protein 4 expression in visceral and subcutaneous fat in human obesity. Physiol. Res., 2008, 57: 927-934.

[21] HardyOT, et al. . Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity. Surg. Obes. Relat. Dis., 2011, 7: 60-67.

[22] WeberGF, AshkarS, GlimcherMJ, CantorH. Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science, 1996, 271: 509-512.

[23] HruskaKA, RolnickF, HuskeyM, AlvarezU, ChereshD. Engagement of the osteoclast integrin alpha v beta 3 by osteopontin stimulates phosphatidylinositol 3-hydroxyl kinase activity. Endocrinology, 1995, 136: 2984-2992.

[24] HuDD, LinEC, KovachNL, HoyerJR, SmithJW. A biochemical characterization of the binding of osteopontin to integrins alpha v beta 1 and alpha v beta 5. J. Biol. Chem., 1995, 270: 26232-26238.

[25] AliD, TencerovaM, FigeacF, KassemM, JafariA. The pathophysiology of osteoporosis in obesity and type 2 diabetes in aging women and men: the mechanisms and roles of increased bone marrow adiposity. Front. Endocrinol., 2022, 13. 981487

[26] WilsonN, et al. . Role of hyaluronan in human adipogenesis: evidence from in-vitro and in-vivo studies. Int. J. Mol. Sci., 2019, 20: 2675.

[27] NomiyamaT, et al. . Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J. Clin. Investig., 2007, 117: 2877-2888.

[28] ChapmanJ, et al. . Osteopontin is required for the early onset of high fat diet-induced insulin resistance in mice. PLoS One, 2010, 5: e13959.

[29] LanchaA, et al. . Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice. PLoS One, 2014, 9: e98398.

[30] BertolaA, et al. . Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity. Diabetes, 2009, 58: 125-133.

[31] ChenQ, et al. . Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?. Cell Death Differ., 2016, 23: 1128-1139.

[32] YangHJ, et al. . A novel role for neural cell adhesion molecule in modulating insulin signaling and adipocyte differentiation of mouse mesenchymal stem cells. J. Cell Sci., 2011, 124: 2552-2560.

[33] PrustyD, ParkBH, DavisKE, FarmerSR. Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor gamma (PPARgamma) and C/EBPalpha gene expression during the differentiation of 3T3-L1 preadipocytes. J. Biol. Chem., 2002, 277: 46226-46232.

[34] BostF, AouadiM, CaronL, BinetruyB. The role of MAPKs in adipocyte differentiation and obesity. Biochimie, 2005, 87: 51-56.

[35] KohiS, SatoN, KogaA, MatayoshiN, HirataK. KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer. Oncotarget, 2017, 8: 17156-17163.

[36] XuJ, et al. . Association between KIAA1199 overexpression and tumor invasion, TNM stage, and poor prognosis in colorectal cancer. Int. J. Clin. Exp. Pathol., 2015, 8: 2909-2918

[37] MatsuzakiS, et al. . Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann. Surg. Oncol., 2009, 16: 2042-2051.

[38] TiwariA, et al. . Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS One, 2013, 8: e69473.

[39] JamiMS, et al. . Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness. BMC Cancer, 2014, 14. 194

[40] MotalnH, et al. . Human mesenchymal stem cells exploit the immune response mediating chemokines to impact the phenotype of glioblastoma. Cell Transplant., 2012, 21: 1529-1545.

[41] FinkSP, et al. . Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival. Oncotarget, 2015, 6: 30500-30515.

[42] ShimizuH, et al. . Hyaluronan-binding protein involved in hyaluronan depolymerization is up-regulated and involved in hyaluronan degradation in human osteoarthritic cartilage. Am. J. Pathol., 2018, 188: 2109-2119.

[43] NagaokaA, et al. . Regulation of hyaluronan (HA) metabolism mediated by HYBID (hyaluronan-binding protein involved in HA depolymerization, KIAA1199) and HA synthases in growth factor-stimulated fibroblasts. J. Biol. Chem., 2015, 290: 30910-30923.

[44] ShiozawaJ, et al. . Implication of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization) in hyaluronan degradation by synovial fibroblasts in patients with knee osteoarthritis. Am. J. Pathol., 2020, 190: 1046-1058.

[45] OhtsukiT, et al. . Induction of CEMIP in chondrocytes by inflammatory cytokines: underlying mechanisms and potential involvement in osteoarthritis. Int. J. Mol. Sci., 2020, 21: 3140.

[46] ZaidiM, et al. . Bone circuitry and interorgan skeletal crosstalk. Elife, 2023, 12: e83142.

[47] SimonsenJL, et al. . Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat. Biotechnol., 2002, 20: 592-596.

Funding

National Natural Science Foundation of China (National Science Foundation of China)(32060155)

Guangxi Medical and Health Key Discipline Construction Project

Odense University Hospital PhD fellowship (2014)

Novo Nordisk Fonden (Novo Nordisk Foundation)(NNF15OC0016284)

The innovation foundation of Denmark (5166-00002B)

RIGHTS & PERMISSIONS

The Author(s)