{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T18:59:20Z","timestamp":1775588360283,"version":"3.50.1"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,3,23]],"date-time":"2015-03-23T00:00:00Z","timestamp":1427068800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,3,23]],"date-time":"2015-03-23T00:00:00Z","timestamp":1427068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Obesity is a risk factor for ischemic necrosis of the femoral head (INFH). The purpose of this study was to determine if leptin treatment of INFH stimulates new bone formation to preserve femoral head shape in rats with diet-induced obesity. Rats were fed a high-fat diet (HFD) or normal chow diet (NCD) for 16 weeks to induce progressive development of obesity. Avascular necrosis of the femoral head (AVN) was surgically induced. Adenovirus-mediated introduction of the leptin gene was by intravenous injection 2 days before surgery-induced AVN. At 6 weeks post-surgery, radiologic and histomorphometric assessments were performed. Leptin signaling in tissues was examined by Western blot. Osteogenic markers were analyzed by real-time RT-PCR. Radiographs showed better preservation of femoral head architecture in the HFD-AVN-Leptin group than the HFD-AVN and HFD-AVN-LacZ groups. Histology and immunohistochemistry revealed the HFD-AVN-Leptin group had significantly increased osteoblastic proliferation and vascularity in infarcted femoral heads compared with the HFD-AVN and HFD-AVN-LacZ groups. Intravenous injection of leptin enhanced serum VEGF levels and activated HIF-1\u03b1 pathways. Runx 2 and its target genes were significantly upregulated in the HFD-AVN-Leptin group. These results indicate that leptin resistance is important in INFH pathogenesis. Leptin therapy could be a new strategy for INFH.<\/jats:p>","DOI":"10.1038\/srep09397","type":"journal-article","created":{"date-parts":[[2015,3,23]],"date-time":"2015-03-23T10:19:42Z","timestamp":1427105982000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Leptin ameliorates ischemic necrosis of the femoral head in rats with obesity induced by a high-fat diet"],"prefix":"10.1038","volume":"5","author":[{"given":"Lu","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyu Yun","family":"Jang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young Jae","family":"Moon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sajeev","family":"Wagle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoung Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwang Bok","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung-Hyun","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Ryul","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,3,23]]},"reference":[{"key":"BFsrep09397_CR1","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.2106\/JBJS.H.00654","volume":"91","author":"HK Kim","year":"2009","unstructured":"Kim, H. K., Stephenson, N., Garces, A., Aya-ay, J. & Bian, H. Effects of disruption of epiphyseal vasculature on the proximal femoral growth plate. J Bone Joint Surg Am 91, 1149\u20131158 (2009).","journal-title":"J Bone Joint Surg Am"},{"key":"BFsrep09397_CR2","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.bone.2009.01.366","volume":"44","author":"BH Park","year":"2009","unstructured":"Park, B. H. et al. COMP-Angiopoietin-1 ameliorates surgery-induced ischemic necrosis of the femoral head in rats. Bone 44, 886\u2013892 (2009).","journal-title":"Bone"},{"key":"BFsrep09397_CR3","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jor.22415","volume":"31","author":"JH Lee","year":"2013","unstructured":"Lee, J. H. et al. Role of leptin in Legg-Calve-Perthes disease. J Orthop Res 31, 1605\u20131610 (2013).","journal-title":"J Orthop Res"},{"key":"BFsrep09397_CR4","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1038\/27376","volume":"395","author":"JM Friedman","year":"1998","unstructured":"Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763\u2013770 (1998).","journal-title":"Nature"},{"key":"BFsrep09397_CR5","doi-asserted-by":"publisher","first-page":"40283","DOI":"10.1074\/jbc.M607545200","volume":"281","author":"BH Park","year":"2006","unstructured":"Park, B. H. et al. Combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats: implications for obesity treatment. J Biol Chem 281, 40283\u201340291 (2006).","journal-title":"J Biol Chem"},{"key":"BFsrep09397_CR6","doi-asserted-by":"publisher","first-page":"E10","DOI":"10.1152\/ajpendo.00468.2002","volume":"285","author":"WA Banks","year":"2003","unstructured":"Banks, W. A. & Farrell, C. L. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 285, E10\u201315; 10.1152\/ajpendo.00468.2002 (2003).","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFsrep09397_CR7","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1126\/science.7624777","volume":"269","author":"JL Halaas","year":"1995","unstructured":"Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543\u2013546 (1995).","journal-title":"Science"},{"key":"BFsrep09397_CR8","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/S0092-8674(00)81294-5","volume":"84","author":"H Chen","year":"1996","unstructured":"Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db\/db mice. Cell 84, 491\u2013495 (1996).","journal-title":"Cell"},{"key":"BFsrep09397_CR9","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1002\/jbmr.1734","volume":"28","author":"RT Turner","year":"2013","unstructured":"Turner, R. T. et al. Peripheral leptin regulates bone formation. J Bone Miner Res 28, 22\u201334 (2013).","journal-title":"J Bone Miner Res"},{"key":"BFsrep09397_CR10","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1002\/jbmr.406","volume":"26","author":"SM Bartell","year":"2011","unstructured":"Bartell, S. M. et al. Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1 and the expression of osteogenic genes in leptin-deficient ob\/ob mice. J Bone Miner Res 26, 1710\u20131720 (2011).","journal-title":"J Bone Miner Res"},{"key":"BFsrep09397_CR11","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1016\/j.peptides.2009.01.020","volume":"30","author":"SP Kalra","year":"2009","unstructured":"Kalra, S. P. et al. Leptin increases osteoblast-specific osteocalcin release through a hypothalamic relay. Peptides 30, 967\u2013973 (2009).","journal-title":"Peptides"},{"key":"BFsrep09397_CR12","doi-asserted-by":"publisher","first-page":"254S","DOI":"10.1038\/oby.2006.319","volume":"14","author":"PJ Enriori","year":"2006","unstructured":"Enriori, P. J., Evans, A. E., Sinnayah, P. & Cowley, M. A. Leptin resistance and obesity. Obesity (Silver Spring) 14 Suppl 5254S\u2013258S (2006).","journal-title":"Obesity (Silver Spring)"},{"key":"BFsrep09397_CR13","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1034\/j.1399-5448.2003.00017.x","volume":"4","author":"O Moran","year":"2003","unstructured":"Moran, O. & Phillip, M. Leptin: obesity, diabetes and other peripheral effects--a review. Pediatr Diabetes 4, 101\u2013109 (2003).","journal-title":"Pediatr Diabetes"},{"key":"BFsrep09397_CR14","doi-asserted-by":"publisher","first-page":"M1","DOI":"10.1530\/JOE-14-0224","volume":"223","author":"RT Turner","year":"2014","unstructured":"Turner, R. T. et al. Morbid obesity attenuates the skeletal abnormalities associated with leptin deficiency in mice. J Endocrinol 223, M1\u201315 (2014).","journal-title":"J Endocrinol"},{"key":"BFsrep09397_CR15","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0092-8674(00)81558-5","volume":"100","author":"P Ducy","year":"2000","unstructured":"Ducy, P. et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100, 197\u2013207 (2000).","journal-title":"Cell"},{"key":"BFsrep09397_CR16","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1210\/endo.140.4.6637","volume":"140","author":"T Thomas","year":"1999","unstructured":"Thomas, T. et al. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 140, 1630\u20131638 (1999).","journal-title":"Endocrinology"},{"key":"BFsrep09397_CR17","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1002\/jcb.10156","volume":"85","author":"JO Gordeladze","year":"2002","unstructured":"Gordeladze, J. O., Drevon, C. A., Syversen, U. & Reseland, J. E. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis and mineralization: Impact on differentiation markers, apoptosis and osteoclastic signaling. J Cell Biochem 85, 825\u2013836 (2002).","journal-title":"J Cell Biochem"},{"key":"BFsrep09397_CR18","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0167-0115(00)00152-X","volume":"92","author":"CM Steppan","year":"2000","unstructured":"Steppan, C. M., Crawford, D. T., Chidsey-Frink, K. L., Ke, H. & Swick, A. G. Leptin is a potent stimulator of bone growth in ob\/ob mice. Regul Pept 92, 73\u201378 (2000).","journal-title":"Regul Pept"},{"key":"BFsrep09397_CR19","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/38717","volume":"389","author":"S Kamohara","year":"1997","unstructured":"Kamohara, S., Burcelin, R., Halaas, J. L., Friedman, J. M. & Charron, M. J. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389, 374\u2013377 (1997).","journal-title":"Nature"},{"key":"BFsrep09397_CR20","doi-asserted-by":"publisher","first-page":"2029","DOI":"10.2337\/diab.46.12.2029","volume":"46","author":"LA Scrocchi","year":"1997","unstructured":"Scrocchi, L. A., Brown, T. J. & Drucker, D. J. Leptin sensitivity in nonobese glucagon-like peptide I receptor -\/- mice. Diabetes 46, 2029\u20132034 (1997).","journal-title":"Diabetes"},{"key":"BFsrep09397_CR21","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1016\/S0026-0495(98)90336-5","volume":"47","author":"ZQ Shi","year":"1998","unstructured":"Shi, Z. Q., Nelson, A., Whitcomb, L., Wang, J. & Cohen, A. M. Intracerebroventricular administration of leptin markedly enhances insulin sensitivity and systemic glucose utilization in conscious rats. Metabolism 47, 1274\u20131280 (1998).","journal-title":"Metabolism"},{"key":"BFsrep09397_CR22","doi-asserted-by":"publisher","first-page":"3871","DOI":"10.1210\/endo.139.9.6206","volume":"139","author":"GS Tannenbaum","year":"1998","unstructured":"Tannenbaum, G. S., Gurd, W. & Lapointe, M. Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone. Endocrinology 139, 3871\u20133875 (1998).","journal-title":"Endocrinology"},{"key":"BFsrep09397_CR23","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1172\/JCI119818","volume":"100","author":"RN Kulkarni","year":"1997","unstructured":"Kulkarni, R. N. et al. Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. J Clin Invest 100, 2729\u20132736 (1997).","journal-title":"J Clin Invest"},{"key":"BFsrep09397_CR24","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1073\/pnas.96.2.674","volume":"96","author":"J Seufert","year":"1999","unstructured":"Seufert, J., Kieffer, T. J. & Habener, J. F. Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob\/ob mice. Proc Natl Acad Sci U S A 96, 674\u2013679 (1999).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep09397_CR25","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/43448","volume":"401","author":"I Shimomura","year":"1999","unstructured":"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\u201376 (1999).","journal-title":"Nature"},{"key":"BFsrep09397_CR26","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1359\/JBMR.050103","volume":"20","author":"MW Hamrick","year":"2005","unstructured":"Hamrick, M. W. et al. Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob\/ob mice. J Bone Miner Res 20, 994\u20131001 (2005).","journal-title":"J Bone Miner Res"},{"key":"BFsrep09397_CR27","doi-asserted-by":"publisher","first-page":"39S","DOI":"10.1016\/S8756-3282(96)00133-0","volume":"19","author":"H Winet","year":"1996","unstructured":"Winet, H. The role of microvasculature in normal and perturbed bone healing as revealed by intravital microscopy. Bone 19, 39S\u201357S (1996).","journal-title":"Bone"},{"key":"BFsrep09397_CR28","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1126\/science.281.5383.1683","volume":"281","author":"MR Sierra-Honigmann","year":"1998","unstructured":"Sierra-Honigmann, M. R. et al. Biological action of leptin as an angiogenic factor. Science 281, 1683\u20131686 (1998).","journal-title":"Science"},{"key":"BFsrep09397_CR29","doi-asserted-by":"publisher","first-page":"6390","DOI":"10.1073\/pnas.101564798","volume":"98","author":"R Cao","year":"2001","unstructured":"Cao, R., Brakenhielm, E., Wahlestedt, C., Thyberg, J. & Cao, Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A 98, 6390\u20136395 (2001).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"BFsrep09397_CR30","first-page":"265","volume":"8","author":"D Ribatti","year":"2001","unstructured":"Ribatti, D. et al. Angiogenic activity of leptin in the chick embryo chorioallantoic membrane is in part mediated by endogenous fibroblast growth factor-2. Int J Mol Med 8, 265\u2013268 (2001).","journal-title":"Int J Mol Med"},{"key":"BFsrep09397_CR31","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/emm.2001.17","volume":"33","author":"HY Park","year":"2001","unstructured":"Park, H. Y. et al. Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med 33, 95\u2013102 (2001).","journal-title":"Exp Mol Med"},{"key":"BFsrep09397_CR32","doi-asserted-by":"publisher","first-page":"2041","DOI":"10.1359\/jbmr.040911","volume":"19","author":"HK Kim","year":"2004","unstructured":"Kim, H. K. et al. Increased VEGF expression in the epiphyseal cartilage after ischemic necrosis of the capital femoral epiphysis. J Bone Miner Res 19, 2041\u20132048 (2004).","journal-title":"J Bone Miner Res"},{"key":"BFsrep09397_CR33","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1007\/s00223-007-9046-9","volume":"81","author":"HZ Ma","year":"2007","unstructured":"Ma, H. Z., Zeng, B. F. & Li, X. L. Upregulation of VEGF in subchondral bone of necrotic femoral heads in rabbits with use of extracorporeal shock waves. Calcif Tissue Int 81, 124\u2013131 (2007).","journal-title":"Calcif Tissue Int"},{"key":"BFsrep09397_CR34","doi-asserted-by":"publisher","first-page":"e18823","DOI":"10.1371\/journal.pone.0018823","volume":"6","author":"E Garonna","year":"2011","unstructured":"Garonna, E. et al. Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PLoS One 6, e18823; 10.1371\/journal.pone.0018823 (2011).","journal-title":"PLoS One"},{"key":"BFsrep09397_CR35","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1158\/0008-5472.CAN-03-2751","volume":"64","author":"M Ruiz","year":"2004","unstructured":"Ruiz, M. et al. Activator protein 2alpha inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells. Cancer Res 64, 631\u2013638 (2004).","journal-title":"Cancer Res"},{"key":"BFsrep09397_CR36","doi-asserted-by":"publisher","first-page":"2812","DOI":"10.1073\/pnas.90.7.2812","volume":"90","author":"J Herz","year":"1993","unstructured":"Herz, J. et al. Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. Proc Natl Acad Sci U S A 90, 2812\u20132816 (1993).","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep09397","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep09397.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep09397.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:20:16Z","timestamp":1672964416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep09397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,23]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,8,14]]}},"alternative-id":["BFsrep09397"],"URL":"https:\/\/doi.org\/10.1038\/srep09397","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,23]]},"assertion":[{"value":"2 December 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9397"}}