{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:58:13Z","timestamp":1787003893153,"version":"build-2736575974"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,11,30]],"date-time":"2015-11-30T00:00:00Z","timestamp":1448841600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,11,30]],"date-time":"2015-11-30T00:00:00Z","timestamp":1448841600000},"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>\n                  <jats:p>\n                    High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    ) mice exposed to HFD (\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    \/HFD mice) revealed increased glucose-6-phosphatase (\n                    <jats:italic>G6pc<\/jats:italic>\n                    ) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    \/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased\n                    <jats:italic>G6pc<\/jats:italic>\n                    expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    \/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    \/HFD liver. Reduced\n                    <jats:italic>Cyp7a1<\/jats:italic>\n                    expression in\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    \/HFD liver was rescued by WAT transplantation and the expression of\n                    <jats:italic>Cyp7a1<\/jats:italic>\n                    was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in\n                    <jats:italic>Insr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>P1195L\/<\/jats:italic>\n                      +\n                    <\/jats:sup>\n                    \/HFD liver.\n                  <\/jats:p>","DOI":"10.1038\/srep17565","type":"journal-article","created":{"date-parts":[[2015,11,30]],"date-time":"2015-11-30T04:57:01Z","timestamp":1448859421000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in InsrP1195L\/+ mice fed high-fat-diet"],"prefix":"10.1038","volume":"5","author":[{"given":"Eun Young","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Sakurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitoku","family":"Toda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoaki","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meizi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Shirasawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Tachibana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koutaro","family":"Yokote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Vidal-Puig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiko","family":"Minokoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Miki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,30]]},"reference":[{"key":"BFsrep17565_CR1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/S0140-6736(11)60614-4","volume":"378","author":"CJ Nolan","year":"2011","unstructured":"Nolan, C. J., Damm, P. & Prentki, M. Type 2 diabetes across generations: from pathophysiology to prevention and management. The Lancet 378, 169\u2013181 (2011).","journal-title":"The Lancet"},{"key":"BFsrep17565_CR2","doi-asserted-by":"publisher","first-page":"3382","DOI":"10.1007\/s00125-012-2703-1","volume":"55","author":"A Nakamura","year":"2012","unstructured":"Nakamura, A. et al. Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance. Diabetologia 55, 3382\u20133391 (2012).","journal-title":"Diabetologia"},{"key":"BFsrep17565_CR3","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1146\/annurev.physiol.68.040104.124723","volume":"68","author":"SB Biddinger","year":"2006","unstructured":"Biddinger, S. B. & Kahn, C. R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123\u2013158 (2006).","journal-title":"Annu. Rev. Physiol."},{"key":"BFsrep17565_CR4","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1210\/er.2010-0020","volume":"32","author":"RK Semple","year":"2011","unstructured":"Semple, R. K., Savage, D. B., Cochran, E. K., Gorden, P. & O'Rahilly, S. Genetic syndromes of severe insulin resistance. Endocr. Rev. 32, 498\u2013514 (2011).","journal-title":"Endocr. Rev."},{"key":"BFsrep17565_CR5","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1016\/j.cell.2012.01.034","volume":"148","author":"T Kadowaki","year":"2012","unstructured":"Kadowaki, T., Ueki, K., Yamauchi, T. & Kubota, N. SnapShot: Insulin signaling pathways. Cell 148, 624 624.e1 (2012).","journal-title":"Cell"},{"key":"BFsrep17565_CR6","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1677\/joe.1.06849","volume":"190","author":"J Ogino","year":"2006","unstructured":"Ogino, J. et al. Insulin resistance and increased pancreatic beta-cell proliferation in mice expressing a mutant insulin receptor (P1195L). J. Endocrinol. 190, 739\u2013747 (2006).","journal-title":"J. Endocrinol."},{"key":"BFsrep17565_CR7","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/S1097-2765(05)00015-8","volume":"6","author":"MD Michael","year":"2000","unstructured":"Michael, M. D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87\u201397 (2000).","journal-title":"Mol. Cell"},{"key":"BFsrep17565_CR8","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1007\/s00125-013-2869-1","volume":"56","author":"MP Czech","year":"2013","unstructured":"Czech, M. P., Tencerova, M., Pedersen, D. J. & Aouadi, M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 56, 949\u2013964 (2013).","journal-title":"Diabetologia"},{"key":"BFsrep17565_CR9","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1038\/82630","volume":"26","author":"J Martinez-Botas","year":"2000","unstructured":"Martinez-Botas, J. et al. Absence of perilipin results in leanness and reverses obesity in Lepr(db\/db) mice. Nat. Genet. 26, 474\u2013479 (2000).","journal-title":"Nat. Genet."},{"key":"BFsrep17565_CR10","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1126\/science.1100747","volume":"306","author":"R Zimmermann","year":"2004","unstructured":"Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383\u20131386 (2004).","journal-title":"Science"},{"key":"BFsrep17565_CR11","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/nature13477","volume":"510","author":"V Peirce","year":"2014","unstructured":"Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76\u201383 (2014).","journal-title":"Nature"},{"key":"BFsrep17565_CR12","doi-asserted-by":"publisher","first-page":"1861","DOI":"10.1074\/jbc.M111.305789","volume":"287","author":"T Li","year":"2012","unstructured":"Li, T. et al. Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity. J. Biol. Chem. 287, 1861\u20131873 (2012).","journal-title":"J. Biol. Chem."},{"key":"BFsrep17565_CR13","doi-asserted-by":"publisher","first-page":"10402","DOI":"10.1073\/pnas.95.18.10402","volume":"95","author":"T Miki","year":"1998","unstructured":"Miki, T. et al. Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc. Natl. Acad. Sci. USA 95, 10402\u201310406 (1998).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep17565_CR14","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1194\/jlr.M001602","volume":"51","author":"S Cipriani","year":"2010","unstructured":"Cipriani, S., Mencarelli, A., Palladino, G. & Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa\/fa) obese rats. J. Lipid Res. 51, 771\u2013784 (2010).","journal-title":"J. Lipid Res."},{"key":"BFsrep17565_CR15","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cmet.2009.08.001","volume":"10","author":"C Thomas","year":"2009","unstructured":"Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167\u2013177 (2009).","journal-title":"Cell Metab."},{"key":"BFsrep17565_CR16","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nature04330","volume":"439","author":"M Watanabe","year":"2006","unstructured":"Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484\u2013489 (2006).","journal-title":"Nature"},{"key":"BFsrep17565_CR17","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1016\/S0140-6736(06)69703-1","volume":"368","author":"KH Yoon","year":"2006","unstructured":"Yoon, K. H. et al. Epidemic obesity and type 2 diabetes in Asia. The Lancet 368, 1681\u20131688 (2006).","journal-title":"The Lancet"},{"key":"BFsrep17565_CR18","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1111\/j.1464-5491.2004.01403.x","volume":"22","author":"K Waki","year":"2005","unstructured":"Waki, K. et al. Alcohol consumption and other risk factors for self-reported diabetes among middle-aged Japanese: a population-based prospective study in the JPHC study cohort I. Diabet. Med. 22, 323\u2013331 (2005).","journal-title":"Diabet. Med"},{"key":"BFsrep17565_CR19","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.coph.2010.08.004","volume":"10","author":"RH Wong","year":"2010","unstructured":"Wong, R. H. & Sul, H. S. Insulin signaling in fatty acid and fat synthesis: a transcriptional perspective. Curr. Opin. Pharmacol. 10, 684\u2013691 (2010).","journal-title":"Curr. Opin. Pharmacol."},{"key":"BFsrep17565_CR20","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.2337\/diab.34.10.1049","volume":"34","author":"DE James","year":"1985","unstructured":"James, D. E., Burleigh, K. M. & Kraegen, E. W. Time dependence of insulin action in muscle and adipose tissue in the rat in vivo. An increasing response in adipose tissue with time. Diabetes 34, 1049\u20131054 (1985).","journal-title":"Diabetes"},{"key":"BFsrep17565_CR21","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.cell.2014.09.035","volume":"159","author":"MM Yore","year":"2014","unstructured":"Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318\u2013332 (2014).","journal-title":"Cell"},{"key":"BFsrep17565_CR22","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1016\/S0140-6736(13)62154-6","volume":"383","author":"SE Kahn","year":"2014","unstructured":"Kahn, S. E., Cooper, M. E. & Del Prato, S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present and future. The Lancet 383, 1068\u20131083 (2014).","journal-title":"The Lancet"},{"key":"BFsrep17565_CR23","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/nm1785","volume":"14","author":"SB Biddinger","year":"2008","unstructured":"Biddinger, S. B. et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat. Med. 14, 778\u2013782 (2008).","journal-title":"Nat. Med"},{"key":"BFsrep17565_CR24","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1002\/hep.23721","volume":"52","author":"T Li","year":"2010","unstructured":"Li, T. et al. Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice. Hepatology 52, 678\u2013690 (2010).","journal-title":"Hepatology"},{"key":"BFsrep17565_CR25","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1194\/jlr.M004929","volume":"51","author":"R Cao","year":"2010","unstructured":"Cao, R. et al. Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway. J. Lipid Res. 51, 2234\u20132244 (2010).","journal-title":"J. Lipid Res."},{"key":"BFsrep17565_CR26","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.tem.2014.03.007","volume":"25","author":"J Prawitt","year":"2014","unstructured":"Prawitt, J., Caron, S. & Staels, B. Glucose-lowering effects of intestinal bile acid sequestration through enhancement of splanchnic glucose utilization. Trends Endocrinol. Metab. 25, 235\u2013244 (2014).","journal-title":"Trends Endocrinol. Metab."},{"key":"BFsrep17565_CR27","doi-asserted-by":"publisher","first-page":"16417","DOI":"10.1074\/jbc.M500924200","volume":"280","author":"T Baba","year":"2005","unstructured":"Baba, T. et al. Estrogen, insulin and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice. J. Biol. Chem. 280, 16417\u201316426 (2005).","journal-title":"J. Biol. Chem."},{"key":"BFsrep17565_CR28","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1055\/s-2006-954580","volume":"38","author":"K Ishikawa","year":"2006","unstructured":"Ishikawa, K. et al. Subcutaneous fat modulates insulin sensitivity in mice by regulating TNF-alpha expression in visceral fat. Horm. Metab. Res. 38, 631\u2013638 (2006).","journal-title":"Horm. Metab. Res."},{"key":"BFsrep17565_CR29","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0021-9258(18)51687-2","volume":"239","author":"M Rodbell","year":"1964","unstructured":"Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J. Biol. Chem. 239, 375\u2013380 (1964).","journal-title":"J. Biol. Chem."},{"key":"BFsrep17565_CR30","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1194\/jlr.D800041-JLR200","volume":"50","author":"M Hagio","year":"2009","unstructured":"Hagio, M., Matsumoto, M., Fukushima, M., Hara, H. & Ishizuka, S. Improved analysis of bile acids in tissues and intestinal contents of rats using LC\/ESI-MS. J. Lipid Res. 50, 173\u2013180 (2009).","journal-title":"J. Lipid Res."},{"key":"BFsrep17565_CR31","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.jchromb.2012.05.023","volume":"900","author":"A Muto","year":"2012","unstructured":"Muto, A. et al. Detection of Delta4-3-oxo-steroid 5beta-reductase deficiency by LC-ESI-MS\/MS measurement of urinary bile acids. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 900, 24\u201331 (2012).","journal-title":"J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep17565","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17565.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17565.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T14:19:15Z","timestamp":1672928355000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep17565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,30]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,22]]}},"alternative-id":["BFsrep17565"],"URL":"https:\/\/doi.org\/10.1038\/srep17565","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,30]]},"assertion":[{"value":"14 June 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 November 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":"17565"}}