{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:00:16Z","timestamp":1791295216699,"version":"4.1.0"},"reference-count":50,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"vor","delay-in-days":3987,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,12,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>The liver plays a critical role in integrating and controlling glucose metabolism. Thus, it is important that the liver receive and react to signals from other tissues regarding the nutrient status of the body. Leptin, which is produced and secreted from adipose tissue, is a hormone that relays information regarding the status of adipose depots to other parts of the body. Leptin has a profound influence on glucose metabolism, so we sought to determine if leptin may exert this effect in part through the liver.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>To explore this possibility, we created mice that have disrupted hepatic leptin signaling using a Cre-lox approach and then investigated aspects of glucose metabolism in these animals.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>The loss of hepatic leptin signaling did not alter body weight, body composition, or blood glucose levels in the mild fasting or random-fed state. However, mice with ablated hepatic leptin signaling had increased lipid accumulation in the liver. Further, as male mice aged or were fed a high-fat diet, the loss of hepatic leptin signaling protected the mice from glucose intolerance. Moreover, the mice displayed increased liver insulin sensitivity and a trend toward enhanced glucose-stimulated plasma insulin levels. Consistent with increased insulin sensitivity, mice with ablated hepatic leptin signaling had increased insulin-stimulated phosphorylation of Akt in the liver.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>These data reveal that unlike a complete deficiency of leptin action, which results in impaired glucose homeostasis, disruption of leptin action in the liver alone increases hepatic insulin sensitivity and protects against age- and diet-related glucose intolerance. Thus, leptin appears to act as a negative regulator of insulin action in the liver.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db10-0074","type":"journal-article","created":{"date-parts":[[2010,9,29]],"date-time":"2010-09-29T02:36:25Z","timestamp":1285727785000},"page":"3032-3040","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":68,"title":["Disruption of Hepatic Leptin Signaling Protects Mice From Age- and Diet-Related Glucose Intolerance"],"prefix":"10.2337","volume":"59","author":[{"given":"Frank K.","family":"Huynh","sequence":"first","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasna","family":"Levi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather C.","family":"Denroche","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Voshol","sequence":"additional","affiliation":[{"name":"Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula H.","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Speck","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Streamson C.","family":"Chua","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Covey","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"},{"name":"Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Kieffer","sequence":"additional","affiliation":[{"name":"Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;"},{"name":"Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2010,9,28]]},"reference":[{"key":"2022031217394524200_B1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/372425a0","article-title":"Positional cloning of the mouse obese gene and its human homologue","volume":"372","author":"Zhang","year":"1994","journal-title":"Nature"},{"key":"2022031217394524200_B2","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/nm1195-1155","article-title":"Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects","volume":"1","author":"Maffei","year":"1995","journal-title":"Nat Med"},{"key":"2022031217394524200_B3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/BF00429772","article-title":"Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice","volume":"14","author":"Coleman","year":"1978","journal-title":"Diabetologia"},{"key":"2022031217394524200_B4","first-page":"241","article-title":"Age effects on glycosylated blood proteins in lean and obese hyperglycaemic (ob\/ob) mice","volume":"3","author":"Flatt","year":"1986","journal-title":"Diabetes Res"},{"key":"2022031217394524200_B5","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/BF01221993","article-title":"Hyperinsulinemia in pre-weaning diabetes (db) mice","volume":"10","author":"Coleman","year":"1974","journal-title":"Diabetologia"},{"key":"2022031217394524200_B6","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1073\/pnas.96.2.674","article-title":"Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob\/ob mice","volume":"96","author":"Seufert","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031217394524200_B7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2009.11.007","article-title":"Antidiabetic effects of IGFBP2, a leptin-regulated gene","volume":"11","author":"Hedbacker","year":"2010","journal-title":"Cell Metab"},{"key":"2022031217394524200_B8","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S1043-2760(00)00309-X","article-title":"Lipoatrophy revisited","volume":"11","author":"Reitman","year":"2000","journal-title":"Trends Endocrinol Metab"},{"key":"2022031217394524200_B9","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1056\/NEJMoa012437","article-title":"Leptin-replacement therapy for lipodystrophy","volume":"346","author":"Oral","year":"2002","journal-title":"N Engl J Med"},{"key":"2022031217394524200_B10","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/27376","article-title":"Leptin and the regulation of body weight in mammals","volume":"395","author":"Friedman","year":"1998","journal-title":"Nature"},{"key":"2022031217394524200_B11","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.cmet.2009.05.003","article-title":"Leptin-dependent control of glucose balance and locomotor activity by POMC neurons","volume":"9","author":"Huo","year":"2009","journal-title":"Cell Metab"},{"key":"2022031217394524200_B12","doi-asserted-by":"crossref","first-page":"4502","DOI":"10.1210\/en.2009-0445","article-title":"Hypothalamic leptin signaling regulates hepatic insulin sensitivity via a neurocircuit involving the vagus nerve","volume":"150","author":"German","year":"2009","journal-title":"Endocrinology"},{"key":"2022031217394524200_B13","doi-asserted-by":"crossref","first-page":"31160","DOI":"10.1074\/jbc.273.47.31160","article-title":"Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes","volume":"273","author":"Liu","year":"1998","journal-title":"J Biol Chem"},{"key":"2022031217394524200_B14","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/0092-8674(95)90151-5","article-title":"Identification and expression cloning of a leptin receptor, OB-R","volume":"83","author":"Tartaglia","year":"1995","journal-title":"Cell"},{"key":"2022031217394524200_B15","doi-asserted-by":"crossref","first-page":"6231","DOI":"10.1073\/pnas.93.13.6231","article-title":"Defective STAT signaling by the leptin receptor in diabetic mice","volume":"93","author":"Ghilardi","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031217394524200_B16","doi-asserted-by":"crossref","first-page":"7001","DOI":"10.1073\/pnas.94.13.7001","article-title":"Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues","volume":"94","author":"Fei","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031217394524200_B17","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1126\/science.274.5290.1185","article-title":"Modulation of insulin activities by leptin","volume":"274","author":"Cohen","year":"1996","journal-title":"Science"},{"key":"2022031217394524200_B18","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1073\/pnas.050580497","article-title":"Selective interaction between leptin and insulin signaling pathways in a hepatic cell line","volume":"97","author":"Szanto","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031217394524200_B19","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1677\/jme.0.0320415","article-title":"Leptin reduces glucose transport and cellular ATP levels in INS-1 \u03b2-cells","volume":"32","author":"Lam","year":"2004","journal-title":"J Mol Endocrinol"},{"key":"2022031217394524200_B20","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1172\/JCI200113914","article-title":"Selective deletion of leptin receptor in neurons leads to obesity","volume":"108","author":"Cohen","year":"2001","journal-title":"J Clin Invest"},{"key":"2022031217394524200_B21","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1038\/oby.2004.200","article-title":"Quantitative body composition analysis in awake mice and rats by magnetic resonance relaxometry","volume":"12","author":"K\u00fcnnecke","year":"2004","journal-title":"Obes Res"},{"key":"2022031217394524200_B22","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2337\/diabetes.50.2.315","article-title":"Lipotoxicity of the pancreatic \u03b2-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids","volume":"50","author":"Briaud","year":"2001","journal-title":"Diabetes"},{"key":"2022031217394524200_B23","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.2337\/diabetes.50.11.2585","article-title":"In muscle-specific lipoprotein lipase\u2013overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake","volume":"50","author":"Voshol","year":"2001","journal-title":"Diabetes"},{"key":"2022031217394524200_B24","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.neuron.2004.06.004","article-title":"Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis","volume":"42","author":"Balthasar","year":"2004","journal-title":"Neuron"},{"key":"2022031217394524200_B25","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s00335-004-2340-1","article-title":"An allelic series for the leptin receptor gene generated by CRE and FLP recombinase","volume":"15","author":"McMinn","year":"2004","journal-title":"Mamm Genome"},{"key":"2022031217394524200_B26","doi-asserted-by":"crossref","first-page":"14563","DOI":"10.1074\/jbc.275.19.14563","article-title":"Activation of downstream signals by the long form of the leptin receptor","volume":"275","author":"Banks","year":"2000","journal-title":"J Biol Chem"},{"key":"2022031217394524200_B27","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.cmet.2004.12.004","article-title":"The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity","volume":"1","author":"Coppari","year":"2005","journal-title":"Cell Metab"},{"key":"2022031217394524200_B28","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.neuron.2005.12.021","article-title":"Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis","volume":"49","author":"Dhillon","year":"2006","journal-title":"Neuron"},{"key":"2022031217394524200_B29","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1074\/jbc.274.1.305","article-title":"Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic \u03b2-cell-specific gene knock-outs using Cre recombinase","volume":"274","author":"Postic","year":"1999","journal-title":"J Biol Chem"},{"key":"2022031217394524200_B30","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1074\/jbc.M512373200","article-title":"RIP-Cre revisited, evidence for impairments of pancreatic \u03b2-cell function","volume":"281","author":"Lee","year":"2006","journal-title":"J Biol Chem"},{"key":"2022031217394524200_B31","doi-asserted-by":"crossref","first-page":"5629","DOI":"10.1074\/jbc.M008553200","article-title":"Liporegulation in diet-induced obesity: the antisteatotic role of hyperleptinemia","volume":"276","author":"Lee","year":"2001","journal-title":"J Biol Chem"},{"key":"2022031217394524200_B32","doi-asserted-by":"crossref","first-page":"13656","DOI":"10.1073\/pnas.96.24.13656","article-title":"Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes","volume":"96","author":"Shimomura","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031217394524200_B33","doi-asserted-by":"crossref","first-page":"G592","DOI":"10.1152\/ajpgi.00063.2005","article-title":"Acute hepatic steatosis in mice by blocking \u03b2-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production","volume":"289","author":"Grefhorst","year":"2005","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2022031217394524200_B34","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1126\/science.760211","article-title":"Obesity genes: beneficial effects in heterozygous mice","volume":"203","author":"Coleman","year":"1979","journal-title":"Science"},{"key":"2022031217394524200_B35","first-page":"E762","article-title":"The obese gene is expressed in lean littermates of the genetically obese mouse (C57BL\/6J ob\/ob)","volume":"276","author":"Haller","year":"1999","journal-title":"Am J Physiol"},{"key":"2022031217394524200_B36","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/43448","article-title":"Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy","volume":"401","author":"Shimomura","year":"1999","journal-title":"Nature"},{"key":"2022031217394524200_B37","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1126\/science.1163971","article-title":"Regulation of pancreatic \u03b2-cell mass by neuronal signals from the liver","volume":"322","author":"Imai","year":"2008","journal-title":"Science"},{"key":"2022031217394524200_B38","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1139\/Y09-130","article-title":"Attenuation of age- and sucrose-induced insulin resistance and syndrome X by a synergistic antioxidant cocktail: the AMIS syndrome and HISS hypothesis","volume":"88","author":"Lautt","year":"2010","journal-title":"Can J Physiol Pharmacol"},{"key":"2022031217394524200_B39","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1096\/fj.02-0158rev","article-title":"Analysis of paradoxical observations on the association between leptin and insulin resistance","volume":"16","author":"Ceddia","year":"2002","journal-title":"FASEB J"},{"key":"2022031217394524200_B40","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.mce.2005.07.003","article-title":"In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus","volume":"242","author":"Benomar","year":"2005","journal-title":"Mol Cell Endocrinol"},{"key":"2022031217394524200_B41","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1210\/me.2002-0193","article-title":"Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression","volume":"18","author":"Lam","year":"2004","journal-title":"Mol Endocrinol"},{"key":"2022031217394524200_B42","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1210\/mend.16.7.0867","article-title":"Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2","volume":"16","author":"Anderwald","year":"2002","journal-title":"Mol Endocrinol"},{"key":"2022031217394524200_B43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1096\/fj.06-6557com","article-title":"Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo","volume":"21","author":"Fishman","year":"2007","journal-title":"FASEB J"},{"key":"2022031217394524200_B44","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1126\/science.283.5407.1544","article-title":"Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene","volume":"283","author":"Elchebly","year":"1999","journal-title":"Science"},{"key":"2022031217394524200_B45","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1515\/BC.2003.016","article-title":"Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver","volume":"384","author":"Carvalheira","year":"2003","journal-title":"Biol Chem"},{"key":"2022031217394524200_B46","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.2337\/diab.46.6.1087","article-title":"Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic \u03b2-cells","volume":"46","author":"Kieffer","year":"1997","journal-title":"Diabetes"},{"key":"2022031217394524200_B47","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cmet.2006.09.005","article-title":"The pancreatic \u03b2-cell is a key site for mediating the effects of leptin on glucose homeostasis","volume":"4","author":"Covey","year":"2006","journal-title":"Cell Metab"},{"key":"2022031217394524200_B48","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1172\/JCI30910","article-title":"Disruption of leptin receptor expression in the pancreas directly affects \u03b2-cell growth and function in mice","volume":"117","author":"Morioka","year":"2007","journal-title":"J Clin Invest"},{"key":"2022031217394524200_B49","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.1073\/pnas.0801981105","article-title":"Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome","volume":"105","author":"Wang","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031217394524200_B50","doi-asserted-by":"crossref","first-page":"10585","DOI":"10.1074\/jbc.272.16.10585","article-title":"Leptin impairs metabolic actions of insulin in isolated rat adipocytes","volume":"272","author":"M\u00fcller","year":"1997","journal-title":"J Biol Chem"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/59\/12\/3032\/396189\/zdb01210003032.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/59\/12\/3032\/396189\/zdb01210003032.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:22:11Z","timestamp":1667406131000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/59\/12\/3032\/26445\/Disruption-of-Hepatic-Leptin-Signaling-Protects"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,28]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2010,9,28]]},"published-print":{"date-parts":[[2010,12,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db10-0074","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,9,28]]}}}