{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T09:00:54Z","timestamp":1792659654577,"version":"4.5.0"},"reference-count":43,"publisher":"American Diabetes Association","issue":"11","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,11,1]]},"abstract":"<jats:p>Voluntary overfeeding rapidly induces resistance to the effects of systemic insulin and leptin on liver glucose metabolism. To examine whether central administration of recombinant leptin can restore leptin and insulin action on liver glucose fluxes, we infused leptin in the third cerebral ventricle of conscious overfed rats during pancreatic-insulin clamp studies. The effect of leptin on the phosphorylation of the signal transducer and activator of transcription-3 in the arcuate nuclei of the hypothalamus was similar in animals fed a regular diet or a high-fat diet for 3 days. The infusion of leptin in the third cerebral ventricle markedly inhibited glucose production in rats fed a high-fat diet mainly by decreasing glycogenolysis. The inhibition of glycogenolysis was sufficient to normalize glucose production and was accompanied by leptin-induced decreases in the hepatic expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Thus central administration of leptin rescues the hepatic insulin resistance induced by short-term hyperphagia.<\/jats:p>","DOI":"10.2337\/diabetes.54.11.3182","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"3182-3189","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":124,"title":["Central Leptin Acutely Reverses Diet-Induced Hepatic Insulin Resistance"],"prefix":"10.2337","volume":"54","author":[{"given":"Alessandro","family":"Pocai","sequence":"first","affiliation":[{"name":"Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimyata","family":"Morgan","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Buettner","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Gutierrez-Juarez","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana","family":"Obici","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Rossetti","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031217183509000_R1","doi-asserted-by":"crossref","unstructured":"Flier JS: Leptin expression and action: new experimental paradigms. Proc Natl Acad Sci U S A\u200894:4242\u20134245,1997","DOI":"10.1073\/pnas.94.9.4242"},{"key":"2022031217183509000_R2","doi-asserted-by":"crossref","unstructured":"Friedman JM: The alphabet of weight control. Nature\u2008385:119\u2013120,1997","DOI":"10.1038\/385119a0"},{"key":"2022031217183509000_R3","doi-asserted-by":"crossref","unstructured":"Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM: Weight-reducing effects of the plasma protein encoded by the obese gene. Science\u2008269:543\u2013546,1995","DOI":"10.1126\/science.7624777"},{"key":"2022031217183509000_R4","doi-asserted-by":"crossref","unstructured":"Gutierrez-Juarez R, Obici S, Rossetti L: Melanocortin-independent effects of leptin on hepatic glucose fluxes. J Biol Chem\u2008279:49704\u201349715,2004","DOI":"10.1074\/jbc.M408665200"},{"key":"2022031217183509000_R5","doi-asserted-by":"crossref","unstructured":"Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM: Leptin enters the brain by a saturable system independent of insulin. Peptides\u200817:305\u2013311,1996","DOI":"10.1016\/0196-9781(96)00025-3"},{"key":"2022031217183509000_R6","doi-asserted-by":"crossref","unstructured":"Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrell CL: Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology\u2008141:1434\u20131441,2000","DOI":"10.1210\/endo.141.4.7435"},{"key":"2022031217183509000_R7","doi-asserted-by":"crossref","unstructured":"Elmquist JK, Ahima RS, Elias CF, Flier JS, Saper CB: Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci U S A\u200895:741\u2013746,1998","DOI":"10.1073\/pnas.95.2.741"},{"key":"2022031217183509000_R8","doi-asserted-by":"crossref","unstructured":"Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P: Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett\u2008387:113\u2013116,1996","DOI":"10.1016\/0014-5793(96)00473-5"},{"key":"2022031217183509000_R9","doi-asserted-by":"crossref","unstructured":"Bjorbaek C, Kahn BB: Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res\u200859:305\u2013331,2004","DOI":"10.1210\/rp.59.1.305"},{"key":"2022031217183509000_R10","doi-asserted-by":"crossref","unstructured":"Campfield LA, Smith FJ, Burn P: The OB protein (leptin) pathway: a link between adipose tissue mass and central neural networks. Horm Metab Res\u200828:619\u2013632,1996","DOI":"10.1055\/s-2007-979867"},{"key":"2022031217183509000_R11","doi-asserted-by":"crossref","unstructured":"Farooqi IS, O\u2019Rahilly S: Monogenic human obesity syndromes. Recent Prog Horm Res\u200859:409\u2013424,2004","DOI":"10.1210\/rp.59.1.409"},{"key":"2022031217183509000_R12","doi-asserted-by":"crossref","unstructured":"Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV: Leptin: the tale of an obesity gene. Diabetes\u200845:1455\u20131462,1996","DOI":"10.2337\/diab.45.11.1455"},{"key":"2022031217183509000_R13","doi-asserted-by":"crossref","unstructured":"Igel M, Kainulainen H, Brauers A, Becker W, Herberg L, Joost HG: Long-term and rapid regulation of ob mRNA levels in adipose tissue from normal (Sprague Dawley rats) and obese (db\/db mice, fa\/fa rats) rodents. Diabetologia\u200839:758\u2013765,1996","DOI":"10.1007\/s001250050508"},{"key":"2022031217183509000_R14","doi-asserted-by":"crossref","unstructured":"El Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS: Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest\u2008105:1827\u20131832,2000","DOI":"10.1172\/JCI9842"},{"key":"2022031217183509000_R15","doi-asserted-by":"crossref","unstructured":"Munzberg H, Flier JS, Bjorbaek C: Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology\u2008145:4880\u20134889,2004","DOI":"10.1210\/en.2004-0726"},{"key":"2022031217183509000_R16","doi-asserted-by":"crossref","unstructured":"Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis HR Jr: Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest\u200899:385\u2013390,1997","DOI":"10.1172\/JCI119171"},{"key":"2022031217183509000_R17","doi-asserted-by":"crossref","unstructured":"Munzberg H, Myers MG: Molecular and anatomical determinants of central leptin resistance. Nat Neurosci\u20088:566\u2013570,2005","DOI":"10.1038\/nn1454"},{"key":"2022031217183509000_R18","doi-asserted-by":"crossref","unstructured":"Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature\u2008401:73\u201376,1999","DOI":"10.1038\/43448"},{"key":"2022031217183509000_R19","doi-asserted-by":"crossref","unstructured":"Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, Wang J, Rossetti L: Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem\u2008273:31160\u201331167,1998","DOI":"10.1074\/jbc.273.47.31160"},{"key":"2022031217183509000_R20","doi-asserted-by":"crossref","unstructured":"Rossetti L, Massillon D, Barzilai N, Vuguin P, Chen W, Hawkins M, Wu J, Wang J: Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem\u2008272:27758\u201327763,1997","DOI":"10.1074\/jbc.272.44.27758"},{"key":"2022031217183509000_R21","doi-asserted-by":"crossref","unstructured":"Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L: Overfeeding rapidly induces leptin and insulin resistance. Diabetes\u200850:2786\u20132791,2001","DOI":"10.2337\/diabetes.50.12.2786"},{"key":"2022031217183509000_R22","doi-asserted-by":"crossref","unstructured":"Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L: Central melanocortin receptors regulate insulin action. J Clin Invest\u2008108:1079\u20131085,2001","DOI":"10.1172\/JCI200112954"},{"key":"2022031217183509000_R23","doi-asserted-by":"crossref","unstructured":"Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L: Hypothalamic K(ATP) channels control hepatic glucose production. Nature\u2008434:1026\u20131031,2005","DOI":"10.1038\/nature03439"},{"key":"2022031217183509000_R24","doi-asserted-by":"crossref","unstructured":"Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L: Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med\u200811:320\u2013327,2005","DOI":"10.1038\/nm1201"},{"key":"2022031217183509000_R25","doi-asserted-by":"crossref","unstructured":"Wen Z, Zhong Z, Darnell JE Jr: Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell\u200882:241\u2013250,1995","DOI":"10.1016\/0092-8674(95)90311-9"},{"key":"2022031217183509000_R26","doi-asserted-by":"crossref","unstructured":"Burguera B, Couce ME, Curran GL, Jensen MD, Lloyd RV, Cleary MP, Poduslo JF: Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes\u200849:1219\u20131223,2000","DOI":"10.2337\/diabetes.49.7.1219"},{"key":"2022031217183509000_R27","doi-asserted-by":"crossref","unstructured":"Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS: Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med\u20081:1311\u20131314,1995","DOI":"10.1038\/nm1295-1311"},{"key":"2022031217183509000_R28","doi-asserted-by":"crossref","unstructured":"Neel JV: The \u201cthrifty genotype\u201d in 1998. Nutr Rev\u200857:S2\u2013S9,1999","DOI":"10.1111\/j.1753-4887.1999.tb01782.x"},{"key":"2022031217183509000_R29","doi-asserted-by":"crossref","unstructured":"Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte D Jr, Woods SC, Seeley RJ, Weigle DS: Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob\/ob mice. Diabetes\u200845:531\u2013535,1996","DOI":"10.2337\/diabetes.45.4.531"},{"key":"2022031217183509000_R30","doi-asserted-by":"crossref","unstructured":"Schwartz MW, Niswender KD: Adiposity signaling and biological defense against weight gain: absence of protection or central hormone resistance?J Clin Endocrinol Metab\u200889:5889\u20135897,2004","DOI":"10.1210\/jc.2004-0906"},{"key":"2022031217183509000_R31","doi-asserted-by":"crossref","unstructured":"Mistry AM, Swick AG, Romsos DR: Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob\/ob mice. J Nutr\u2008127:2065\u20132072,1997","DOI":"10.1093\/jn\/127.10.2065"},{"key":"2022031217183509000_R32","doi-asserted-by":"crossref","unstructured":"Seeley RJ, van Dijk G, Campfield LA, Smith FJ, Burn P, Nelligan JA, Bell SM, Baskin DG, Woods SC, Schwartz MW: Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm Metab Res\u200828:664\u2013668,1996","DOI":"10.1055\/s-2007-979874"},{"key":"2022031217183509000_R33","doi-asserted-by":"crossref","unstructured":"Morgan K, Obici S, Rossetti L: Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem\u2008279:31139\u201331148,2004","DOI":"10.1074\/jbc.M400458200"},{"key":"2022031217183509000_R34","doi-asserted-by":"crossref","unstructured":"Banks WA, DiPalma CR, Farrell CL: Impaired transport of leptin across the blood-brain barrier in obesity. Peptides\u200820:1341\u20131345,1999","DOI":"10.1016\/S0196-9781(99)00139-4"},{"key":"2022031217183509000_R35","doi-asserted-by":"crossref","unstructured":"Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV: Decreased cerebrospinal-fluid\/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet\u2008348:159\u2013161,1996","DOI":"10.1016\/S0140-6736(96)03173-X"},{"key":"2022031217183509000_R36","doi-asserted-by":"crossref","unstructured":"Seeley RJ, Drazen DL, Clegg DJ: The critical role of the melanocortin system in the control of energy balance. Annu Rev Nutr\u200824:133\u2013149,2004","DOI":"10.1146\/annurev.nutr.24.012003.132428"},{"key":"2022031217183509000_R37","doi-asserted-by":"crossref","unstructured":"Clegg DJ, Benoit SC, Air EL, Jackman A, Tso P, D\u2019Alessio D, Woods SC, Seeley RJ: Increased dietary fat attenuates the anorexic effects of intracerebroventricular injections of MTII. Endocrinology\u2008144:2941\u20132946,2003","DOI":"10.1210\/en.2002-0218"},{"key":"2022031217183509000_R38","doi-asserted-by":"crossref","unstructured":"Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr: STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature\u2008421:856\u2013859,2003","DOI":"10.1038\/nature01388"},{"key":"2022031217183509000_R39","doi-asserted-by":"crossref","unstructured":"Munzberg H, Huo L, Nillni EA, Hollenberg AN, Bjorbaek C: Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology\u2008144:2121\u20132131,2003","DOI":"10.1210\/en.2002-221037"},{"key":"2022031217183509000_R40","doi-asserted-by":"crossref","unstructured":"Wilsey J, Zolotukhin S, Prima V, Scarpace PJ: Central leptin gene therapy fails to overcome leptin resistance associated with diet-induced obesity. Am J Physiol Regul Integr Comp Physiol\u2008285:R1011\u2013R1020,2003","DOI":"10.1152\/ajpregu.00193.2003"},{"key":"2022031217183509000_R41","doi-asserted-by":"crossref","unstructured":"Zhang X, Blenis J, Li HC, Schindler C, Chen-Kiang S: Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science\u2008267:1990\u20131994,1995","DOI":"10.1126\/science.7701321"},{"key":"2022031217183509000_R42","doi-asserted-by":"crossref","unstructured":"Chung J, Uchida E, Grammer TC, Blenis J: STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol\u200817:6508\u20136516,1997","DOI":"10.1128\/MCB.17.11.6508"},{"key":"2022031217183509000_R43","doi-asserted-by":"crossref","unstructured":"Sengupta TK, Talbot ES, Scherle PA, Ivashkiv LB: Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases. Proc Natl Acad Sci U S A\u200895:11107\u201311112,1998","DOI":"10.1073\/pnas.95.19.11107"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/54\/11\/3182\/379381\/3182.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/54\/11\/3182\/379381\/3182.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:24:26Z","timestamp":1667406266000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/54\/11\/3182\/25608\/Central-Leptin-Acutely-Reverses-Diet-Induced"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,11,1]]},"references-count":43,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2005,11,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.54.11.3182","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,11,1]]}}}