{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:58:30Z","timestamp":1790427510720,"version":"4.1.0"},"reference-count":36,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>It is known that the circadian rhythm in hepatic phosphoenolpyruvate carboxykinase expression (a limiting catalytic step of gluconeogenesis) and hepatic glucose production is maintained by both daily oscillation in autonomic inputs to the liver and night feeding behavior. However, increased glycemia and reduced melatonin (Mel) levels have been recently shown to coexist in diabetic patients at the end of the night period. In parallel, pinealectomy (PINX) is known to cause glucose intolerance with increased basal glycemia exclusively at the end of the night. The mechanisms that underlie this metabolic feature are not completely understood. Here, we demonstrate that PINX rats show night-time hepatic insulin resistance characterized by reduced insulin-stimulated RAC-\u03b1 serine\/threonine-protein kinase phosphorylation and increased phosphoenolpyruvate carboxykinase expression. In addition, PINX rats display increased conversion of pyruvate into glucose at the end of the night. The regulatory mechanism suggests the participation of unfolded protein response (UPR), because PINX induces night-time increase in activating transcription factor 6 expression and prompts a circadian fashion of immunoglobulin heavy chain-binding protein, activating transcription factor 4, and CCAAT\/enhancer-binding protein-homologous protein expression with Zenith values at the dark period. PINX also caused a night-time increase in Tribble 3 and regulatory-associated protein of mammalian target of rapamycin; both were reduced in liver of PINX rats treated with Mel. Treatment of PINX rats with 4-phenyl butyric acid, an inhibitor of UPR, restored night-time hepatic insulin sensitivity and abrogated gluconeogenesis in PINX rats. Altogether, the present data show that a circadian oscillation of UPR occurs in the liver due to the absence of Mel. The nocturnal UPR activation is related with night-time hepatic insulin resistance and increased gluconeogenesis in PINX rats.<\/jats:p>","DOI":"10.1210\/en.2010-1088","type":"journal-article","created":{"date-parts":[[2011,2,9]],"date-time":"2011-02-09T03:05:55Z","timestamp":1297220755000},"page":"1253-1263","source":"Crossref","is-referenced-by-count":98,"title":["Absence of Melatonin Induces Night-Time Hepatic Insulin Resistance and Increased Gluconeogenesis Due to Stimulation of Nocturnal Unfolded Protein Response"],"prefix":"10.1210","volume":"152","author":[{"given":"Tatiane C.","family":"Nogueira","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo","family":"Lellis-Santos","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Jesus","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Taneda","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra C.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda G.","family":"Amaral","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria S.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Cipolla-Neto","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana","family":"Bordin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics (T.C.N., C.L.-S., D.S.J., M.T., S.C.R., F.G.A., A.M.S.L., J.C.-N., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel F.","family":"Anh\u00ea","sequence":"additional","affiliation":[{"name":"Department of Pharmacology (G.F.A.), Faculty of Medical Sciences, State University of Campinas, Campinas 13084-971, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2011,2,8]]},"reference":[{"key":"2020071613403834700_B1","first-page":"E934","article-title":"Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats.","volume":"275","author":"Lima","year":"1998","journal-title":"Am J Physiol"},{"key":"2020071613403834700_B2","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1055\/s-2004-825723","article-title":"Light\/dark cycle-dependent metabolic changes in adipose tissue of pinealectomized rats.","volume":"36","author":"Alonso-Vale","year":"2004","journal-title":"Horm Metab Res"},{"key":"2020071613403834700_B3","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1046\/j.1365-2826.2001.00717.x","article-title":"Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations.","volume":"13","author":"la Fleur","year":"2001","journal-title":"J Neuroendocrinol"},{"key":"2020071613403834700_B4","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1034\/j.1600-079X.2002.02925.x","article-title":"Daily rhythm of glucose-induced insulin secretion by isolated islets from intact and pinealectomized rat.","volume":"33","author":"Picinato","year":"2002","journal-title":"J Pineal Res"},{"key":"2020071613403834700_B5","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/305549a0","article-title":"Inhibition of transcription of the phosphoenolpyruvate carboxykinase gene by insulin.","volume":"305","author":"Granner","year":"1983","journal-title":"Nature"},{"key":"2020071613403834700_B6","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1111\/j.1460-9568.2005.04439.x","article-title":"The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes 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