title: Absence of melatonin induces night-time hepatic insulin resistance and increased gluconeogenesis due to stimulation of nocturnal unfolded protein response.
abstract: 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-α 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.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil.
authors.forename: Tatiane C
authors.initials: TC
authors.lastname: Nogueira
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Jesus
authors.forename: Marco
authors.initials: M
authors.lastname: Taneda
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Rodrigues
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: Amaral
authors.forename: Ana Maria S
authors.initials: AM
authors.lastname: Lopes
authors.forename: José
authors.initials: J
authors.lastname: Cipolla-Neto
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Anhê
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002940:Circadian Rhythm; D004435:Eating / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D015151:Immunoblotting; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010870:Pineal Gland / Q000502:physiology / Q000601:surgery; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D051058:Oncogene Protein v-akt; D008550:Melatonin