title: Non-alcoholic fatty pancreas disease pathogenesis: a role for developmental programming and altered circadian rhythms.
abstract: OBJECTIVE
  Emerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock--molecular core circadian genes (CCG) in the generation of NAFPD.
  
  
  METHODS
  Female C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined.
  
  
  RESULTS
  Offspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-β and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (-4.818, p<0.01), REV-ERB-α (-1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (-0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG.
  
  
  CONCLUSIONS
  Fetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Carter
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Angelina
authors.initials: A
authors.lastname: Mouralidarane
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Junpei
authors.initials: J
authors.lastname: Soeda
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Shuvra
authors.initials: S
authors.lastname: Ray
authors.affiliation: Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Pombo
authors.affiliation: Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom; Department of Pathology, University College London, London, United Kingdom.
authors.forename: Ruma
authors.initials: R
authors.lastname: Saraswati
authors.affiliation: Department of Pathology, University College London, London, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.affiliation: Hepatobiliary and Liver Transplant Unit, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fusai
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rappa
authors.affiliation: Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Saracino
authors.affiliation: Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.affiliation: Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Poston
authors.affiliation: Division of Women's Health, King's College London and King's Health Partners, London, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Taylor
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom; Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy; Department of Medical Sciences, Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Jude A
authors.initials: JA
authors.lastname: Oben
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008810:Mice, Inbred C57BL; D010182:Pancreatic Diseases / Q000209:etiology* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D056926:CLOCK Proteins; C538944:Clock protein, mouse