Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system.

• Klíčová slova
• Non-Alcoholic Fatty Liver Disease, developmental programming, intra-abdominal fat, maternal nutrition, obesity,
• MeSH
• alanintransaminasa krev   MeSH
• aspartátaminotransferasy krev   MeSH
• fyziologie výživy v mateřství * MeSH
• játra metabolismus   MeSH
• krevní glukóza metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši obézní MeSH
• myši MeSH
• obezita genetika   MeSH
• perinatální péče MeSH
• receptor melanokortinový typ 4 nedostatek   genetika   MeSH
• regulace genové exprese MeSH
• těhotenství MeSH
• triglyceridy krev   MeSH
• zpožděný efekt prenatální expozice genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alanintransaminasa MeSH
• aspartátaminotransferasy MeSH
• krevní glukóza MeSH
• MC4R protein, mouse MeSH Prohlížeč
• receptor melanokortinový typ 4 MeSH
• triglyceridy MeSH

We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis.

• Klíčová slova
• ER stress, NAFLD, Obesity, circadian rhythm, developmental programming,
• MeSH
• chaperon endoplazmatického retikula BiP MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• endoplazmatické retikulum fyziologie   MeSH
• fyziologický stres účinky léků   MeSH
• homeostáza MeSH
• játra účinky léků   MeSH
• krmivo pro zvířata analýza   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita chemicky indukované   metabolismus   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH