ffects of maternal diet-induced obesity on metabolic disorders and age-associated miRNA expression in the liver of male mouse offsprin

Author(s):Show less -

Mennitti, Lais Vales ^{[1, 2, 3]} ; Carpenter, Asha A. M. ^{[2, 3]} ; Loche, Elena ^{[2, 3]} ; Pantaleao, Lucas C. ^{[2, 3]} ; Fernandez-Twinn, Denise S. ^{[2, 3]} ; Schoonejans, Josca M. ^{[2, 3]} ; Blackmore, Heather L. ^{[2, 3]} ; Ashmore, Thomas J. ^{[2, 3]} ; Pisani, Luciana Pellegrini ^{[1, 2, 3]} ; Tadross, John A. ^{[4, 2, 3]} ; Hargreaves, Iain ^[5] ; Ozanne, Susan E. ^{[2, 3]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biosci, Lab Nutr & Endocrine Physiol, BR-11015020 Santos, SP - Brazil

^[2] Univ Cambridge, Metab Res Labs, Cambridge CB2 OQQ - England

^[3] Univ Cambridge, MRC Metab Dis Unit, Cambridge CB2 OQQ - England

^[4] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP - England

^[5] Liverpool John Moores Univ, Dept Pharm & Biomol Sci, Byrom St, Liverpool L3 5UA, Merseyside - England

• Document type: Journal article
• Source: International Journal of Obesity; v. 46, n. 2 OCT 2021.
• Web of Science Citations: 0

Abstract

Objective This study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA. Methods A mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring. Results Body weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 +/- 0.8 g versus 10.4 +/- 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 +/- 2.1 g versus 12.9 +/- 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgf beta 1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPK alpha, total AMPK alpha and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (-3p: 7.34 +/- 1.35 versus 1.39 +/- 0.50, p < 0.0001 and -5p: 4.66 +/- 1.16 versus 1.63 +/- 0.65, p < 0.05). Conclusion Our findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny. (AU)

• FAPESP's process: 19/22635-4 - The effects of maternal obesity on offspring health focussed on the role of adipose tissue miRNA
• Grantee: Luciana Pellegrini Pisani
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 14/10683-0 - Effect of different fatty acids maternal intake during pregnancy and lactation on epigenetic modifications and pro-inflammatory status of the fetus and 21-D-OLD offspring
• Grantee: Laís Vales Mennitti
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/16637-9 - The role of miRNAs in the programming of offspring fatty liver by maternal diet-induced obesity
• Grantee: Laís Vales Mennitti
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate