Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

Abstract

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.

Characterizing and Quenching Autofluorescence in Fixed Mouse Adrenal Cortex Tissue

“…MaxBlock is a commercialized AF treatment designed to reduce background AF on paraffin-embedded and frozen tissue sections. It has been used to diminish AF in several tissues, such as the liver [ 56 ], heart [ 57 ], lung [ 58 , 59 ], pancreas [ 60 ], and skin [ 61 ] tissues.…”

The importance of translational science within the respiratory field

“…The first speaker, Jaco Selle (Germany), presented a pre-clinical study describing that maternal obesity influenced the offspring by increasing their body weight, adipocyte hypertrophy and plasma interleukin (IL)-6, and by decreasing the numbers of alveolar progenitor and alveolar type 2 cells [ 24 ]. Perinatal obesity enhanced the DNA damage response, transcriptional stress and ageing-associated pathways [ 25 ]. IL-6 emerged as a central modulator of these effects, as substantiated by the protection observed in IL-6-null mice and pharmacologically inhibited IL-6 signalling against the repercussions of perinatal obesity [ 26 ].…”

The Effect of Maternal Exposure to a Diet High in Fats and Cholesterol on the Placental Function and Phenotype of the Offspring in a Rabbit Model: A Summary Review of About 15 Years of Research

“…The H/H liver and kidneys were also lighter than those of the controls. Such hepatic hypotrophy was shown in male offspring at weaning from C56BL/6N mice fed a high-fat diet inducing maternal obesity through possible premature hepatic aging [91] as well as in weaned offspring rats, but the liver weight increased in adult males [66]. The intermediate groups, H/C and C/H, were used to explore the critical window of exposure.…”