Transient postnatal overfeeding causes liver stress-induced premature senescence in adult mice

Abstract

Unbalanced nutrition early in life is increasingly recognized as an important factor in the development of chronic, non-communicable diseases at adulthood, including metabolic diseases. We aimed to determine whether transient postnatal overfeeding (OF) leads to liver stress-induced premature senescence (SIPS) of hepatocytes in association with liver structure and hepatic function alterations. Litters sizes of male C57BL/6 mice were adjusted to 9 pups (normal feeding, NF) or reduced to 3 pups during the lactation period to induce transient postnatal OF. Compared to the NF group, seven-month-old adult mice transiently overfed during the postnatal period were overweight and developed glucose intolerance and insulin resistance. Their livers showed microsteatosis and fibrosis, while hepatic insulin signaling and glucose transporter protein expressions were altered. Increased hepatic oxidative stress (OS) was observed, with increased superoxide anion production, glucose-6-phosphate dehydrogenase protein expression, oxidative DNA damage and decreased levels of antioxidant defense markers, such as superoxide dismutase and catalase proteins. Hepatocyte senescence was characterized by increased p21WAF, p53, Acp53, p16INK4a and decreased pRb/Rb and Sirtuin-1 (SIRT-1) protein expression levels. Transient postnatal OF induces liver OS at adulthood, associated with hepatocyte SIPS and alterations in liver structure and hepatic functions, which could be mediated by a SIRT-1 deficiency.

Renal Programming by Transient Postnatal Overfeeding: The Role of Senescence Pathways

“…Importantly, these alterations in senescence pathways and Sirt1 expression in the context of transient postnatal overfeeding do not seem to be specific to the kidney. Our group previously showed similar alterations in the liver at adulthood in the same animal model (Yzydorczyk et al, 2017). However, none of the alterations in protein expression described at weaning in the kidney were observed at adulthood.…”

“…Furthermore, we recently demonstrated that early postnatal overfeeding leads to modifications of senescence pathways and Sirt-1 expression in the liver (Yzydorczyk et al, 2017).…”

Perinatal Origins of Adult Disease

“…Of note, postnatal overnutrition fol- lowing early intrauterine undernutrition (with/without extrauterine undernutrition) and growth restriction is a particularly deleterious growth pattern for later vascular, renal, and metabolic functions, as observed by our group and others in rats [2,3]. Interestingly, transient postnatal overfeeding during lactation in the absence of any prenatal nutritional alteration leads to hypertension, heart dysfunction, and metabolic disorders in adulthood [35,36]. Calorie restriction at adulthood allows a reversal of heart dysfunction in this model [36].…”

Calorie Restriction in Adulthood Reduces Hepatic Disorders Induced by Transient Postnatal Overfeeding in Mice

“…At seven months of life, the livers from the NF ( n = 5), OF ( n = 5), NFCR ( n = 5) and OFCR ( n = 5) groups were rapidly removed and fixed in formol as previously described [13]. Equatorial cross-sections were paraffin-embedded and stained with hematoxylin and eosin (H/E) for hepatic structure evaluation and with Masson’s Trichrome to evaluate hepatic fibrosis.…”

“…We have previously observed that transient postnatal OF during the suckling period in mice led to liver microsteatosis and fibrosis in adulthood, and this outcome was associated with OS and stress-induced premature senescence (SIPS) [13]. Calorie restriction (CR), as a potential preventive strategy for metabolic disorders, has received considerable interest.…”