Undernourishment in utero Primes Hepatic Steatosis in Adult Mice Offspring on an Obesogenic Diet; Involvement of Endoplasmic Reticulum Stress

Abstract

In order to investigate the possible involvement of endoplasmic reticulum (ER) stress in the developmental origins of hepatic steatosis associated with undernourishment in utero, we herein employed a fetal undernourishment mouse model by maternal caloric restriction in three cohorts; cohort 1) assessment of hepatic steatosis and the ER stress response at 9 weeks of age (wks) before a high fat diet (HFD), cohort 2) assessment of hepatic steatosis and the ER stress response on a HFD at 17 wks, cohort 3) assessment of hepatic steatosis and the ER stress response at 22 wks on a HFD after the alleviation of ER stress with a chemical chaperone, tauroursodeoxycholic acid (TUDCA), from 17 wks to 22 wks. Undernourishment in utero significantly deteriorated hepatic steatosis and led to the significant integration of the ER stress response on a HFD at 17 wks. The alleviation of ER stress by the TUDCA treatment significantly improved the parameters of hepatic steatosis in pups with undernourishment in utero, but not in those with normal nourishment in utero at 22 wks. These results suggest the pivotal involvement of the integration of ER stress in the developmental origins of hepatic steatosis in association with undernourishment in utero.

Undernourishment in utero and hepatic steatosis in later life: A potential issue in Japanese people

“…The alleviation of ER stress by the treatment with TUDCA significantly improved the parameters of hepatic steatosis (liver weight, ratio of liver weight/body weight, TG content, and total TG amount per liver) in pups with undernourishment in utero, but not in normal nourishment controls (Fig. 4B) (Muramatsu-Kato et al 2015). The alleviation of the ER stress response was confirmed in some of its parameters, such as the splicing of XBP1 mRNA, gene expression of ERdj4 and GADD34, and protein expression of CHOP and p-eIF2α (Muramatsu-Kato et al 2015).…”

“…We noted that the deterioration of hepatic steatosis had developed in pups with fetal undernourishment by HFD between 9 and 17 weeks of age, and was markedly improved Fig. 6 Prevalence of NAFLD (Masarone et al 2014;Fan et al 2007;Kojima et al 2003) and hypothetical background underlying the increasing prevalence of NAFLD in Japan (Muramatsu-Kato et al 2015). NAFLD, nonalcoholic fatty liver disease.…”

“…2A) and found that the maximum risk of general obesity (fat deposition and body weight) was observed in pups from dams with 35% caloric reduction (Fig. 2B), while the maximum risk of hepatic steatosis (liver weight, ratio of liver weight/body weight, triglyceride [TG] content, and total TG amount per liver) was noted in the pups of dams with 40% caloric reduction ( Figs 2B and 3) (Muramatsu-Kato et al 2015). We then exposed dams to 40% caloric reduction in subsequent studies in order to investigate the developmental origins of hepatic steatosis.…”

“…We established a mouse model of undernourishment in utero by maternal energy caloric reductions during pregnancy (Kawamura et al 2009;Kawamura et al 2007;Kohmura et al 2013;Muramatsu-Kato et al 2015;Yura et al 2008). We found that undernourishment in utero caused earlier and greater deviations in the 'leptin surge' in neonates, namely, a 'premature leptin surge' (Yura et al 2005), and that the 'premature leptin surge' induced low hypothalamic sensitivity to circulating leptin as well as specific changes in the development of neuronal circuitries in the hypothalamus, resulting in the development of an obesity-prone phenotype (Yura et al 2005).…”

“…Evidence obtained from human studies (Gregor et al 2009;Lake et al 2014) and experimental studies (Fu et al 2012;Gentile et al 2011) demonstrated the important causative contribution of ER stress to the development of hepatic steatosis. Undernourishment in utero did not augment hepatic steatosis or ER stress response parameters in the livers of pups at 9 weeks old before a high fat diet (HFD; formula number D12492, Research Diets Inc.) containing 60% lipids (Muramatsu-Kato et al 2015). In contrast, undernourishment in utero induced the deterioration of hepatic steatosis in the livers of pups at 17 weeks old after HFD (Figs 3 and 4A) and simultaneously caused significant augmentations in ER stress response parameters, i.e., the splicing of X-box binding protein 1 (XBP1) mRNA, gene expression of ER-localized DnaJ 4 (ERdj4) and growth arrest and DNA damage inducible 34 (GADD34), and protein expression of the C/EBP-homologous protein (CHOP), phospho-inositol-requiring enzyme 1α (p-IRE1α), and phosphoeukaryotic initiation factor 2α (p-eIF2α) (Muramatsu-Kato et al 2015).…”