High Fat Diet and In Utero Exposure to Maternal Obesity Disrupts Circadian Rhythm and Leads to Metabolic Programming of Liver in Rat Offspring

Abstract

The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBα, CRY, PER) and metabolic (PPARα, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPARα mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPARα transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPARα transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPARα expression prior to obesity development.

Animal models of obesity in rodents. An integrative review

“…In diets with ratio of 40% to 60% of lipids, obesity induction occurred in all groups, regardless of the strains of rodents 6,[9][10][11][12]15,17,18,[22][23][24] . In experiments with diets containing 60% lipids, mice obtained in addition to weight gain and epididymal fat, hyperglycemia and insulin resistance 11,12,23 .…”

“…The main data found in these works were shown in Table 2. In the reports evaluated in our review, the use of rat in experiments 6,[8][9][10][14][15][16]21,22 and mice 7,[11][12][13][14]17,18,20,23,24 are identical.…”

“…Most of the selected works in this review used male animals, probably this preference may be related to own existing biological structure between the sexes [6][7][8][9][10][11][12][13][15][16][17][18][19][20][21][22][23][24] . Male have hormonal factors that are related to body growth, which reflected in higher body weight 23 .…”

The Impact of Traditional Food and Lifestyle Behavior on Epigenetic Burden of Chronic Disease

“…Human/ cohort study Childhood obesity [206][207][208][209][210][211] Increased DNA methylation of the CASP10, CDKN1C, EPHA1, HLADOB3, IRF5, MMP9, MPL, NID1, retinoid X receptor-α, IGF2/ H19, and POMC, and lower methylation of LINE1 in children are strongly associated with childhood obesity Hypo-and hypermethylation and gene expression changes of the TACSTD2 gene at birth associated with childhood obesity Rat Maternal high fat diet prior to, and during pregnancy and lactation [127,131,172,176,178,179,[182][183][184][185]187,189,194,199] Higher placental weight, birth weight, and blood glucose at birth Increased expression (mRNA) of hepatic lipogenesis, oxidative stress, and inflammatory genes Decreased hepatic expression (mRNA) of Pon1, Pon2, Pon3, and Sod1, Gpx1…”

‘Food addiction’. What happens in childhood?

“…Animal models may also facilitate understanding the role of in utero experiences in "food addiction". While it is known that prenatal nutrition and exposure to maternal obesity influence the risk for obesity and metabolic dysregulations in offspring (e.g., Borengasser et al, 2014), examining and comparing the role in abuse liability of in utero exposure to psychoactive drugs versus dietary constituents might present an important paradigm.…”