Maternal obesity and post‐natal high fat diet disrupt hepatic circadian rhythm in rat offspring

Abstract

Offspring of obese (Ob) rat dams gain greater body wt and fat mass when fed high fat diet (HFD) as compared to controls. Alterations of diurnal circadian rhythms are known to detrimentally impact metabolically active tissues such as liver. We sought to determine if maternal obesity (MOb) leads to perturbations of circadian rhythm and energy metabolism in offspring liver following a short (2 wk) high fat (HFD) challenge. mRNA expression on PND35 of putative circadian (CLOCK, Reverbα, Bmal1, Cry, Per) and metabolic (PPARα, SIRT1) genes were suppressed following HFD in lean and Ob groups. Further suppression was evident in Ob‐offspring indicating circadian disruption. Using a mathematical model for the circadian clock, analyses of PPARα and SIRT1 temporal changes in relative mRNA abundance revealed exposure to MOb and/or HFD disrupts the circadian rhythm by (i) decreasing mRNA synthesis via a rate limiting activation constant of expression of nuclear Bmal1 and (ii) increasing non‐specific mRNA degradation of both PPARα and SIRT1. HDAC3 a known regulator of circadian rhythmicity and hepatic lipid metabolism, was decreased at 5/6 time points (4 hr intervals) by exposure to HFD and MOb. HFD disrupts core hepatic clock machinery and key regulators of energy metabolism and is further exacerbated by MOb which may increase the risk for harmful adiposity gains in adulthood. Support NIHR01‐DK084225