Programmed increases in LXRα induced by paternal alcohol use enhance offspring metabolic adaptation to high-fat diet induced obesity

Abstract

ObjectivesPaternally inherited alterations in epigenetic programming are emerging as relevant factors in numerous disease states, including the growth and metabolic defects observed in fetal alcohol spectrum disorders. In rodents, chronic paternal alcohol use induces fetal growth restriction, as well as sex-specific alterations in insulin signaling and lipid homeostasis in the offspring. Based on previous studies, we hypothesized that the observed metabolic irregularities are the consequence of paternally inherited alterations liver x receptor (LXR) activity.MethodsMale offspring of alcohol-exposed sires were challenged with a high-fat diet and the molecular pathways controlling glucose and lipid homeostasis assayed for LXR-induced alterations.ResultsSimilar to findings in studies employing LXR agonists we found that the male offspring of alcohol-exposed sires display resistance to diet-induced obesity and improved glucose homeostasis when challenged with a high-fat diet. This improved metabolic adaptation is mediated by LXRα trans-repression of inflammatory cytokines, releasing IKKβ inhibition of the insulin signaling pathway. Interestingly, paternally programmed increases in LXRα expression are liver-specific and do not manifest in the pancreas or visceral fat.ConclusionsThese studies identify LXRα as a key mediator of the long-term metabolic alterations induced by preconception paternal alcohol use.

Gestational exposure to particulate air pollution exacerbates the growth phenotypes induced by preconception paternal alcohol use: a multiplex model of exposure

“…During these experiments, we utilized a well-established breeder diet, to which dams had unrestricted access and subjected the mice to minimal handling stress. We did not observe cannibalism in any of our previous postnatal studies examining the offspring of alcohol-exposed sires [ 10 , 11 ], or in the Control-FA treatment group, indicating the strong possibility that these outcomes were associated with the treatments. After 30 days of postnatal growth, we terminated the experiments due to the low number of surviving offspring ( Fig.…”

Intergenerational implications of alcohol intake: metabolic disorders in alcohol-naïve rat offspring

“…Paternally inherited alterations in epigenetic programming were also shown to be related to metabolic defects observed in foetal alcohol spectrum disorders. In rodents, chronic paternal alcohol use affected insulin signaling and lipid homeostasis in the offspring through paternally inherited alterations in liver × receptor activity ( Chang et al, 2019a ). Similar findings were reported by Chang et al (2019b) , assessing long-term impacts of chronic preconception paternal alcohol use in mice.…”

“…In another study examining parental binge alcohol abuse, differences in the expression of genes involved in neurogenesis, reproductive function, and regulation of obesity were observed in offspring ( Przybycien-Szymanska et al, 2014 ). Also, the studies of Chang et al (2019a) and Chang et al (2019b) using a mouse model of paternal alcohol exposure have identified the markers of hepatic fibrosis and abnormalities in both lipid production and insulin signaling in the offspring of alcohol-exposed sires. The aforementioned studies raise the possibility that alcohol affects naïve offspring even in the absence of direct foetal alcohol exposure, and epigenetic inheritance may be the mechanism responsible for this phenomenon.…”

Programmed suppression of oxidative phosphorylation and mitochondrial function by gestational alcohol exposure correlate with widespread increases in H3K9me2 that do not suppress transcription

“…We washed cells twice with PBS containing protease inhibitor cocktail (Cat# 78437; Thermo Scientific) and re-suspended them in medium (DMEM F-12 Cat# 11320-033; Invitrogen) containing 0.1 volume crosslinking solution [ 33 ]. We carried out chromatin immunoprecipitation reactions following the previously published protocol [ 34 ]. The specific antibodies used in this study include anti-H3K9me2 (Cat# 39239; Active Motif, RRID:AB_2793199), antiH3K9me3 (Cat# 05-1242; Millipore-Sigma, RRID:AB_1587136), antiH4K20me3 (Cat# 91107; Active Motif, RRID:AB_2793777), anti-SATB2 (Cat# ab34735; Abcam, RRID:AB_2301417) and the negative IgG control (Cat# SC-2027; Santa Cruz, RRID:AB_737197).…”