Nov 22 :Inheritance of a sex-specific high fat diet-resistance phenotype : epigenetic mechanisms
Speaker：Claudine Junien
Host: Qihan Wu
When: 2013-11-22 13:30-14:30
Where: Conference Room 534, School of Life Sciences
Abstract：There is accumulating evidence that both paternal and maternal malnutrition, obesity and type 2 diabetes (T2D) at conception and during gestation/lactation increase susceptibility to the development of obesity and T2D in the offspring during adulthood. However when mice are fed a HFD there is always a significant proportion that can resist the palatability of a HFD and adjust their caloric intake without becoming hyperphagic. But when the mothers previously fed a high fat diet (HFD), become obese and diabetic, and are fed a control diet (CD) during this period, a pronounced sex-specific shift (17% to 43%) from susceptibility to resistance to a HFD, but only in the female offspring is observed. Similar processes, but transmitted by males, are observed with exposure of the parent to substances such as carbon tetrachloride triggering liver damage, and cocaine-self administration in rats. In both cases a heritable epigenetic determinant has been uncovered in epigenetic marks in sperm that escape erasure after fertilizaton. We showed an enhancement of pathways protecting against steatosis, the recruitment of unexpected neurotransmission-related genes highlighting a brain–liver connection, and the modulation of a vast imprinted gene network when obesity prone (OP) and obesity resistant (OR) offspring born to either lean of obese mothers were compared.
Our objective were to further explain the unexpected greater sex-specific resistance in the offspring of obese mothers. Using Affymetrix microarrays comparison of OP and OR offspring of obese mothers discovered that the top-ranking genes were the leptin receptor Lepr and the leptin gene (Lep) in liver and muscle respectively, highlighting the prominent role of leptin-leptin receptor cytokine pathways and a cross-talk between these tissues. Locus-specific epigenetic analyses by bisulphite-pyrosequencing and ChIP PCR Lep, Lepr and Socs2 emphasized the hitherto unsuspected role of the Lepr gene in peripheral leptin-resistance, its liver specificity and a striking sexual dimorphism. This work is the first to describe epigenetic changes in Lepr, associated with its downregulation, potentially useful markers in the follow-up of leptin-resistance treatment, in a sex-specific manner.
Global DNA methylation (LUMA) and several histone marks (western blotting, ChIP-PCR) as well as the expression of 14 genes for chromatin-modifying enzymes supported the response and adaptation to HFD, in a tissue-specific manner and according to the maternal status (lean or obese). Using principal component (PCA) and between groups (BGA) analyses, epigenetic factors that best characterized the separation between the sexes and/or leanness or obesity of the mother and hepatosteatosis under a HFD were identified. Reminiscent of those for paternal exposure to other environmental factors, these findings represent a proof of concept that exposure in the mother may therefore lead to the same unexpected inheritance of a sex-specific greater resistance to a HFD in the offspring, when obese mothers are fed a CD during gestation.