Epigenetics of weight control

Anatomical, cellular and molecular heterogeneity in the CNS control of food intake and energy homeostasis. Contreras, Schriever & Pfluger, Front. Genet. 2019. https://doi.org/10.3389/fgene.2019.01015

Epigenetic mechanisms in the CNS control of body weight

 

In this project, we aim to interrogate mechanisms in the CNS that impede sustainable weight loss and drive weight regain, an effect termed Yoyo dieting. Specifically, we hypothesise that orexigenic CNS circuits harbour an epigenetic memory for obesity that ultimately drives the Yoyo dieting effect. In our work, we explore how epigenetic mechanisms in the hypothalamus drive long-lasting deleterious adaptations and the imprinted obesogenic memory effect that prevents sustainable weight loss. By applying FAC sorting on Cre-specific reporter mice, we isolate specific neuronal as well as non-neuronal sub-populations, and subsequently assess the impact of obesity, weight loss or weight cycling on their transcriptomic and epigenomic landscapes. Subsequently, we use Crispr-Cas9-based transepigenetic remodelling approaches to test whether the epigenetic memory for obesity can be reset by genetically manipulating single, or groups of genes.

 

 

Metabolic control by class IIa histone deacetylase 5

A key mechanism to modulate gene environment interactions is the acetylation of lysine residues in histone and non-histone proteins, tightly controlled by histone acetyltransferases (HATs) and histone deacyetylases (HDACs).  We recently showed that hypothalamic Histone Deacetylase 5 (HDAC5) is an important regulator of  food intake and body weight. Specifically, we showed that Hdac5 acts as novel hypothalamic STAT3 acetyl-phospho switch that fine-tunes leptin signaling in direct response to metabolic changes and environmental stimuli. Built upon our recent Horizon 2020-funded European Training Network Consortium on Chromatin & Metabolism, we currently aim to assess the impact of HDAC5 in the control of body weight under non-obesogenic conditions. Our focus is directed towards a novel role of HDAC5 in dopaminergic signaling and the CNS control of peripheral metabolism.

Fluorescence-activated cell sorting (FACS) of TH-positive cells in the hypothalamus (R. Contreras, unpublished data).