H2020Индивидуална стипендия2017–2019

EASY · Epigenetic approach for the treatment of obesity

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2017-07-01 → 2019-12-01
Финансиране от ЕС: 168 277 €
Участници: 1
Схема: MSCA-IF-EF-SE

Линиите свързват координатора с партньорите.

Накратко на български

Епигенетичният регулатор Suv4-20h и неговото влияние върху кафявата мастна тъкан се анализират, за да се разбере как се контролира метаболизмът. Това е важно, защото помага за разясняване на механизмите, които водят до затлъстяване при взаимодействие между гените и околната среда.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Epigenetic approach for the treatment of obesity

Obesity is one of the greatest public health challenges of the 21st century. In 2016, 39% of the world’s adults were overweight, of which over 650 million adults were obese. Current treatments mainly aim at limiting energy intake, but have very little efficacy, implying the involvement of additional factors. Beside the genetic contribution to the disease, in the last years much attention has been given to epigenetic deregulation as major contributor to metabolic disorders. Epigenetic refers to heritable changes in gene expression (active versus inactive genes), which occur without alteration in DNA sequence. There is a strong interplay between environmental/genetic factors and epigenetic changes in the establishment of obesity. Genes and environment can interact through their influence on the epigenome, and epigenetic marks can directly lead to increased adiposity. Although epigenetic changes may cause obesity, it is often not really clear if they precede obesity, or vice versa. Adipose tissues (AT), classified as white (WAT) and brown (BAT) are key organs for metabolic disorders. WAT is the major energy store site of the body. Conversely, BAT is rich in mitochondria and has energy expenditure properties. Owing to its ability to dissipate energy as heat, BAT has attracted scientific interest as an antiobesity tissue. Preliminary data generated in the lab pointed toward a role for the epigenetic regulator Suv4-20h in improving BAT activity through epigenetic modification. Hence, my project aims at defining how Suv4-20h proteins influence metabolism regulation in response to environmental stimuli. Moreover, I want to identify and characterize the molecular mechanism(s) through which Suv4-20h proteins regulate adipogenesis. My hypothesis is that interfering with Suv4-20h activity in BAT results in increased metabolic activity and weight loss. Through in vivo, ex-vivo, in vitro and genome-wide studies we characterized the role of Suv420h proteins in the regulation of metabolism and body weight. We found that Suv420h proteins respond to environmental stimuli by directly inhibiting the expression of PPAR-γ, a master transcriptional regulator of glycemic metabolism, adipogenesis, energy balance and lipid biosynthesis. Mice lacking Suv420h proteins specifically in BAT display a strong PPAR-γ activation signature, increased BAT mitochondria respiration, improved glucose tolerance, reduction in AT and resistance to obesity. In addition, we found significant Suv4-20h1 and Suv4-20h2 upregulation and PPAR-γ downregulation in human obesity. To the best of our knowledge, Suv420h1/2 are the first HMTases inhibiting BAT metabolism. Moreover, we describe the first epidrug able to activate BAT metabolic activity. Our results promote Suv4-20h proteins as key epigenetic regulator of PPAR-γ and the pathways controlling metabolism and weight balance in response to environmental stimuli.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

It has been estimated a threefold increase in the number of obese people in Europe since the 1980’s. Currently, EUcountries spend an average of 7% of their public health budgets on diseases linked to obesity. The socio-economic impact ofobesity epidemic cannot be overrated. European societal needs require desperately a shift forward in the field of obesityresearch to be able to build new therapeutics strategies. Recent scientific evidences point toward a role of epigeneticchanges as major contributor in the obesity etiology. In the last decades, a huge amount of data clearly link epigeneticdysregulation to obesity onset. Yet, it remains unclear whether epigenetic dysregulation contributes meaningfully to obesityepidemic. Because weight gain only occurs when energy intake exceed energy expenditure, burning off excess fuelrepresent an attractive path to reduce obesity when diet and exercise are not enough. My preliminary data indicate thehistone methyltransferases Suv420h1 and Suv420h2 as pivotal players in metabolism regulation. By using knockout micespecifically in brown adipose tissue, this project aims at dissecting the role of Suv420h proteins in the etiology ofobesity. I will combine in vivo and in vitro analyses and genome wide studies to: 1) dissect the role of Suv420h proteinsin the epigenetic regulation of the pathways controlling weight balance in response to nutritional or environmental stimuli; 2) identify genes involved in the generation, maintenance or transmission of the epigenetic memory of exposure; 3) provide useful markers or therapeutic targets to treat obesity and metabolic diseases. My results have the potential to translate into therapeutics. This research will contribute to provide new clinical targets against obesity. The Experienced Researcher will emerge from the project with new skills, and the capability to lead her own research group.

Оригинален текст от CORDIS (на английски).

Участници

OSPEDALE SAN RAFFAELE SRL · MilanoКоординаторИталия