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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Epigenetic encoding of the thermogenic capacity of human adipose tissue

Alternative title: Epigenetisk koding av termogen potensialet til humant fettvev

Awarded: NOK 12.0 mill.

Fat tissue is a major area of research because fat tissue can store energy in the form of lipids in white fat cells (called white adipocytes), and dissipate energy by heat in another type of adipocytes (called brown adipocytes) that are thermogenic. Worldwide, more than 2 billion adults are overweight and 1 billion are clinically obese. Heat-producing adipocytes are important because they help maintain body weight and protect against metabolic diseases such as type-2 diabetes or cardiovascular diseases. So there is a strong interest in understanding where these adipocytes come from and how they can be activated to produce heat in response to cold. A key link between the environment and what a cell becomes or does is the epigenome, the record of chemical modifications on DNA which control expression of genes. These modifications build a code, the epigenetic code, which is read by proteins regulating gene expression. In this project, we will decipher this code by determining the nature of these epigenetic modification in stem cells from human white fat tissue, and manipulate this code to understand how white fat adipocytes can be turned into cells that generate heat. Specifically, we will identify, in fat tissue, stem cells that can give rise to thermogenic adipocytes, characterize their epigenetic code and how it is affected by stimuli that mimic cold exposure, and identify treatments that effectively convert fat-storing cells into heat-producing cells. This is a basic science project, but we expect our work to provide data to identify potential molecules that could promote the conversion of unhealthy white fat cells into protective heat-producing fat cells to treat obesity-associated diseases and improve overall metabolism in the elderly, who tend to lose heat-producing fat cells.

Human adipose tissue is a major research focus because of its ability to store energy in the form of lipids in white adipocytes, and dissipate energy by heat in brown and beige thermogenic adipocytes. The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic diseases prompts studies of their origin and mechanism of activation in response to stimuli such as cold exposure. A key link between environment and phenotype is the epigenome, the record of chemical modifications on chromosomes (and genes) which, in specific 3-dimensional (3D) conformations, regulate gene expression. We propose to identify 3D epigenetic process underlying the formation and activation of thermogenic beige adipocytes. Focusing on gene promoter-enhancer relationships, we first aim to unveil the epigenetic features of beige-able human adipose progenitor cells allowing thermogenic beige adipogenesis. Beige adipocytes can convert between a white phenotype and a thermogenic beige phenotype (‘beiging’) in response to cold exposure. We will explore how this plasticity is encoded epigenetically and by the 3D architecture of genes and regulatory elements involved in beiging. This ambitious project integrates adipose, functional studies, genome-wide epigenetics, 3D chromatin conformation analyses, and computational modeling in a model of human beige adipogenesis. We expect to obtain new insights on the molecular basis of epigenetic priming of beige progenitors, of thermogenic activation and of the adaptive capacity of adipocytes, and a holistic yet detailed view of how thermogenic genes are regulated in 3D space. The most critical challenges are i) ability to isolate/enrich human beige progenitors and ii) detection of 3D chromatin conformations specific to the thermogenic potential of adipocytes. Our preliminary data and fall-back strategies however argue for feasibility and success of the project.

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FRIMED2-FRIPRO forskerprosjekt, medisin og helse