Title: Applying genomic technologies to understand adipose inflammation
Funder: The Academy of Medical Sciences

Abstract: This study investigates adipose inflammation in obesity. It will exploit genomic technologies to achieve the following primary aims: - To test the hypothesis that adipose chromatin is remodelled in a mouse model of diet-induced obesity. - To identify, using a mouse model of metabolically healthy obesity, which gene expression programmes in which adipose cell-types distinguish inflamed vs. non-inflamed obese adipose. We have previously found, in a mouse model, that adipocyte-targeted deletion of the core clock gene Reverbα (Reverbαfl/flAdipoCre+/-) limits the development of adipose inflammation when obesity is induced with high-fat diet feeding. Remarkably, Reverbα deletion in the basal state does very little, indicating reprogramming of the regulatory environment in obesity. Furthermore, the healthy phenotype of the obese Reverbαfl/flAdipoCre+/- mouse suggests that metabolic reprogramming of adipocytes is sufficient to influence the function of the non-adipocyte effector cells (e.g. immune cells, fibroblasts) that drive the inflammation itself. To address the first aim, I will profile chromatin accessibility in non-obese and obese mouse adipose, comparing the two to determine which genomic regions are reprogrammed by obesity. To address the second aim, I will profile the transcriptome, at the single cell level, of non-obese and obese adipose, with and without Reverbα. Taken together, these data will inform how adipocyte Reverbα alters cell signatures of gene expression in both adipocyte and non-adipocyte populations, triggering inflammation, and how chromatin remodelling in obesity reprogrammes the environment in which REVERBα operates.

Lay abstract: Obesity is associated with an increased risk of health problems such as type 2 diabetes and cancer. One of the proposed reasons for this association is the development of inflammation within the fat tissue (adipose). Inflamed adipose differs from healthy adipose, being stiffer, and containing activated white blood cells. In most cells of our body, we have a clock - a network of genes which keep time. We have found, in mice, that we can delete one of the clock genes in fat cells, and produce mice that don't develop inflamed adipose when we feed them high-fat diet. They are obese, but not unhealthy. Mice that still have the clock gene in their fat cells develop inflamed adipose and are unhealthy. Interestingly, this difference is only apparent when the mice are fed the high-fat diet, not when they are fed normal food and stay slim. I want to investigate two related questions which stem from this finding. Firstly, why is the difference only apparent when mice become obese? If I use a technique to look at the environment in which the clock gene is operating, will I see a difference? Secondly, can I use a new scientific technique to understand why deletion of the clock gene leads to healthier adipose? This technique looks at individual cells in the tissue, rather than all the tissue together, to unpick differences between conditions. This information will give me insight into how adipose inflammation develops, and potentially how future research might help address it.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE