REVing-down: targeting the circadian clock in metabolic disease

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Obesity and diabetes are major threats to public health, and the incidence of both conditions continues to rise. Non-surgical intervention strategies including lifestyle modification are generally ineffective due to poor compliance, and current pharmacological options are plagued by poor efficacy and adverse side effects. Novel strategies and therapeutic targets are needed. Human and animal studies have shown that adipose tissue inflammation is driving factor in the progress of obesity to life-threatening conditions, such as diabetes and cardiovascular disease. White adipose tissue (WAT) is an essential energy buffer, balancing energy storage and release during natural cycles of fasting and feeding. Chronic positive energy balance leads to expansion (hypertrophy) of the tissue, and this state can result in adipocyte dysfunction. Consequential to WAT hypertrophy there is a major shift in the immune system within the adipose tissue; where immune cells which are normally beneficial to adipocyte function (eg iNKT and ILC2 cells) are replaced by pro-inflammatory immune cells, such as inflammatory monocytes and macrophages. It is this inflammatory state which perpetuates WAT dysfunction, and drives dyslipidaemia, insulin resistance and adipocyte cell death. The challenge is to identify events that signal the transition from normal 'healthy' fat storage to adipose dysfunction and inflammation.We have recently demonstrated in mice that lack of the protein REVERBa predisposes to efficient adipocyte function and resulting WAT hypertrophy. Strikingly, although fat mass is increased they do not show the expected reduced insulin sensitivity or high levels of adipose tissue inflammation normally associated hypertrophic adipose tissue. The mice also show an elevated production of adiponectin - a hormone produced by healthy adipose tissue, and known to have many beneficial metabolic effects in humans. This indicates that REVERBa plays an important role in the adaption of WAT during obesity. In this project, we want to understand how REVERBa controls WAT function, and in particular elucidate how REVERB acting in adipocytes, regulates WAT immune function to attenuate obesity-related inflammation and insulin resistance.To achieve this, we will use novel genetic targeting in mice to manipulate REVERBa expression and activity specifically in adipocytes. This will allow us to define how REVERBa drives adipocyte function under normal circumstances and during obesity to promote/attenuate the development of tissue inflammation and insulin-resistance. We will also define mechanisms though which REVERBa controls adiponectin production (a valuable therapeutic target).Exploiting this unique model, we will next characterize how immune cell dynamics differ between mice that develop obesity related inflammation and insulin resistance, with those that remain insulin-sensitive in the face of obesity. Using state-of-the-art imaging, cell sorting and genomic techniques, we will not only identify and quantify immune populations, but also determine their relative state of activation. This is important as it goes beyond the immediate impact of REVERBa to identify cells/events that signal more broadly, the development of WAT dysfunction.Alongside animal models, we will similarly define adipose-immune dynamics in visceral adipose collected from obese patients undergoing bariatric surgery and normal weight controls. This will determine which cells and events are common in the progression of obese WAT to an inflamed insulin-resistant state in both humans and mice. Importantly, we will determine whether target pathways are amenable to pharmacological manipulation in human WAT using drugs that increase or decrease REVERBa activity. The parallel nature of these studies will allow important pathways to be cross validated between human and mouse tissues, and greatly increase our ability to identify new strategies in the fight against obesity-related disease.