TollSOME

Obesity is a worldwide epidemic, affecting countries rich and poor, and is one of the greatest public health challenges of the 21th century. According to World Health Organization (WHO), in 2014 more than 1.9 billion (39%) adults were overweight and of these over 600 million (13%) were obese. Childhood obesity has also increased and is estimated to be over 42 million. As a detrimental health condition, the development of obesity is associated with multiple metabolic abnormalities, including insulin resistance, hyperglycemia, dyslipidemia, hypertension and nonalcoholic fatty liver disease, which are collectively defined as metabolic syndrome, exposing to diabetes and cardiovascular diseases. Obesity is responsible for about 5% for all deaths worldwide, and its global economic impact accounts to $2 trillions annually. The fundamental cause of obesity and overweight is an energy imbalance between calories consumed and calories expended. Attempts to prevent obesity by dietary management and physical activity have been moderately effective as a preventive measure for obesity. Various recent studies indicate that obesity is a heritable condition that is highly sensitive to the environment. Thus, effective obesity prevention and management is dependent on the acknowledgement that obesity goes beyond environmental factors and individual behaviour and is influenced by genetics. Understanding the molecular roots of obesity is an important prerequisite to improve both prevention and management of this condition. Obesity is characterized as a systemic chronic low-grade inflammation stage in different metabolic tissues that develops in response to an excess of nutrient influx. Toll-like receptors (TLRs) are evolutionary conserved transmembrane receptors that drive innate and adaptive immunity through the recognition of various microbial components and endogenous molecules released by damaged or dead cells. Excessive nutrients can also be sensed by the TLR family that lately has emerged as a critical link between inflammation and a contributor to obesity and insulin resistance both in humans and mice. Recently, we showed that TLR8 restrain TLR7 function and that TLR8 deficiency in mice results in increased TLR7 signalling by dendritic cells and the development of lupus autoimmunity (Demaria et al, J Clin Invest, 2010; Desnues et al., PNAS, 2014). Interestingly, our preliminary in vivo data strongly indicate that TLR7 signalling and dendritic cells can contribute to obesity and metabolic syndrome. The main objective of TollSOME is to explore the novel idea that TLR7 signalling can contribute to obesity and that blocking TLR7 function might have a protective and therapeutic role on the development of obesity and its harmful effects. Specifically we aim at exploring the contribution of TLR7 and dendritic cells in the development of obesity and metabolic syndrome using various in vivo animal models and transcriptomic analysis, and mobilizing a multidisciplinary consortium of three partners with expertise in immunology, metabolism and magnetic resonance imaging. The main expected outcome of TollSOME is to provide the first proof of concept of the therapeutic potential of blocking TLR7 as a target to prevent inflammation in the metabolic disease of obesity. Our studies will advance our understanding regarding the contribution of TLR7 signalling and dendritic cells in obesity and might lead to novel avenues for the prevention and treatment of this epidemic metabolic disorder that reduces life expectancy and has huge socioeconomic consequences.