TLR7 at the interface of obesity and metabolic syndrome – TollSOME

TLR8ko, double TLR7/8ko, TLR7ko mice and their corresponding wild-type littermates were fed with a high fat diet or standard chow diet for 6 months. Body weight gain was recorded weekly and metabolic parameters were evaluated at 8 months old mice by performing glucose and insulin tolerance test, as well as, FACS analysis, histology, quantitative PCR in mouse tissues (spleen, liver and adipose tissue). Moreover, the protein levels of TLR7 and TNF expression were evaluated in dendritic cells and macrophages derived from TLR8ko, double TLR7/8ko, TLR7ko mice and their corresponding wild-type mice.

Upon high fat diet feeding TLR8ko mice develop more severe metabolic abnormalities than wild- type mice. Interestingly, TLR7/8 ko and TLR7ko mice are protected from high fat diet-induced metabolic syndrome, including body weight gain, hepatic inflammation, glucose intolerance, and immune cell activation. Thus, TLR7 blockage might have beneficial effects on the development of obesity and its metabolic consequences. Moreover, we that high fat diet feeding leads to increased TLR7 expression and signalling in dendritic cells, but not macrophages, and thus dendritic cells might play a central role in the chronic inflammation that is seen in high fat diet-induced metabolic syndrome.

Our original observation that increased TLR7 signalling contributes to obesity and metabolic syndrome, and hypothesis that reducing TLR7 function might prevent the development of obesity and its harmful effects, it has been strengthen with our so far experiments. In the future energy expenditure will be evaluated in high fat diet versus standard diet fed TLR8ko, TLR7/8ko and wild type mice. We will characterise the transcriptional profile of TLR8ko, wild type and TLR7ko dendritic cells. Moreover, we will generate and study transgenic mice that overexpress TLR7 in conventional dendritic cells or plasmacytoid dendritic cells. We believe that our studies could lead to novel avenues for the prevention and treatment of the epidemic disorder of obesity and its metabolic complications, by targeting TLR7.

Hanna Kazazian N, Wang , Roussel-Queval A, Marcadet L, Chasson L, Laprie C, Desnues B, Charaix J, Irla M, and Alexopoulou L. Lupus autoimmunity and metabolic parameters are exacerbated upon high fat diet-induced obesity due to TLR7 signalling. Front Immunol, 2019, 10:2015.

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.