A new therapeutic strategy to combat metabolic complications of obesity : the inhibition of fat cell lipolysis – ObeLip

To date, there are 600 million obese individuals worldwide. In France, 14.5% of the adult population is classified as obese. The increase in the number of obese individuals has led to an explosion of type 2 diabetes and cardiovascular diseases. Insulin resistance constitutes a cornerstone of the metabolic and cardiovascular complications of obesity. Understanding the mechanisms underlying the link between obesity and insulin resistance remains to date elusive. However, such understanding is essential to propose new therapeutic strategies. Despite the increased prevalence of obesity and its complications, the paucity of drugs available is striking. Lifestyle interventions aimed at 5-10% weight loss are recommended as first-line treatment. The record of anti-obesity drugs has been very poor. Instead of aiming at drug-mediated weight loss, a new paradigm might be to combine non therapeutic weight management protocols (e.g., through dietary interventions or physical exercise) and pharmacotherapies that amplify the beneficial effect of a decrease in fat mass, e.g., on insulin resistance. In ObeLip, we propose and investigate a new therapeutic strategy to combat the metabolic complications of obesity: the inhibition of fat cell lipolysis. Based on a comprehensive series of unpublished data, we believe that inhibiting adipose tissue lipolysis is a promising strategy to alleviate insulin resistance. Three major tasks have been defined that correspond to the major objectives of the project. Task 1 aims at understanding the consequences of the dysregulation in adipose tissue lipase expression observed in human obesity. It will rely on mouse models of decreased lipase expression which will be characterized in terms of lipolytic capacity, body composition, insulin and glucose tolerance and exercise capacity. To mimic human conditions, experiments will be performed at thermoneutrality. Task 2 aims at identifying the mechanisms associating the inhibition of lipolysis and the improvement of insulin action. Work will be performed on transgenic mice with partial global or adipose tissue-specific deficiency in hormone-sensitive lipase. Metabolism of adipose tissue, skeletal muscle and liver as well as insulin signaling will be investigated. Cell autonomous consequences of decreased lipase expression will be studied on human adipocytes. Special emphasis will be given to the importance of adipokine production, signaling lipid species, de novo lipogenesis and, using novel mouse models, to the roles of the hepatic transcription factors ChREBP and PPAR?. Task 3 aims at evaluating the preclinical therapeutic effect of lipolysis blockade. The long term effect of a partial inhibition of adipose tissue lipolysis will be assessed. The combination of calorie restriction or physical training and lipolysis blockade will be evaluated. Through modulation of the diet fatty acid composition, the interaction between essential fatty acids and hormone-sensitive lipase in the modulation of insulin sensitivity will be studied. Two mechanisms of action for lipolysis inhibition will be compared using a specific hormone-sensitive lipase inhibitor and a novel GPR109A agonist. The 3 partners (Dominique Langin, Institut des Maladies Métaboliques et Cardiovasculaires, Inserm/Université, Toulouse; Catherine Postic, Institut Cochin, Inserm/CNRS/Université, Paris and Hervé Guillou, Toxicologie Alimentaire, INRA/INP/Université, Toulouse) have complementary expertise to achieve ObeLip goals notably in lipolysis, adipose tissue biology, insulin signaling, lipidomics, transcriptional control of hepatic metabolism, dietary interventions and physical exercise. Altogether, the program will bring mechanistic insight in the consequences of decreased fat cell lipase expression and in the action of antilipolytic drugs but also pave the way for future therapeutic development targeting obesity-associated insulin resistance.