Running projects supported by grants ****************************************************************************************** * 1. The role of Adipose tissue and muscle crosstalk in regulation of METabolic flexibilit novel predictors of the lifestyle Intervention Success in obese (AMETIS) ****************************************************************************************** Czech Health Research Council project NU23-01-00509 Our position: PI The incidence of obesity and related diseases such as type 2 diabetes, cardiovascular dise steatosis and cancer is increasing worldwide. The need for innovative early intervention a patients with obesity is therefore pressing. One of the core yet understudied pathophysiol underlying metabolic dysregulation in obesity is metabolic inflexibility, characterized by efficiently adapt metabolism to substrate demand or availability. However, an accurate yet of metabolic flexibility is lacking, and clinically relevant marker of metabolic flexibili readily identify at risk patients with high specificity and sensitivity is needed. Therefo of this study is to identify surrogate markers of metabolic flexibility, with the capacity success of complex lifestyle intervention in patients with obesity. We hypothesize that th be factors responsible for paracrine and endocrine communication between skeletal muscle a in the context of metabolic flexibility. Therefore, samples of (i) vastus lateralis muscle intramuscular adipose tissue, and (iii) subcutaneous adipose tissue will be collected from with well-characterized metabolic flexibility (glucose ingestion/feeding: Oral glucose tol euglycemic hyperinsulinemic clamp; exercise test: VO2max, low intensity cycling) and chara state-of-the-art transcriptomic, proteomic and metabolomic methods. The mechanism of actio molecular markers of metabolic flexibility derived from these studies will be tested using cultures of human muscle cells and adipocytes. Clinical relevance of the identified marker flexibility will be validated in the large and complex dataset generated in previous cross intervention (exercise and/or dietary) studies. Colaborators: biomedical Research Center of the Slovak Academy of Sciences, Faculty Hospit Vinohrady ****************************************************************************************** * 2. Relation of de novo lipogenesis and peroxisomal metabolism in obesity (PEROXI) ****************************************************************************************** GAUK 254923 Our position: PI Adipose tissue (AT) dysfunction in obese patients is associated with a decrease in de novo (DNL) in adipocytes. These changes likely result in alterations in the membrane lipidome a sensitivity. According to recent data, it appears that ether-phosphatidylcholines, which a in peroxisomes, probably play an important role in the development of dysfunctional AT. Th phospholipids are induced when DNL decreases and may contribute to the development of oxid and subsequently insulin rezistance. Thus, we focus in this study on the association of re with peroxisome metabolism and ether-phospholipid production. We will also investigate the of DNL inhibition with oxidative stress and insulin sensitivity using ex-vivo AT samples f studies and in vitro primary adipocyte cell cultures. Unraveling the relationship between insulin sensitivity pathways should help to establish new strategies for the treatment of resistance and diabetes. ****************************************************************************************** * 3. Novel approaches to enhance insulin-sensitizing effects of exercise: targeting PAHSA (ETAPA) ****************************************************************************************** Czech Health Research Council project NU21-01-00469 Our position: co-PI Exercise is an important tool in the prevention and treatment of metabolic disorders assoc obesity and aging, such as type 2 diabetes and cardiovascular disease. In addition to skel and its myokines metabolic effects of exercise also depend on inducing beneficial changes adipose tissue. Adipose tissue, for example, is a source of lipokines of the ester family with hydroxy fatty acids (PAHSA), which have anti-inflammatory and insulin-sensitising pro recently shown that 4 months of exercise increases PAHSA levels in adipose tissue and circ However, the mechanisms involved in the induction of PAHSA levels in response to exercise Therefore, the aim of the ETAPA project is to investigate the regulation of of PAHSA metab to acute and chronic exercise, and at the same time investigate strategies that could enha exercise on PAHSA levels, thereby increasing insulin sensitivity and maximising therapeuti Colaborators: Institute of Physiology ASCR, Faculty Hospital Kralovske Vinohrady ****************************************************************************************** * 4. Gene Therapy to restore lymphatic flow lymphedema (TheraLymph) ****************************************************************************************** H2020 SC1-BHC-07-2019, Project # 874708 Our position: partner, WP3 Lymphedema is a disabling condition induced by the accumulation of fluid and fat in the ar leg. It is an untreatable disease that affects 4 millions people in Europe and more than 1 people worldwide. It is handicapping, painful and impacts substantially the quality of lif countries, lymphedema is generally a consequence of cancer treatments i.e. ten to fifteen will develop lymphedema after breast cancer. The main objective of Theralymph will be to e integrative gene therapy for this unmet medical need. The theralymph translational researc together bench scientists from 5 European countries and physicians from the hosted Ranguei which the PI institute is located to perform a Phase I/II trial focusing on women who deve after breast cancer. Our team (partner # 8) will participate in the project by analysing t interrelationships between adipocytes and lymphatic endothelial cells in in vitro models. https://theralymph-europe.eu/ [ URL "https://theralymph-europe.eu/"] Collaborators: 1.(Coordinator) Institut national de la santé et de la recherche médicale (Inserm) France 2.University of Helsinki (UnivHel) Finland 3.University of Lausanne (UnivLau) Switzerland 4.Uppsala University (UnivUps) Sweden 5.University of Louvain (UniLou) Belgium 6.University of Liege (UniLiege) Belgium 7.Centre National de la Recherche Scientifique (CNRS) France 8.Centre Hospitalier Universitaire, Toulouse hospital (CHUT) France 9.Flash Therapeutics (FTX) France 10Inserm Transfert (IT) France ****************************************************************************************** * 5. Ketogenic diet as a modulator of de novo lipogenesis in liver and amount of visceral (KETOLIVA) ****************************************************************************************** Czech Health Research Council project NU20J-01-00005 Our position: co-PI The hypocaloric ketogenic diet (KD), a diet with very low carbohydrate energy, has become dietary option for weight loss. However, it remains less clear whether the beneficial meta can be attributed to an isocaloric KD containing predominantly lipids. Recent research sug isocaloric KD may worsen the lipid profile and insulin sensitivity of the liver. This sugg switching to an isocaloric KD or carbohydrate diet, which usually follows a hypocaloric KD adverse metabolic changes in liver metabolism. Therefore, this project aims to investigate isocaloric KD followed by a carbohydrate diet on ectopic fat accumulation and de novo lipo liver in relation to metabolic status in obese women and to describe the communication bet adipose tissue in response to this type of dietary load through miRNA and cytokine analysi extracellular vesicles. The project combines state-of-the-art imaging technologies and mol techniques. Collaborator: The Institute for Clinical and Experimental Medicine ****************************************************************************************** * 6. The Role of De Novo Lipogenesis in Regulation of Insulin Sensitivity in adipose tissu (DELISA) ****************************************************************************************** Czech Health Research Council project NV19-01-00263 Our position: PI One of the manifestations of adipose tissue (TT) dysfunction in the obese is impaired de n (DNL). DNL impairment in TT plays a role in the metabolic complications of obesity. The ai is to study novel factors regulating DNL in TT. DNL will be monitored during nutritional i in healthy and obese subjects: exposure to a 2-day high carbohydrate diet, which will be a fasting period b) a multi-week ketogenic diet. The chosen nutritional protocol creates con study the change of DNL in TT: suppression of DNL during fasting or ketogenic diet and sti the subsequent high carbohydrate phase. Relevant systemic phenotypic traits will be monito protocols and the spectrum of molecular markers of DNL regulation will be investigated in TT samples, with specific attention to the newly described factors hormone-sensitive lipas transcription factor ChREBP. Collaborators: Faculty Hospital Kralovske Vinohrady ****************************************************************************************** * 7. Pancreatic cancer: metabolic derangements assiocated with insulin resistance (PAMIR) ****************************************************************************************** Czech Health Research Council project NV19-01-00101 Our position: co-PI Pancreatic cancer (PC), whose incidence is increasing in the Western countries, ranks amon the worst prognosis. PC is associated with early development of cancer cachexia, a systemi leading to the depletion of host substrate reserves. The project aims to identify key meta of the tumour and adipose tissue related to cancer cachexia. Patients with PC will be char (anthropometry, insulin sensitivity and secretion, substrate utilization, inflammatory par describe complex metabolic phenotype. Primary cultures of the tumour will be subjected to analyses, specifically related to glutamine and branched chain amino acid metabolism and i their degradation pathways. Peripancreatic fat will be analysed for its lipolytic and secr In differentiated adipocytes, the ability of insulin sensitizing drugs to ameliorate lipol tumour medium will be assessed. Results will enable to describe host-tumour substrate cros identify potential treatment targets of PC induced cachexia. Collaborators: Faculty Hospital Kralovske Vinohrady, Institute of Physiology ASCR