Final Report Summary - FUEGO (Global Network of Excellence for Research on Adipose Tissue Plasticity and Human Thermogenesis)
An alarmingly high incidence of obesity and cardio-metabolic disease has substantially contributed to Europe having one of the highest mortality rates for adults aged 15–59 in the world. Cardio-metabolic disease (CMD) is not only associated with reduced life expectancy, but also drastically impacts health services, industry, education and government - with a multi-billiondollar cost to the economy. Moreover, recent reports predict that the global market for drugs treating obesity and cardio-metabolic disease will nearly double to reach ~$40 billion by 2019. Despite the growing cost spent on anti-obesity agents, experts in the field continue to express concern that the drugs fail to provide lasting benefits for health and wellbeing. This stems from the fact that obesity drug developers focus on the latest mechanism of action, despite multiple failed attempts. Considering the growing list of side effects, such as the cardiovascular concerns associated with Avandia and Meridia, it is evident that a fresh perspective is necessary for the creation of a novel and safe approach that will prepare us the massive projected increase of obesity and cardio-metabolic disease over the next decades. The FUEGO project, funded by the 7th Framework Programme of the European Commission, created a multiannual joint programme which was dedicated to exchanges of research staff between European (Sweden, Greece, UK) research entities and other third countries (Brazil, Belarus) to increase knowledge on adipose tissue plasticity and human thermogenesis. Through these activities, the FUEGO project fostered a mutual understanding of the different disciplines, encouraging entrepreneurship and long-term interdisciplinary collaboration regarding adipose tissue plasticity and human thermogenesis. The contribution of FUEGO to the study of adipose tissue plasticity and human thermogenesis was significant, as it became the means through which research centres collaborated in order to produce high-quality research. Exploiting the participants’ complementary expertise and creating synergies amongst them by fusing their research interests and specialisations in order to develop diverse research approaches, inexorably led to breakthroughs in our understanding of the mechanisms of adipose tissue plasticity and human thermogenesis. The FUEGO project was designed to exploit the complimentary expertise of EU and third country research organisations through knowledge sharing and transfer between countries. This was achieved by establishing a Network of Excellence that incorporated staff secondments for the purpose of networking, training activities, workshops, and joint research. The FUEGO partners boast an outstanding group of researchers, extensive collaboration and knowledge transfer networks, a large number of relevant publications, as well as very active participation in research programs funded by the European Commission. Moreover, the partners’ experience and specialisation in CMD research, their extensive experience in networks of excellence and international collaborations, and their broad infrastructures provided the level of quality required to transform the FUEGO joint exchange programme into a successful multi-national network of excellence for CMD research.
Our joint exchange programme significantly contributed to strengthen the cooperative potential for health-related RTD between EU/AC and EECA countries through staff exchanges and networking activities. This is exemplified by the total of six papers published by the consortium partners in reputable journals. In our first paper by Svensson et al. (2014), we for the first time characterized the human perirenal adipose tissue depot on molecular, protein and cellular levels. Our results report the presence of BAT in this depot as confirmed by the presence of both multi- and unilocular UCP1-positive adipocytes-albeit a large inter-individual variation within the samples collected-, and a higher expression of BAT-related genes that were highly correlated to UCP1 gene compared to the ones expressed specifically to WAT. We also identified gene RXRγ as a new transcription factor that could be involved in the development of BAT. In our second paper by Valente et al. (2015), we found that a single L-menthol skin administration increased thermogenesis and metabolic rate in humans. These effects are minor following L-menthol oral administration probably due to faster glucuronidation and greater blood menthol glucuronide levels. Based on the aforementioned findings, and emerging evidence on the beneficial cooling effects of L-menthol on UCP1-mediated thermogenesis and BAT-like activity in classical WAT depots, in our third paper by Sakellariou et al. (2016), we proposed a L-Menthol-induced browning of WAT hypothesis model, whereby chronic L-menthol dietary treatment could putatively activate cold-sensitive TRPM8 and TRPA1 receptors located on the cell membrane of human white adipocytes, thus inducing an intracellular [Ca2+] increased and browning of WAT. In our fourth paper by de França et al. (2016), we demonstrated that a higher sympathetic flux to inguinal BAT as a consequence of the administration of a low-protein high-carbohydrate diet to rats activates thermogenesis and UCP1 content in the tissue. Finally, in our fifth paper by Pereira et al. (2017), we reported that a low-protein high-carbohydrate diet to rats led to browning in the perirenal WAT, and that higher utilization of fatty acids from blood lipoproteins acted as fuel for thermogenesis. Increased G3P generation by glyceroneogenesis increased fatty acids re-esterification from lipolysis, explaining the increased triacylglycerol storage in the inguinal WAT. In our sixth paper by Flouris et al. (2017), we conducted a systematic review to evaluate the effect of regular exercise training on UCP1 expression in BAT in experimental animal models.
Our analysis revealed that regular exercise training may possibly not represent a major stimulus of UCP1 expression in BAT. We concluded that additional research should focus on the physiological effects of exercise training on BAT thermogenic activity, especially in humans, given the remarkable inconsistency in the results from the analysed studies, and the limited available evidence.
Through the secondments, the researchers gained benefits such as new skills, personal development, career progress, exposure to a different organizational culture, opportunity to change direction, transfer of knowledge, and time for contemplation and re-evaluation of existing skills and abilities. In addition, the researchers had the chance to attend conferences through which they shared knowledge and information regarding the impact of genetics on cardiometabolic disease.
Our joint exchange programme significantly contributed to strengthen the cooperative potential for health-related RTD between EU/AC and EECA countries through staff exchanges and networking activities. This is exemplified by the total of six papers published by the consortium partners in reputable journals. In our first paper by Svensson et al. (2014), we for the first time characterized the human perirenal adipose tissue depot on molecular, protein and cellular levels. Our results report the presence of BAT in this depot as confirmed by the presence of both multi- and unilocular UCP1-positive adipocytes-albeit a large inter-individual variation within the samples collected-, and a higher expression of BAT-related genes that were highly correlated to UCP1 gene compared to the ones expressed specifically to WAT. We also identified gene RXRγ as a new transcription factor that could be involved in the development of BAT. In our second paper by Valente et al. (2015), we found that a single L-menthol skin administration increased thermogenesis and metabolic rate in humans. These effects are minor following L-menthol oral administration probably due to faster glucuronidation and greater blood menthol glucuronide levels. Based on the aforementioned findings, and emerging evidence on the beneficial cooling effects of L-menthol on UCP1-mediated thermogenesis and BAT-like activity in classical WAT depots, in our third paper by Sakellariou et al. (2016), we proposed a L-Menthol-induced browning of WAT hypothesis model, whereby chronic L-menthol dietary treatment could putatively activate cold-sensitive TRPM8 and TRPA1 receptors located on the cell membrane of human white adipocytes, thus inducing an intracellular [Ca2+] increased and browning of WAT. In our fourth paper by de França et al. (2016), we demonstrated that a higher sympathetic flux to inguinal BAT as a consequence of the administration of a low-protein high-carbohydrate diet to rats activates thermogenesis and UCP1 content in the tissue. Finally, in our fifth paper by Pereira et al. (2017), we reported that a low-protein high-carbohydrate diet to rats led to browning in the perirenal WAT, and that higher utilization of fatty acids from blood lipoproteins acted as fuel for thermogenesis. Increased G3P generation by glyceroneogenesis increased fatty acids re-esterification from lipolysis, explaining the increased triacylglycerol storage in the inguinal WAT. In our sixth paper by Flouris et al. (2017), we conducted a systematic review to evaluate the effect of regular exercise training on UCP1 expression in BAT in experimental animal models.
Our analysis revealed that regular exercise training may possibly not represent a major stimulus of UCP1 expression in BAT. We concluded that additional research should focus on the physiological effects of exercise training on BAT thermogenic activity, especially in humans, given the remarkable inconsistency in the results from the analysed studies, and the limited available evidence.
Through the secondments, the researchers gained benefits such as new skills, personal development, career progress, exposure to a different organizational culture, opportunity to change direction, transfer of knowledge, and time for contemplation and re-evaluation of existing skills and abilities. In addition, the researchers had the chance to attend conferences through which they shared knowledge and information regarding the impact of genetics on cardiometabolic disease.