Periodic Reporting for period 1 - FATarget (Drugs targets in sympathetic neurons controlling adiposity.)
Berichtszeitraum: 2019-06-03 bis 2021-06-02
Obesity is one of the most significant public health challenges of this century. Its global prevalence continues to increase dramatically, particularly among children in the last years. Obesity has been recognised by the World Health Organization (WHO) as a worldwide epidemic, and the European Association for the Study of Diabetes (EASD) has recognised the prevention and treatment of obesity as “the most important public health issue worldwide”. Obesity results in mechanical and psychological problems, however, the major concern it is that has been associated with several chronic diseases such as diabetes, heart disease, high blood pressure, stroke, fatty liver, and cancer, as well as a increased risk of severe illness from COVID-19. Commonly, obesity is caused by excess food intake relative to energy loss via our physical activity and our body metabolic processes. However, the etiology of obesity is multifactorial and extraordinarily complex. Physiological, behavioural and genetic factors play a crucial role in the etiology of this disease. No single cause has been assigned to obesity, so the study of each implicated components is vital for a successful approach against this global problem.
Globally, approximately 1.5 billion adults are overweight, and among them, 200 million men and about 300 million women are obese (data from WHO). Obesity is not just associated with higher mortality or worse life quality, but also has a huge impact on society in terms of healthcare costs linked to the treatment of this pathology and its complications. Although the main option to treat obesity is lifestyle modifications, this result is unsuccessful over the long term; thus, the addition of pharmacotherapy is considered as another approach to treat obesity.
The excess of energy in an organism is accumulated in the form of fat. The optimal maintenance of body weight and fat mass is a complex biological process that depends on the brain´s capacity to receive, integrate, and send a wide range of signals which it must adjust and keep balanced via the peripheral nervous system. Within the peripheral nervous system, the sympathetic nervous system (SNS) is strongly linked to obesity. Thus, several models of obesity have shown low levels of activity in SNS, suggesting that its low activity predisposes to and is associated with obesity. SNS plays a crucial role in the regulation of several metabolic processes in fat, including lipolysis, number of adipocytes and secretion of hormones. However, simultaneously, the SNS is implicated in other essential metabolic processes, including cardiovascular function. The general objective of this project was to better understand the mechanisms that underlie obesity related to the role of the SNS; more specifically, we tried to identify drug targets in SNS neurons innervating exclusively fat, which could be suitable for an anti-obesity therapy avoiding any side effect that could have consequences in key organs.
Globally, approximately 1.5 billion adults are overweight, and among them, 200 million men and about 300 million women are obese (data from WHO). Obesity is not just associated with higher mortality or worse life quality, but also has a huge impact on society in terms of healthcare costs linked to the treatment of this pathology and its complications. Although the main option to treat obesity is lifestyle modifications, this result is unsuccessful over the long term; thus, the addition of pharmacotherapy is considered as another approach to treat obesity.
The excess of energy in an organism is accumulated in the form of fat. The optimal maintenance of body weight and fat mass is a complex biological process that depends on the brain´s capacity to receive, integrate, and send a wide range of signals which it must adjust and keep balanced via the peripheral nervous system. Within the peripheral nervous system, the sympathetic nervous system (SNS) is strongly linked to obesity. Thus, several models of obesity have shown low levels of activity in SNS, suggesting that its low activity predisposes to and is associated with obesity. SNS plays a crucial role in the regulation of several metabolic processes in fat, including lipolysis, number of adipocytes and secretion of hormones. However, simultaneously, the SNS is implicated in other essential metabolic processes, including cardiovascular function. The general objective of this project was to better understand the mechanisms that underlie obesity related to the role of the SNS; more specifically, we tried to identify drug targets in SNS neurons innervating exclusively fat, which could be suitable for an anti-obesity therapy avoiding any side effect that could have consequences in key organs.
The main objective of my proposed action was to identify drug targets in SNS neurons innervating fat which could be suitable for an anti-obesity therapy and would evade serious side effects. To achieve this, we used the technology known as Translational Ribosome Affinity Purification (TRAP). The TRAP method involves transgenic tissue-specific expression of the fusion protein GFP-L10a. In this method, GFP serves an epitope tag that can be used to specifically precipitate polysomes from cells that express it; in our case, cells expressing tyrosine hydroxylase (TH), a sympathetic marker. Using this method, we tried to genetically characterise the sympathetic fibres innervating subcutaneous white adipose tissue. However, several difficulties were encountered during the process: collection of a sufficient number of fibres and their homogenisation (hard tissue) made it a long process such that the integrity of RNA was compromised. The project was readdressed using other technical approaches but working with the same general objective. Thus, we tested the metabolic role in catecholaminergic cells of two different main players in the metabolism of norepinephrine (NE), which is the main sympathetic neurotransmitter. Evaluation of food intake, body weight and glucose metabolism (glucose and insulin tolerance test) were performed. Also, we included NE measurements as well as analysis of thermogenic and lipolytic pathways. One of those targets evaluated provided us exciting results and is still in progress. Thus, ablation of this sympathetic player provokes increases in body weight and decreased glucose and insulin sensitivity without differences in food intake. Our results are promising because they concur with previous results found in humans. Exploitation and dissemination of results was and will be done in the scientific community but also to the general public. Any updates in our findings will be upload to the Domingos’ lab website.
Obesity is a metabolic disorder with unmet medical needs for which pharmacotherapy is urgently required. Direct and targeted activation of sympathetic inputs to adipose tissues could represent a new strategy for the induction of fat loss that would avoid central leptin resistance as well as the challenges of drug delivery across the blood-brain barrier. We discovered two essential players in sympathetic cells that could have repercussions in metabolism and obesity. NE is the principal neurotransmitter of the SNS, therefore manipulations that enhance central and peripheral NE activity are a promising approach for the treatment of obesity. However, we should consider that, although in the past the low activity of the SNS related to obese individuals seemed to be a clear cause, currently the idea of regionally increased sympathetic outflow during obesity is more accurate. This points out the importance of individualisation in the study of sympathetic innervation in each organ specifically and the relevance of our project.