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Delineation of a brain circuit regulating energy expenditure to impact body weight

Periodic Reporting for period 1 - NeuroEE (Delineation of a brain circuit regulating energy expenditure to impact body weight)

Reporting period: 2016-02-01 to 2018-01-31

The World Health Organisation now classifies obesity as a global “epidemic” based on its rapidly increasing prevalence. This presents a major challenge to human health because obesity predisposes to chronic medical illnesses such as diabetes, heart disease and cancer. Though obesity is now incredibly common, it remains very difficult to reverse. The objective of the research in NeuroEE is to examine a new way to treat obesity by increasing energy expenditure. By stimulating energy expenditure, calories that are stored are burned and body weight is reduced. To achieve this, my research targeted a particular brain region that sends signals to a key type of fat called brown adipose tissue that functions as one of the body’s major furnaces that burns energy to keep us warm, Using new technology, I was able to regulate the activity of this essential energy expenditure centre, and by increasing energy expenditure, reduce body weight in experimental subjects. The impact of this discovery is that it may lead to a new type of obesity treatment that could ultimately improve human health on a global scale.
During the first stage of the NeuroEE (2016 Q1) I started my integration into the University of Aberdeen (UoA) and into The Rowett Institute of Nutrition and Health (RINH). I completed the different induction packs necessary to work in the UoA. I also developed my scientific career plan with my supervisor, which was be reviewed every 4 months. In this first stage, I also attended seminars and training courses necessary to develop my research activities, including Health and Safety courses, Diversity courses, Inductions for different facilities and equipment, a Radioactive Training Course and Home Office Licences Courses for animal work.

The second stage of the NeuroEE (2016 Q2) involved the training and evaluation necessary to carry out in vivo experiments with live animals. During this time, I began attending seminars and training to gather scientific public engagement skills. I was also invited to give a presentation in the International Behavioural and Neuronal Genetics Society annual meeting in Maine, USA.

After completing the training objectives, I started the research program. First, I characterized 5-HT producing cells in the brainstem raphe pallidus (RPa-5-HT) under different energy availability states. By means of immunohistochemistry techniques, I found the 5-HT neurons in the RPa changed their activity in response to different energy states. Also during this period, I applied for a small grant to investigate a different neuronal population that may be important and complementary to this project.

The next step in the NeuroEE (2016-Q3 and Q4) was to interrogate specifically RPa-5-HT and its role in energy expenditure. I produced some very interesting results during this period. My experiments showed that RPa-5-HT neurons were required for maintaining an appropriate energy balance during a short period of refed after fasting challenge. I have found that the inhibition of 5-HT RPa neurons activity induces feeding and produces a shift in the overall energy balance increasing body weight. I have presented these results in seminars and revised the research program to update it in light of these results. Also, I attended the British Society of Neuroendocrinology 2016 annual meeting where I met experts and shared my results.

During the last months of 2016 and until the third quarter of 2017, I performed the major bulk of the research program. At the beginning (2017-Q1 and Q2) I performed the chemogenetic interrogations of 5-HT-RPa cells. Specifically, I introduced genetically modified receptors in the 5-HT-RPa cells (via infection with viral particles expressing Designer Receptors Exclusively Activated by Designer Drug) that allowed me to activate and inhibit their overall activity by means of injecting a designer drug. I then interrogated the role of 5-HT-RPa cells in the regulation if the energy balance and thermogenic program in the brown adipose tissue. I found that 5-HT-RPa cells form a key hub of neurons that modulate both energy expenditure and feeding behavior in situations of energy imbalance. I next interrogated the role of these neurons in a chronic model. To achieve this, I genetically block the expression of the gene involved in the production of 5-HT only in the RPa. The results obtained were exciting and revealed a key role of 5-HT-RPa in the regulation of the energy expenditure. Specifically, preventing 5-HT-RPa production increased energy expenditure and reduced body weight. This was directly mediated by the modulation of the thermogenic program in the brown adipose tissue. I presented these results in an invited talk at the prestigious Keystone Symposium in Copenhagen in 2017. Thus, my hypotheses proposed in NeuroEE were supported and I uncovered a new energy expenditure circuit that improves obesity.

Having achieved my primary research objectives, milestones and tasks, I am now working on the write up of these key discoveries for publication. I have also submitted a small grant to continue to build upon the results. My goal now is to obtain funding to establish my own laboratory clarifying how the brain regulates energy expenditure.
Obesity represents a substantial challenge to human health on a global scale. Understanding how an organism uses and stores energy is necessary to design strategies to prevent and palliate this epidemic. NeuroEE has focused on the identification of a particular circuit involved in the energy expenditure. Specifically, how our brain drives the production of heat by mobilization the fat stores. Through the course of these two years, NeuroEE has uncovered a neuronal population that serves as switch in this process. Future analysis will examine how this discovery may be translated to the clinic. As a component of this, I aim to examine several brain nuclei that may function as the initial trigger to this hub and ways that these nuclei may be modulated. The ultimate aim is to discover points along the circuit that may be amenable to pharmacological activation to improve human obesity.