Brainstem GABA neurons orchestrate feeding and body weight

The average person living in the UK today is overweight or obese. The reason this is important is because poor diet and excess body fat commonly have a detrimental impact on health. Obesity increases the risk of developing multiple diseases and dying from COVID-19. Obesity also shortens lifespan by nearly a decade, and costs the UK £5.8 billion every year in medical fees. The primary cause of excess body weight is the consumption of more food than the body requires, calories that are then stored in fat. The focus of this application is clarifying the biology behind food choice (why do we prefer cake to cabbage?), meal size and increasing body fat. Another focus of this research is understanding why it can be difficult to lose weight over the long term through dieting. Hunger is commonly the reason it can be difficult to stick to a diet or to keep the weight off. Here we examine a new way to suppress or diminish hunger to help promote long term weight loss. Our focus is on the brain because it is the master coordinator of hunger, employing discrete interwoven circuits to continually appraise and respond to changes in energy availability taken in from food. A principal intersection within this network is the part of the brain called the nucleus of the solitary tract (NTS). Digested nutrients from food in the bloodstream, hormones from our organs and other signals converge within the NTS to inform the brain about our energy status. The NTS integrates this information and forwards a decision to other parts of the brain that control hunger and fullness that then prompt our behaviour (e.g. feel hungry and find food or feel full and stop eating). However, discoveries in this direction have been hindered by a lack of precise tools to understand how hunger, appetite and body weight are controlled. Recent technological advances now provide a means to overcome this obstacle, affording a way to discover how the brain works to monitor energy levels (low or high) to then instruct behaviour (to eat or not to eat), which influences body weight. We can now uncover the location of the chemicals made by the brain that influence our decisions about which foods we choose to eat, how much food we eat and whether these calories are then used or stored in body fat. We think that a chemical called GABA, which our brain makes to typically turn other cells off, works to turn off hunger. Specifically, we believe that GABA made in the NTS receives information from the body when we are eating food and then transmits this information to remove the feeling of hunger so we stop eating. Our initial work on GABA in the NTS supports this idea. Using a combination of state of the art techniques, we will test the function of this specific source of GABA in hunger and body fat in the proposed research programme. This work is important because we believe we have found an essential way that the brain controls hunger, food choice and body weight. We anticipate that these studies will provide fundamental insight into the biological underpinnings of appetite, food choice, body weight and body fat, findings relevant to the prevention and treatment of obesity.

Obesity is now one of the key challenges facing human health. The national prevalence of obesity emphasises the need for a greater understanding of the physiological mechanisms underlying hunger, feeding behaviour and body fat accrual. On the basis of our preliminary data, we hypothesise the GABA subpopulation of neurons within the brainstem nucleus of the solitary tract (NTS) sense and respond to the ingestion of food to control hunger. Further, we hypothesise that GABA NTS neuron responsiveness to feeding is diminished with obesity, permitting the over-consumption of food. We will test this hypothesis using in vivo fibre photometry to perform the first live recordings of GABA NTS neuron activity in mice as they respond to hunger and food stimuli while lean, obese and following the reversal of obesity. We will also undertake the first targeted manipulation of GABA NTS neuron activity to determine whether activating these neurons treats obesity by decreasing hunger, food intake and body weight, whereas preventing GABA NTS production promotes obesity by increasing hunger, food intake and body weight. We will examine the brain circuit through which these effects are achieved by stimulating or inhibiting GABA NTS release specifically within the homeostatic brain region the arcuate nucleus of the hypothalamus (ARC) and monitoring subsequent behaviour and the activity of hunger neurons. These studies have the potential to clarify a new circuit through which the brain controls hunger, feeding (food choice and meal size) and body weight/body fat. Thereby, this programme of research will offer important insight into the discrete neuronal circuits governing hunger, ingestive behaviour, food choice, body weight and body fat accumulation. Given the pervasiveness of obesity within the global community and the resulting socio-medical ramifications, deciphering the neuronal circuits governing the physiological control of ingestive behaviour and body fat is essential.