Gut-derived signals regulate metabolism, appetite, and behaviors important for mental health. We have performed a large-scale multidimensional screen to identify gut hormones and nutrient-sensing mechanisms in the intestine that regulate metabolism and behavior in the fruit fly Drosophila. We identified several gut hormones that affect fecundity, stress responses, metabolism, feeding, and sleep behaviors, many of which seem to act sex-specifically. We show that in response to nutrient intake, the enteroendocrine cells (EECs) of the adult Drosophila midgut release hormones that act via inter-organ relays to coordinate metabolism and feeding decisions. These findings suggest that crosstalk between the gut and other tissues regulates food choice according to metabolic needs, providing insight into how that intestine processes nutritional inputs and into the gut-derived signals that relay information regulating nutrient-specific hungers to maintain metabolic homeostasis.

It is clear that the cause of obesity is a result of eating more than you burn. It is physics. What is more complex to answer is why some people eat more than others? Differences in our genetic make-up mean some of us are slightly more hungry all the time and so eat more than others. We now know that the genetics of body-weight, on which obesity sits on one end of the spectrum, is in actuality the genetics of appetite control. In contrast to the prevailing view, body-weight is not a choice. People who are obese are not bad or lazy; rather, they are fighting their biology.

Spatial neglect is a syndrome that is most frequently associated with damage to the right hemisphere, although damage to the left hemisphere can also result in signs of spatial neglect. It is characterised by absent or deficient awareness of the contralesional side of space. The screening and diagnosis of spatial neglect lacks a universal gold standard, but is usually achieved by using various modes of assessment. Spatial neglect is also difficult to treat, although prism adaptation training (PAT) has in the past reportedly showed some promise. This seminar will include highlights from a series of studies designed to identify knowledge gaps, and will suggest ways in which these can be bridged. The first study was conducted to identify and quantify clinicians’ use of assessment tools for spatial neglect, finding that several different tools are in use, but that there is an emerging consensus and appetite for harmonisation. The second study included PAT, and sought to uncover whether PAT can improve engagement in recommended therapy in order to improve the outcomes of stroke survivors with spatial neglect. The final study, a systematic review and meta-analysis, sought to investigate the scientific efficacy (rather than clinical effectiveness) of PAT, identifying several knowledge gaps in the existing literature and a need for a new approach in the study of PAT in the clinical setting.

Obesity and neurodegeneration lead to millions of premature deaths each year and lack broadly effective treatments. Obesity is largely caused by the abnormal function of cell populations in the hypothalamus that regulate appetite. We have developed methods generate human hypothalamic neurons from hPSCs to study how they respond to nutrients and hormones (e.g. leptin) and how disease-associated mutations alter their function. Since human hypothalamic neurons can be produced in large numbers, are functionally responsive, have a human genome that can be readily edited, and are in culture environment that can be readily controlled, there is an unprecedented opportunity to study the genetic and environmental factors underlying obesity. In addition, we are fascinated by the fact that mid-life obesity is a risk factor for dementia later in life, and caloric restriction, exercise, and certain anti-obesity drugs are neuroprotective, suggesting that there are shared mechanisms between obesity and neurodegeneration. Studies of HPSC-derived hypothalamic neurons may help bridge the mechanistic gulf between human genetic data and organismic phenotypes, revealing new therapeutic targets. ​

Reducing protein intake (and that of key amino acids) extends lifespan, especially during mid-life and early late-life. Yet, due to a powerful protein appetite, reducing protein in the diet leads to increased food intake, promoting obesity – which shortens lifespan. That is the protein paradox. In the talk I will bring together pieces of the jigsaw, including: specific nutrient appetites, protein leverage, macronutrient interactions on appetite and ageing, the role of branched-chain amino acids and FGF-21, and then I will conclude by showing how these pieces fit together and play out in the modern industrialised food environment to result in the global pandemic of obesity and metabolic disease.