Examining the biological mechanisms that underlie the drive to eat in humans

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RESEARCH CONTEXT: A major weakness in our current understanding of human appetite is the inability to adequately explain the biological mechanisms underpinning the drive to eat. This drive is perceived as hunger and understanding the biological origins of hunger is fundamental to the management of appetite during under-and-over-nutrition, ageing, and diseases where appetite is impaired. Current scientific approaches focus almost exclusively on feedback signals from adipose tissue (fat) and the gastrointestinal tract (stomach and intestine) when attempting to explain the biological control of appetite. However, these approaches account for the suppression of appetite following meal consumption (e.g., feelings of fullness and satiety) rather than the signals that drive eating. I have recently provided novel evidence that the metabolic activity of fat-free mass (FFM) creates a drive to eat in humans to ensures the energy needs of key tissues and organs are met. However, the signals linking FFM to hunger are unknown and I will use this fellowship to identify these. By positioning FFM as key feature of appetite, my research also provides new opportunities to understand how changes in appetite oppose weight loss. Increased hunger and food intake during energy restriction are one of the key reasons why individuals struggle to achieve and maintain weight loss. However, these changes in hunger are inconsistent; some individuals report increased hunger while others show no change or a decrease in hunger. At present, we cannot adequately explain why. There has been little attempt to date to examine how losses of FFM during weight loss, which occur alongside losses of fat, influence weight-induced changes in appetite. By establishing how and why FFM loss promotes increased appetite and food intake following weight loss, I will provide new understanding of why people fail to maintain weight loss and facilitate the design of novel strategies that counter these changes in appetite. AIMS: My fellowship will develop a new biological model of human appetite that incorporates FFM and its associated energetic demands as determinants of hunger. I will apply this model to conditions of weight loss to explain how changes in appetite act to resist weight loss. To achieve this, I will:1. Conduct a weight loss study in adults with obesity that includes detailed laboratory measures of body composition, energy expenditure and appetite alongside free-living measures of appetite, food intake, energy expenditure derived using wearable wrist-worn activity monitors (Fitbits) and weekly body weights (Bluetooth scales).2. Examine FFM as novel determinant of the drive to eat when individuals are weight stable (i.e., in energy balance) and following weight loss using objective measures of food intake under laboratory and free-living environments.3. Identify the signals linking FFM to hunger and food intake.APPLICATIONS & BENEFITS: By targeting the mechanisms that drive rather than suppress hunger, my fellowship will provide novel insight into the factors that influence appetite in health and disease. Examining these mechanisms during weight loss will provide fundamental insight into how changes in appetite oppose weight loss, facilitating the design of targeted interventions that counter these changes. Quantifying changes in free-living food intake and energy expenditure during weight loss will identify optimal timings for nutritional or behavioural support to better inform nutritional and public health guidelines. By identifying the signals linking FFM to food intake, I will provide important new insight with clinical relevance for those interested in conditions characterised by appetite impairment (ageing, cancers, diabetes). This will also provide opportunities for pharmacological industries interested in body weight control by identifying novel targets that block the specific mechanisms underlying the drive to eat.