The Scent of Appetite: Unlocking the Power of Olfaction on Eating Behaviours.

Dysfunctional feeding behaviour encompasses energy overconsumption (obesity, binge eating) to malnutrition (unhealthy food choices, excessive dieting, anorexia nervosa) and presents significant public health challenges worldwide. Despite numerous social, educational and policy approaches to address disordered eating and pathophysiological consequences, it continues to rise. One key reason for this is an incomplete understanding of the neurobiological mechanisms involved. Indeed, genome-wide association studies (GWAS) have revealed that many genetic variants associated with body weight, appetite and eating behaviour are highly expressed in the brain, highlighting the pivotal role of the brain in controlling metabolism. Thus, there is an urgent need to elucidate the brain mechanisms regulating food intake, feeding behaviours, and ultimately body weight to develop novel treatments for pathological eating habits.Traditionally, research has focused on hypothalamic neural circuits regulating energy homeostasis, yet these efforts have yielded limited pharmacological targets. Indeed, food consumption in humans is not only driven by homeostatic signals but also by sensory environmental cues of food availability and palatability, suggesting an important, yet unexplored, integration of sensory information with hypothalamic feeding circuits. Amongst the different sensory modalities, the sense of smell (olfaction) is the first to detect and categorize environmental cues, often in the absence of accompanying senses such as sight or touch. Olfaction can exert subliminal metabolic effects such as salivation, gastric acid secretion and motivated food-seeking behaviours in response to the sudden whiff of freshly baked bread. Therefore, it is not surprising that various metabolic disorders, such as obesity, malnutrition, or anorexia exhibit altered olfactory function and feeding habits1. Although studies highlight a link between olfaction and feeding, the precise causal mechanisms by which olfaction regulates appetite, motivation and metabolism remain elusive. Therefore, our proposal investigates how olfactory cues modulate hypothalamic hunger (Agouti-protein related peptide; AgRP) and satiety (Pro-opiomelanocortin; POMC) neurons. The impact of olfaction on feeding behaviours and metabolic health has the potential to inform therapeutic strategies for multiple metabolic conditions with dysfunctional feeding behaviour. Question: Does olfaction regulate hypothalamic feeding circuits to control body weight? AIMS: 1.Does impaired or enhanced olfactory function affect AgRP and POMC activity? 2.Does impaired or enhanced olfactory functionaffect AgRP and POMC function? 3.Does impaired or enhanced olfactory functionaffect body weight in an AgRP or POMCdependent manner?