Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism

Abstract

Growing evidence highlights a complex interaction between olfaction and metabolism with impaired olfactory function observed in obesity and increased olfactory sensitivity during hunger. The mechanisms linking metabolic state and olfaction remain unknown, but increased accessibility of hormones, such as ghrelin, and the diverse expression of hormone receptors such as those for ghrelin (GHSRs) in the olfactory system suggests an underappreciated neuroendocrine role. Here, we examined the hypothesis that GHSRs in the olfactory bulb (OB) link hunger with olfactory sensitivity to influence foraging behaviours and metabolism. Selective deletion of OBGHSRs in adult male mice was achieved with adeno-associated viral expression of cre-recombinase in the OB of floxed-Ghsr mice. OBGHSR deletion significantly affected olfactory discrimination and habituation to both food and pheromone odours, with greatest effect under fasted conditions. Anxiety-like and depression-like behaviour was significantly greater after OBGHSR deletion using 3 independent anxiety behavioural tasks and testing for anhedonia, whereas exploratory behaviour was reduced. No effect on spatial navigation and memory was observed. Although OBGHSR deletion did not affect cumulative food intake, it significantly impacted feeding behaviour as evidenced by altered bout number and duration. Moreover, food-finding after fasting or ip ghrelin was attenuated. Intriguingly, OBGHSR deletion caused an increase in body weight and fat mass, spared fat utilisation on a chow diet and impaired glucose metabolism indicating metabolic dysfunction. We conclude that OBGHSRs maintain olfactory sensitivity, particularly during hunger, and facilitate behavioural adaptations that optimise food-seeking in anxiogenic environments, priming metabolic pathways in preparation for food consumption.

The olfactory bulb: A neuroendocrine spotlight on feeding and metabolism

“…Since hunger and high levels of ghrelin increase olfactory sensitivity, 49 we recently examined whether ghrelin links hunger with olfaction and the implications of disrupting this feedback on food intake, metabolism and related foraging behaviours. 112 To investigate the behavioural and metabolic actions of GHSRs in the OB (OB GHSR ), we deleted OB GHSR in adult mice and discovered OB GHSR deletion decreased olfactory sensitivity to food and non-food odours in various olfactory performance tasks. Although daily total food intake or ghrelin-induced food intake were not different, OB GHSR deletion altered feeding behaviour with mice displaying decreased number of feeding bouts in the dark phase, anhedonia, impaired food finding, and exploratory behaviour.…”

“…[237][238][239] Transgenic mice with increased olfactory sensitivity are resistant to weight gain when placed on high-fat diet (HFD), 239 whereas impairing olfactory sensitivity predisposes to weight gain and obesity. 112,240,241 One mechanistic possibility argues that an impaired sense of smell delays the immediate sensory processing of food and thus delays satiety processing, resulting in overconsumption and ultimately weight increase. 209 Of note, despite lower olfactory performance in obesity, obese individuals show an increased preference for odours associated with palatable energy-dense foods, 242 with enhanced activation of reward regions.…”

“…GHSRs are expressed throughout the CNS with significant research focusing on neuronal populations in the hypothalamus, midbrain and hindbrain 110 . However, there is also significant expression in the OB 111,112 in the glomerular, mitral and granule cell layer 49,113–115 . Ghrelin is transported through the BBB and has a high uptake into the OB 116,117 where it is linked to increase olfactory performance and exploratory sniffing behaviour in rats and humans 49 .…”

“…This could be driven by the effects of ghrelin on the OB. Since hunger and high levels of ghrelin increase olfactory sensitivity, 49 we recently examined whether ghrelin links hunger with olfaction and the implications of disrupting this feedback on food intake, metabolism and related foraging behaviours 112 . To investigate the behavioural and metabolic actions of GHSRs in the OB (OB GHSR ), we deleted OB GHSR in adult mice and discovered OB GHSR deletion decreased olfactory sensitivity to food and non‐food odours in various olfactory performance tasks.…”

“…And food odours have been shown to trigger metabolic responses, such as increase of appetite, salivation and the release of digestive enzymes, thus preparing the body for the incoming meal. This interaction between energy metabolism and olfactory perception appears to work both ways, as hunger signals released during fasting (orexigenic hormones) increase olfactory function, potentially aiding in food location, 97,112 and AgRP activity increases preference for food odours over pheromone odours 214 . Recent research has unveiled that both AgRP and POMC neurons receive indirect inputs from overlapping regions within the olfactory cortex, pinpointing the origins of odour‐related signals 215 .…”