A Surprisingly Large Change in Metabolism in Mice Lacking a Sense of Smell

One of the ongoing offshoots from the mainstream of calorie restriction research is the investigation of the impact of sensing food on the effects of dietary intake and the operation of metabolism. While there is no necessary reason for research into sensing of nutritional cues to be connected to research into reduced calorie intake, this is how things have worked out in practice. It all stems from calorie restriction research projects some years back in which the scientists involved noted that the flies in their studies seemed to undergo short-term changes in metabolism that were independent of the content of the food provided, and even occurred a little in advance of the flies actually undertaking the new, lower calorie diet.

Via further experimentation, this led to the conclusion that scent plays an important role in the regulation of metabolism in this and other lower species. For example it is possible to block the benefits of eating less in flies by providing an environment filled with the scent of greater amounts of food. The neural structures involved appear to listen as much to what is scented of food content as to what is actually consumed. In the past few years, this line of inquiry has moved from lower animals into mice. This is reasonable; the calorie restriction response of improved health and extended healthy life span came into being very early in the evolution of life, and appears to some degree or another in near all species and lineages tested to date, mammals included. So if the basic cellular processes are much the same between all of these species, widely dispersed across the tree of life, why not also the importance of olfactory mechanisms?

So we come to today’s research results, which retain the investigation of scent in metabolic response to diet, but depart from calorie restriction for the other end of the spectrum: high calorie diets and obesity. Normally this isn’t all that interesting as a topic for the audience here, but as a new set of data to take back to current investigations of sensory manipulation of calorie restriction responses, it is worth noting. If nothing else, the size of the effect in mice is certainly very surprising, even given somewhat analogous results in flies and worms. It certainly raises questions as to what similar examinations might find in human regulation of metabolism.

Smelling your food makes you fat

Our sense of smell is key to the enjoyment of food, so it may be no surprise that in experiments, obese mice who lost their sense of smell also lost weight. What’s weird, however, is that these slimmed-down but smell-deficient mice ate the same amount of fatty food as mice that retained their sense of smell and ballooned to twice their normal weight. In addition, mice with a boosted sense of smell – super-smellers – got even fatter on a high-fat diet than did mice with normal smell. The findings suggest that the odor of what we eat may play an important role in how the body deals with calories. If you can’t smell your food, you may burn it rather than store it.

These results point to a key connection between the olfactory or smell system and regions of the brain that regulate metabolism, in particular the hypothalamus, though the neural circuits are still unknown. Mice as well as humans are more sensitive to smells when they are hungry than after they’ve eaten, so perhaps the lack of smell tricks the body into thinking it has already eaten. While searching for food, the body stores calories in case it’s unsuccessful. Once food is secured, the body feels free to burn it.

The smell-deficient mice rapidly burned calories by up-regulating their sympathetic nervous system, which is known to increase fat burning. The mice turned their beige fat cells – the subcutaneous fat storage cells that accumulate around our thighs and midriffs – into brown fat cells, which burn fatty acids to produce heat. Some turned almost all of their beige fat into brown fat, becoming lean, mean burning machines. In these mice, white fat cells – the storage cells that cluster around our internal organs and are associated with poor health outcomes – also shrank in size. The obese mice, which had also developed glucose intolerance – a condition that leads to diabetes – not only lost weight on a high-fat diet, but regained normal glucose tolerance.

The Sense of Smell Impacts Metabolic Health and Obesity

The regulation of whole-body energy homeostasis relies on an intricate balance between food intake and energy expenditure. This balance requires the coordinated response of peripheral and central neuronal inputs including hormones, multiple peptides, and neurotransmitters. In the hypothalamus, the melanocortin system in the arcuate nucleus (ARC) controls feeding in response to circulating insulin and leptin levels. Among the many sensory stimuli that influence behavioral decisions about food choice, olfactory inputs are likely to contribute to the regulation of energy homeostasis. Remarkably, the sensory perception of a hidden food cue, without its ingestion, at least transiently switches the activation state of AgRP and POMC neurons. In mice and other rodents, the hypothalamus receives indirect inputs from olfactory sensory neurons (OSNs) through signals entering from the main olfactory bulb (MOB) and transmitted to the centers of the olfactory cortex. Therefore, olfactory signals may prime the activity of key homeostatic neurons in the hypothalamus to adapt systemic metabolism under conditions of anticipated food intake.

We investigated the role of OSNs in the control of energy balance. To this end, we examined the consequence of genetically ablating the ability of animals to smell, by disrupting OSNs, on whole-body energy homeostasis in lean and obese animals. We find that mice with reduced olfaction, i.e., hyposmia, are leaner upon diet-induced obesity (DIO) either before or after the onset of obesity. These animals exhibit increased energy expenditure and enhanced fat burning capacity as a consequence of enhanced sympathetic nerve activity in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). Conversely, we describe that conditional ablation of the IGF1 receptor in OSNs results in enhanced olfactory perception. Complementing the results observed in the hyposmic animals, these hyperosmic mice have increased adiposity and insulin resistance. Collectively, the results reveal a critical role for olfactory sensory perception in coordinately regulating peripheral metabolism via control of autonomic innervation.

The finding that OSNs can control peripheral metabolism is intriguing, and multiple mechanisms could be engaged in this circuitry. It is mainly thought that the hypothalamus receives indirect inputs from OSNs through the MOB and transmitted to the centers of the olfactory cortex. Interestingly, direct connections between discrete subpopulations of OSNs and several nuclei from the hypothalamus have been observed, reinforcing the idea that an active circuitry initiated in OSNs might influence metabolic homeostasis. Our data strongly indicate a circuit that relays information to autonomic neurons and may require central neurons. In line with this hypothesis, fiber photometry recording of AgRP and POMC neurons activity in the hypothalamus of awake, behaving animals shows that the perception of food rapidly switches the activation state of these neurons upon hunger and can be immediately reversed by removing the food cues. Additionally, olfactory inputs may be integrated by a complex interplay of different hypothalamic and brainstem nuclei expressing appetite-modulatory neuropeptides. Regardless, the potential of modulating olfactory signals in the context of metabolic syndrome or diabetes is attractive. The data presented here show that even relatively short-term loss of smell improves metabolic health and weight loss, despite the negative consequences of being on a high-fat diet.

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