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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.

Comments

Hi, interesting study.

Just 2 cent,

I would take this study lightly though (it does not translate to humans),
one study done in centernarians showed taht those who were demented/senile/had more brain problems, oftenly had more 'senses' problems : eyes (vision), nose (olfaction), skin (somatosensation), papilla (gustation), ear (audition), We could have even add another one (telephathics/the third eye 'other dimension'/chakra/brain alpha waves transcendance and 'brain wave' reading in humans/metaphysical 'voyance' (which I know defeats most science and is in the realm of esoterism; just like 'what is there after death?' is)).

The centenarians whom could not smell well (damage to their olfactory bulbs) showed brain/cortex size matter loss; so, in a sense, they were aging faster. It's the same with aged people whom can't 'feel' heat or cold (tactile temperature sensation on skin); if you lose these important sense (in humans) it is Bad sign. It's true that the Nerve/Neural, Neuronal, Endocrinal, Hormonal and IGF/mTOR system is at the cross-road; for mTOR is a fitness improver; as such, it improves these senses and increases fitness (over fragility/frailty). In turn, this means higher IGF levels, which accelerate replicative senescence onset (by increased mTOR levels). IT's not surprising that, here in this study, messing with up with the nerve system, most likely messes up the Neurons responsible for CNS Nerve system (in fact, studies in flies showed that improving neurons responsible for nerve system could Increase Lifespan (and that damaging the nerve system was highly detrimental) - that's because it affected the metabolism - by affecting IGF/mTOR (a form of indirect CR if you will); it would alter the endocrine/hormone levels IGF and thus, mTOR too (and senescnce). Senses (touch, smell, taste, see, hear) are dependent on the nerve system for signal to brain. It makes me think of that experiment they did with 'acupuncture'; they would prick a patient and study why it healed : the needle would 'prick' smack-dab on a nerve and this, activated opiate/brain reward system in brain which cushioned 'pain' (pain relief/analgesic of opiate release like morphine)) When they did not prick 'at the right place'...there was no effect to acupuncture. Smelling does activate IGF/mTOR, for your mouth 'juices/salivating' are flowing and you are 'ready' to 'eat', especially, when it smells 'delicious/eatable'..this, in turn, alters hormones (Leptin (sasiety/full) and Ghrelin (hunger/empty)) - again, altering the hormone IGF axis.

You only need 'puff/whiff' of that 'special tasty' smell - and insulin/IGF levels change because they 'prep' you for eating (this is nutrient 'sensing' in every way possible). Hormones are affected by our senses, and our senses affect our hormones - which, they, affect our aging. Such, as the centenarians, showing that you need to at least 'keep' your senses. the human senses should not have senescence for that can have strong impact on the human (it's not because you don,T hear, smell or feel/touch,. that necessarily, you age faster - but, it's a sign, damage to olfactory bulb or olfactory nerves is a bad sign. I think, I read a while ago, about the ability to 'predict death within 5 years in elderly' from someone's ability to smell/touch (because these are directly linked to brain function). If you are losing your physical senses, it means there is something wrong (most likely) and you may experience oxidative stress inside your organ('s constituents) responsible for that sense. It could mean worse, experiecing nerve damage/brain damage/brain matter loss. SO this study is great but, I have feeling, it is mostly not applicable for humans (the IGF/mTOR is applicable to humans, but humans have different needs/evolutionary goals than mice, hence need their senses for their survival (you can live blind, deaf, unsmelling, untasting and skin non-feeling; but this will be immensely hard to live (on) with for devoid of senses (life be unsensical...sorry I had to do that pun)). Luckily SENS is here to make you feel your SENSES. Ok I rest my case (and my senses).

Posted by: CANanonymity at July 5th, 2017 8:10 PM

@CANanonymity

Interesting comments.
I am reminded that dolphins and the other toothed whales have full olfactory bulbs and tracts but these structures are completely resorbed in adults, along with a much atrophied hippocampus relative to other cerebral mammals like us. My question would be what does the dolphin hypothalamus look like relative to ours, particularly considering the fact that the main output of the hippocampus via the fornix terminates in the mammilary bodies of the hypothalamus and likely provides not just spikes, but nutrient precursors and optimized mitochondria for its many eclectic peptide products which in turn represent honest & reliable signals of metabolic state to the body at large, in particular regarding the elaborate mitochondrial-resident synthesis chains of various steroid hormones, popularly reflected in the so-called 'handicap principle'

Regarding the POMC transfactor factor neurons in the nutrient-active hypothalamus there was just some interesting research published in GeroScience on https://link.springer.com/article/10.1007/s11357-017-9976-8
on the 'Role of DNA methylation in the dietary restriction mediated cellular memory ' which purports to show that early exposure to caloric restriction is associated with methylation and transcription factor changes that persist long after the caloric restriction is relaxed.

Posted by: john hewitt at July 6th, 2017 7:16 AM

Hi John !

Great comments you bring.

I don't know either, but from these studies and looking at dolphin brain pics or other whales or 'dolphinidae' (that are not whales but dolphin descendants), it seems that they have comparable compartments but with visible structural differences. This is akin to Killer Whales/Orcas whom, like dolphins, display extreme intelligence and very deep 'emotional behaviors'; and they have language like us (they communicate via sound screams, and detect surroundings (echolocation) brain sonar waves emitting/rebounding; just like bats do for they are blind and rely on their echolocation to pinpoint flying prey. These 'sensing' systems are ancient and in these animals.). The limbic hippocampus is mostly responsible for Memory recollection, storing & handling (Damage to the hippocampus creates amnesia). I have doubts that dolphins, or Especially Killer Whales/Orcas, forget anything; if anything, Killer Whales are the most Unforgetting of animal - just like elephants; they can remeber your face 50 years later. They remeber exactly the 'sounds' of 'their family' and can detect 'foreign' ones. They have language (screams and whale's 'wail/wailing)' that defies human language; one scream could be an entire 'paragrah's' worth of human language. In humans, hippocampus has far more use but in these whales/dolphins less so, my guess/take is that the many brain structures made their brains evolve for rapid 'singy-songy' wails/talking, rapid 'echolocation' (which we don't have), reduced eye vision (dolphins and killer whales, humpback whales tiny eyes...bad vision, that's because they live 'in the dark/under water, no need for vision but for echolocation (sound/wave/hearing detection/3D spatial detection/they may even share 'GPS' compass like quality of pigeons' brains or other birds whom have spatial-positional memory) and smell (sharks developped immense smelling power/they can smell a drop of blood a mile away in water; while whales can 'hear' whale screams wails from a mile too in water'. So different turns of event, it may be that sharks' ampullae of Lorenzini replaced the job of the olfactory bulb seen in mammals (one mammal that intrigues me is the Bowhead whale, its brain must be quite something for it is a mammal and is a whale; its brain would tell us more of why we have the configuration we do and why dolphins don't).

''Role of DNA methylation in the dietary restriction mediated cellular memory''
Thanks for that, I'm not surprised, DNA methylation is an epigenetic controler for methyl count affects the whole epigenome; this means there is 'signature' from this early CR exposure that lasts after CR is ended. Methyl changes can strongly impact the genetic and our body relies on the levels of Global DNA methylation (which reduce with age); while certain genes become hypermethylated (mostly the tumor suppressor ones (p53..)). CpG rich islands or CpG non-rich islands changes have a deep lasting effect - later on life. It's not just 'damage repair' it's also '(epi)genetic' programming/transcription/methylation/demethylation and so forth. Sometimes I think it will be very hard to make humans go over the 'recorded so far' MLSP (122 years maximum lifespan extension) because CR acts on So Many genes and variables - yet does very little (in terms of lifespan extension, but improves health). And, some centenarians already have a form of hormesis and 'CR' in them (they found SNPs and FOXO genes (SIRT/FOXO3A/IGF) insulin variants in them, that create 'jackpot' 'CR' in them to live longer than others) - as such, doing CR for them would be futile because their body is already in a 'sort of' CR mode.

[Structure of the mammillary bodies of the hypothalamus of the bottlenosed dolphin]
1. https://www.ncbi.nlm.nih.gov/pubmed/3924008

[Myeloarchitectonics of the hypothalamic mammillary bodies in the bottle-nosed dolphin]
2. https://www.ncbi.nlm.nih.gov/pubmed/6201154

Posted by: CANanonymity at July 8th, 2017 3:51 PM

PS :

''Our values reflect the inverse relationship between brain size and neuron density. Thus, the dolphin shows approximately 13,000 neurons/mm3 in its limbic cortex, compared to 12,000 in the beluga whale and 8,000 in the humpback whale. Further, the data provide the first quantitative accounts on a layer by layer basis of the limbic cortices in the whale brain. In the dolphin, the anterior limbic cortices have a much lower cell density than the posterior limbic area. However, in the humpback whale these two cortices have similar neuron densities.''

"Long-finned pilot whale
37,200,000,000 neurons vs 21,000,000 neurons (human)
Globicephala melas: "For the first time, we show that a species of dolphin has more neocortical neurons than any mammal studied to date including humans."

A whale dolphin called Long-finned pilot whale (dolphin) has the most neuron of All Existing Animals, nearly 2X double the amount of neurons in humans (humans being the 2nd most neuron-rich animal); this means 2x more available for 'sensing'. If sharks can smell, whales can hear, dolphins can talk/sing, etc - it means that no problem, their hippocampus lackthereof is just being replaced by another system. Elephants have 5 billion neurons, and this whale dolphin has 40 billion ones; Safe to say that its memory recollection would be probably even stronger and much closer to a human's (which have 20 billion neurons. The False Killer Whale has 10 billion ones and is a delphinadae (dolphin) subspecie - same thing for its cousin the Killer Whale/Orca, also a dolphin (though called a 'Whale') of the delphinadae tree; most likely has a bout 10 billion neuron too; and has great memory capacity even so (it seems when you hit the 1 billion neuron memory is strong enough for sufficient memory (mice have 400,).

The anatomy of the brain of the bottlenose dolphin (Tursiops truncatus). Rhinic lobe (Rhinencephalon): The archicortex.
3. https://www.ncbi.nlm.nih.gov/pubmed/551842

4. https://en.wikipedia.org/wiki/List_of_animals_by_number_of_neurons

The limbic lobe of the dolphin brain: a quantitative cytoarchitectonic study.
5. https://www.ncbi.nlm.nih.gov/pubmed/7161482

The insular formations of the dolphin brain: quantitative cytoarchitectonic studies of the insular component of the limbic lobe.
6. https://www.ncbi.nlm.nih.gov/pubmed/6725651

Posted by: CANanonymity at July 8th, 2017 4:18 PM

PPS:

The Fin whale is a marine mammal; as such a good surogate of the Bowhead whale mammal (too). The Fin whale has 15 Billion cortex neurons, while humans 21 Billion - and Long-finned pilot whale (a dolphin) has 37 Billion ones; that tells me that there was restructuring depeding on the habitat, environment (temperature), energy needs (nutrient sensing), and that if a bowhead whale can live 211 years (MLSP), and a Fin whale can live (150 years MLSP, though some might reach 211 like Bowheads too - they are mammal whale cousins) and human can live 122 years; then, neuron count is important for longevity (such as one study found a positive correlation between levels of Neuregulin-1 NRG-1 and MLSP in animals; neuronally-rich brains could allow more NRG)); the olfactory bulb might not be so important for longevity after all (since the longevity is only from the mechanistic 'consequences' on the metabolism from it); other senses could be helpful or detrimental to lifespan - depending on the Neurons to which they connect with. Having more neurons could also affect that (seen with these species). Anyways, I'm straying off the 'beaten' watery path, but it seems in humans olfaction and memory are far more important- and needed to be kept; dementia and alzheimer's are precursors od losing your senses (dementia, lack of smell, lack of feel touch, lack of taste, vision loss and so forth - humans like African Elephants - *Feel* and need their 100+ billion neurons for that; alzheimer's/dementia/brain gray/white matter loss is in correlation to that and appearance of brain degenerescence/brain death).

Just a 2 cent.

Posted by: CANanonymity at July 8th, 2017 4:37 PM

Never thanked you for the links CANanonymity,
thanks

To understand why dolphin has thin high speed cortex think sonar processing

Posted by: john hewitt at August 18th, 2017 11:23 AM

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