Insulin plays a key role in the maturation and regeneration of immature olfactory sensory neurons

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Researchers have known for some time that insulin plays a vital role in regeneration and growth in some types of neurons that relay environmental sensory information to our brains, such as sight. However, they know relatively little about the role of insulin in the sense of smell.

Now, investigators at the Monell Chemical Senses Center have shown that insulin plays a critical role in the maturation, after injury, of immature olfactory sensory neurons (OSNs).

The team published their findings in eNeuro earlier this month.

“Our findings suggest that applying insulin into the nasal passage could be developed as a therapy for injury caused by a host of issues,” said first author Akihito Kuboki, MD, a postdoctoral fellow in the lab of Johannes Reisert, PhD.”

Knowing that insulin is part of the body’s repair pathway for visual neurons, Kuboki suspected that the hormone might also play a role in the maturation of OSNs after injury. He also notes there are many insulin receptors in the olfactory region of the brain. Taking these factors into account, Kuboki concluded that insulin may also be involved in the sense of smell.

“Although scientists don’t yet have a clear idea of how it works, we know that insulin plays a key role in preventing cell death,” said Kuboki. “If insulin levels are reduced, diabetes patients have a high susceptibility to cell death, which can cause smell loss.” He is pursuing this research path to shed light on why people with diabetes often suffer from smell loss, or anosmia.

The research team induced diabetes type 1 in mice to reduce levels of circulating insulin reaching the OSNs. The reduced insulin interfered with the regeneration of OSNs, resulting in an impaired sense of smell. They analyzed how the structure of the olfactory tissue in the nasal cavity and the olfactory bulb is impaired by comparing the number of mature OSNs and how well the axons of OSNs reached the olfactory bulb.

The team also recorded odorant-induced responses in the OSNs in the nasal cavity. An odor-guided behavioral task, in which the mice needed to find a cookie reward depending on their ability to smell, measured olfactory function.

In addition, the team injured OSNs, which have a unique ability to regenerate in mammals. This approach allowed the investigators to ask whether OSNs required insulin to regenerate, which they found to be true.

What’s more, they discovered that OSNs are highly susceptible to insulin deprivation-induced cell death eight to 13 days after an injury.

This time window indicates that during a critical stage newly generated OSNs are dependent on insulin.

They also found that insulin must be applied to regenerating OSNs at this critical time point in the neurons’ growth to be able to restore a mouse’s sense of smell.

This is a diagram from the study
High dependency of new neurons on insulin signaling. Credit: Monell Chemical Senses Center, eNeuro

Also of significance, the team found that insulin promotes regeneration of regenerating OSNs in both type 1 diabetic and nondiabetic mice. “Even in nondiabetic mice, we found that insulin can promote the regeneration of OSNs, which suggests that this could be a therapy for olfactory dysfunction in patients without diabetes,” said Kuboki.

Specifically, the team only examined the OSN regeneration process after injury in type 1-diabetic mice and did not examine the effects of type 2 diabetes, but plan to in the future.

“Our findings suggest that insulin plays important roles when OSNs need to regenerate after severe injury that induces cell death in many OSNs,” said Kuboki. “From this, we hope that an insulin spray can be potentially applied to treat smell loss for various reasons, including head trauma and viral infection.”

Other members of the research team are Ichiro Matsumoto, PhD, from Monell; Nobuyoshi Otori, MD, PhD and Hiromi Kojima, MD, PhD, from Jikei University School of Medicine; and Shu Kikuta, MD, PhD and Tatsuya Yamasoba, MD, PhD, from the University of Tokyo.


The sense of smell impacts food selection behavior. The olfactory system does not only help to identify the chemical composition of food but also serves as an internal sensor for the nutritional status1,2. Recent observations that odor perception even directly impacts central nervous circuitries3,4 and peripheral metabolism5 have clearly emphasized the relevance of the olfactory system for energy homeostasis, but the underlying mechanisms are still poorly understood.

Olfactory neurons interact with central nervous circuitries regulating food intake and energy expenditure6. Interestingly, already the smell of hidden food stimuli activates AgRP and POMC neurons in the hypothalamus3,4 suggesting a strong influence of olfactory inputs on hypothalamic regulation of energy homeostasis.

Olfactory sensitivity, in turn, is dynamically modulated by the nutritional status. Fasting enhances olfactory acuity, while satiation attenuates olfactory performance7–11. In long term, overconsumption of high fat food causes a loss of olfactory sensory neurons, impairs olfactory functioning and alters olfaction driven behavior12,13. However, it remains unclear how odor perception is modulated by global energy homeostasis.

Insulin is a key candidate for mediating this interaction. Secreted after food intake, blood insulin levels dynamically reflect body fuel availability. In fact, the highest density of central insulin receptors and the highest insulin concentration are found on the olfactory bulb14–16.

The transport across the blood brain barrier is higher in this area compared to the rest of the brain17 suggesting direct modulation of olfactory signaling by insulin. Indeed, acute euglycaemic hyperinsulinaemia deteriorates olfactory performance18. A similar effect was observed after intracerebroventricular insulin application in rats19.

Intranasal insulin application in humans, however, provided so far inconsistent results: While decreased olfactory performance was reported in normosmic subjects20, better olfactory sensitivity was demonstrated after intranasal insulin administration in anosmic subjects21 and hyposmic subjects22.

Here, we investigated the role of peripheral insulin sensitivity, intranasal insulin and reactive blood insulin changes after intranasal administration in the regulation of olfactory performance in humans. To consider variability in peripheral insulin sensitivity, we recruited a sample of healthy- and overweight subjects (BMI 20–30 kg/m2).

Given the evidence that insulin sensitivity is a better indicator for the metabolic state than body weight23,24, and that the homeostasis model assessment of insulin resistance (HOMA-IR) is a good proxy for peripheral insulin sensitivity, we hypothesized that poor insulin sensitivity assessed by HOMA-IR will predict poor olfactory performance.

Second, we explored the modulatory effect of central insulin action on olfactory perception through intranasal administration of different doses. Intranasal insulin applications are associated with reactive blood insulin changes25 that might in turn interact with olfactory perception and mask the intranasal insulin effects.

Therefore, we hypothesized that correcting for reactive changes of blood insulin levels will reveal a dose-dependent modulation of olfactory perception by intranasal insulin with stronger effects of higher doses.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510903/


Original Research: Closed access.
Insulin-dependent maturation of newly generated olfactory sensory neurons after injury” by Akihito Kuboki, Shu Kikuta, Nobuyoshi Otori, Hiromi Kojima, Ichiro Matsumoto, Johannes Reisert and Tatsuya Yamasoba. eNeuro

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