Pei-Yin Shih – Columbia University Postdoc Society Blog

Thanksgiving is just around the corner. The buttery sweet potato casserole, mashed potatoes, and gravy on the Thanksgiving dinner table are delicious and irresistible for most of us. Though fat from buttery food provides important building blocks for our body, overconsumption of fatty food could lead to weight gain and obesity-related diseases such as cardiovascular disease. To help keep our health in check, we need a better understanding of how fat consumption changes our desire for fatty food. A recent study led by Dr. Mengtong Li in the laboratory of Dr. Charles Zuker at the Zuckerman Mind Brain and Behavior Institute at Columbia University has started to reveal some insights.

Previously the research team discovered how sugar preference was established. They found that among the two ways of processing the intake of sugar, taste and gut pathways, the preference for sugar arises from gut and is independent of taste. In line with this finding, the authors discovered that artificial sweeteners do not create a preference because they activate only taste receptors but not the gut pathway.

Built upon what they have learned from sugar preference, the authors first tested if mice have taste-independent preference for fat as well. They gave the mice a choice between oily water and water with artificial sweetener, and they recorded the number of times that the mice licked either of the water bottles as a measurement for preference. They found that the mice predominantly drank from the bottle with oily water two days after exposure to the two choices. Even when the authors directly delivered fat to the gut through surgery, or in mice that did not have taste receptors, the mice could still develop preference for fat. These observations suggested that mice could develop preference for fat through the gut pathway.

Figure 1. The gut-brain axis transfers information of fat intake from the gut to the brain. The orange arrow represents the direction of the information flow. The orange and red dots indicate the activation of the vagus nerve and cNST, respectively. The blue dots represent the hormone cholecystokinin (CCK). The figure was generated using BioRender.

How does the information of fat get transferred to the brain, along the so-called gut-brain axis, and make the mice want fat more than sugar? The authors traced the signals of fat stimuli from gut to brain (Figure 1) through pharmacological and genetic tools. They identified two receptors, G protein-coupled receptors GPR40 and GPR120, that function as fat detectors in the gut. Upon detecting the presence of fat, the gut then releases signaling molecules, including a satiety hormone cholecystokinin, to relay the information to the vagus nerve. Interestingly, while control mice do not have a preference for cherry- versus grape-flavored solutions, the authors were able to create a new preference in experimental mice by artificially activating the subset of vagal neurons that receive cholecystokinin signals from the gut. The vagus nerve travels from gut to brain, and eventually sends the fat signals to the brain region called the caudal nucleus of the solitary tract (cNST) in the brainstem.

Together, the identification of the gut-brain communication might help battle against overindulging in fatty foods. As stress eating could increase the consumption of high calorie foods, it would also be interesting to study how the gut-brain communication is modulated by different emotional states.

Edited by: Maaike Schilperoort, Trang Nguyen, Sam Rossano

The coronavirus SARS-CoV-2 has led to more than six million confirmed deaths worldwide to date throughout the course of the COVID-19 pandemic. While SARS-CoV-2 enters the body through the respiratory system into the lungs, it can also induce damage in other organs. For instance, the sense of smell, which is mediated by the olfactory sensory neurons in our nose along with our brain, is lost in some COVID patients. How this virus affects our ability to smell is a puzzling question, and one that has been investigated by a team led by Dr. Zazhytska in the Lomvardas lab at Columbia University. They have tirelessly worked on solving this puzzle throughout the COVID shutdown period, and their discoveries, which have recently been published in the journal Cell, have started to provide some key answers.

We can smell the scents around us because the olfactory receptors in our olfactory sensory neurons bind to odorant molecules, relay the information through signaling molecules, and eventually signal to our brain (Figure 1). Dr. Zazhytska and her colleagues found that SARS-CoV-2 was rarely detected in the olfactory sensory neurons themselves, indicating that the virus probably doesn’t gain access to our brain through these sensory neurons. In fact, the most commonly infected cells are the neighboring sustentacular cells (Figure 1b), which are important in maintaining the health of the layer of olfactory cells, including the neurons. If the sustentacular cells die, the sensory neurons can be exposed to a stressful environment without support. Thus, the shutdown of the olfactory system might be an indirect effect of SARS-CoV-2 infection.

Figure 1 The basic structure of the olfactory system.
(A) Signal transduction in olfactory sensory neurons. The cell membrane separates the interior of the cell (cell cytoplasm, bottom) from the outside environment (top).
(B) Anatomy of cells in the nose that are involved in smell perception.
(Figure was made using BioRender).

There are about four hundred olfactory receptor genes scattered across our genome, and each neuron only expresses one of them. This stringent setup is achieved by interactions between multiple chromosomes that bring all the dispersed olfactory receptor genes together and form a cluster in the nucleus of the neuron. This cluster arrangement of olfactory receptor genes allows the gene expression machinery to access and turn on only one receptor at a time. Remarkably, Dr. Zazhytska and her colleagues discovered that this organization is disrupted dramatically after SARS-CoV-2 infection in both hamsters and humans. Infected individuals also show reduced expression of not only receptor genes, but also key molecules that are involved in smell perception, likely as consequences of the disrupted organization.

Interestingly, when the team of scientists exposed uninfected hamsters to UV-treated serum from SARS-CoV-2 infected hamsters, which no longer contain virus, they still observed this same disorganization of olfactory receptor genes in the animals. This observation suggests that not the virus itself but some other circulating molecule(s) trigger the abnormal organization. Identifying these molecules may provide potential treatments for COVID-induced loss of smell, as well as other diseases that can affect our olfaction, including early onset Alzheimer’s disease.

Edited by: Sam Rossano, Eric Smith, James Lee, Trang Nguyen, Maaike Schilperoort

Author: Pei-Yin Shih

How our gut communicates with our brain to drive a preference for fat

Making sense of COVID-induced loss of smell

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