Everyone who has lost weight knows that if you want to lose weight successfully, you need to move your legs more and keep your mouth shut. At the same time, you will also find that keeping your mouth shut is too difficult. What is the reason behind this? Research by the team of Charles S. Zuker from Columbia University and Howard Hughes Medical Institute may solve this mystery for everyone.
As early as 2020, the team discovered that sugar can be connected to the brain through the intestines, thereby stimulating the body's intake of sugar. Although artificial sweeteners can deceive the tongue, they cannot activate this gut-brain axis to satisfy the brain's desire for food. This year, the team further discovered that fat can also activate brain through a specific gut-brain axis, further explaining why long-term excessive intake of high-sugar and high-fat foods can make the body addictive. Blocking this gut-brain axis may provide new treatment ideas for weight loss and certain metabolic diseases. The research results were titled "Gut-Brain Circuits for Fat Preference" and were published in "Nature" on September 7, 2022.
As we all know, both developed and developing countries have experienced an era of massive growth in the consumption of high-sugar and high-fat processed foods . High-sugar and high-fat intake is associated with an increase in malnutrition, including a large number of diseases related to metabolic disorders and overnutrition. Sugar and fat are both essential nutrients, so animals have evolved taste signaling pathways that detect and respond to sugar and fat stimuli, leading to appetite and digestive behaviors. Previous research has shown that mice lacking sweetener receptors can still develop a strong behavioral preference for sugar (sugar preference), suggesting that there are other signaling pathways in the body that drive the body's preference for sugar. Researchers in this article demonstrated in 2020 that sugar preference is mediated by a gut-brain axis that is independent of the taste system. In addition, it was also proven that although artificial sweeteners can activate sugar taste receptors, they cannot activate the gut-brain axis pathway that can sense sugar, and therefore do not produce sugar preference. These findings reveal a postdigestive intestinal sugar-sensitive pathway, a gut-brain axis that drives the body's preference for sugar.
The scientific question in this article focuses on fat preference. It has also been proven that fat, like sugar, uses the gut-brain axis to drive fat consumption. And further dissected the nature of intestinal receptors and how neurons mediate fat preference.
- The development of fat preference
To explore the way fat activates the brain, the research team first let two groups of mice consume artificial sweeteners and fat solutions respectively. At first the mice liked both solutions and even preferred the artificial sweetener, but soon the mice showed a preference for fat. After 48 hours, the mice consumed almost exclusively fat and no artificial sweeteners, indicating that this preference was not dependent on calories. Experiments using mice knocked out of TRPM5 (the channel protein that mediates taste receptor transmission) found that this fat preference is independent of the taste system. (Figure 1)
Figure 1 The development of fat preference
2. Fat preference occurs through the gut-brain axis
For animals to develop fat preference, it must distinguish between 2 different stimuli. The research team concluded that if a population of brain nerve cells that are selective for fat intake can be found, it may be possible to explain this fat preference and the specific biological mechanism of "addiction" to fat. The researchers finally found the neurons that are activated by fat in the mouse brain for this taste-independent fat preference. They are located in the caudal nucleus of the solitary tract (cNST) in the brainstem of . When the researchers blocked these neurons, the mice also lost their preference for fat. (Figure 2)
Figure 2. Fat preference can be mediated by the gut-brain axis
3. Fat and sugar can activate vagus nerve neurons
So how does the intestine transmit fat signals to the brain? In previous studies on sugar preference, the team found that a cluster of vagus nerves between the gut and the brain can transmit sugar signals to the brain.Therefore, in this study, they also cut off the vagus nerve and found that cNST neurons could not be activated, thus indicating that is vagus nerve connecting the intestines and the brain. (Figure 3)
Figure 3. Nutrients participate in intestinal-vagus nerve cck-mediated signal transduction
4. Transmission of sugar and fat in the intestine signaling pathway
So how are sugar/nutrient signals transmitted from the intestine to vagus nerve cells? Researchers identified two parallel pathways that mediate fat preference. One pathway is dependent on cholecystokinin (CCK) signaling and can be activated by all nutrients (sugar, fat, and amino acid ). The other is the Trpa1 (transient receptor potential ankyrin 1) pathway that is independent of CCK and can only be activated by fat. Blocking either of the above two pathways can inhibit the body's preference for fat. (Figure 4) (Figure 5)
Figure 4. VIP vagus neurons mediate sugar/nutrient preference
Figure 5. TRPA1 vagus neurons mediate fat-specific preference
5. Sensors for sugar and fat in the intestine
Previously, the research team discovered that sodium-glucose linked transporter-1 (SGLT1) acts as a gut receptor that recognizes glucose and and transmits signals to the brain. This study found that SGLT1 does not affect fat-stimulated signal input, while GPR40 and GPR120 are essential receptors for fat signal transmission through the gut-brain axis. (Figure 6)
Figure 6. Intestinal GPR40 and GPR120 fat receptors activate the gut-brain axis
This research team elaborated on the difference between the body's "like" and "craving" for sugar and fat. The preference for sweets and fat is the result of activation of the taste system. Craving sweets and fats is the result of gut-brain axis signaling. Back to the beginning of the article, we will find that most of the time we are unable to restrain our "addiction" to sugar and fat, which may be caused by the gut-brain axis signals that mediate "sugar preference" and "fat preference". This discovery could help with weight loss and the treatment of related diseases (such as diabetes and cardiovascular disease, etc.).
Full text link: https://www.nature.com/articles/s41586-022-05266-z
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