No wonder it's so hard to lose weight! "Nature" new discovery: addicted to sugar and fat, the intestines and brain have to "carry the pot"

▎ WuXi AppTec content team editor

The craving for sugar and oil has penetrated deeply into our brains, guiding our definition of food, and indirectly leading to the prevalence
of metabolic diseases such as diabetes and obesity.

Why is it so difficult for our brains to resist the temptation of high-sugar and high-fat foods?
The answer to this question lies in the neural pathways that activate the brain with these foods
.

In 2020, Professor Charles Zuker's team at Columbia University published an article in the journal Nature, revealing the pathways by which sugar molecules activate the brain: sugar can connect with the brain through the intestine, thereby stimulating sugar uptake
.

Conversely, sugar substitutes (artificial sweeteners) can trick the tongue but fail to activate the pathway and satisfy the brain
.

(Read more: No wonder sugar-free coke has no soul!) This Nature study gives us a new understanding of sweetness)
Just today, the work of Professor Zuker's team is once again in the journal
Nature.

This time, the study found that the gut-brain axis directly feels not only sugar molecules, but also fat
.

To explore how fat activates the brain, the team first had two groups of mice ingest a sugar substitute solution and a fat solution
, respectively.

Initially, the mice were very fond of both solutions and would even prefer sweet sugar
substitutes.

But soon, there was a noticeable shift in the mice's preferences: 48 hours after the experiment began, the mice consumed almost only fat and lost interest in sugar substitutes
.
Mice developed a preference
for fat.

Over time, they gradually abandon sugar substitutes and choose fat solutions (Image: Reference[1])
The 2020 study has revealed that sugar substitutes cannot activate the brain, and therefore cannot produce sustained cravings
in the brain.

The mice's abiding interest in fat seems to suggest that, like sugar molecules, fat can directly activate the brain
through some channel.
Subsequent experiments further confirmed this conjecture
.

The team knocked out the trpm5 gene, at which point the mice lost the taste receptor TRPM5 protein and were unable to feel fat
in their mouths.

As a result, although these "taste-deprived" mice were initially not interested in fat, they continued to consume fat
after 48 hours.
Li Mengtong, the first author of the latest paper and a postdoctoral fellow in Zuker's laboratory, said: "When we ingest foods containing sugar or fat, we first have to pass through the mouth and tongue, where taste allows us to perceive the delicious taste of food and like food
.

But the post-feeding mechanism of the brain-gut axis causes us to develop an unmet craving for food and want to get more
.
Next, the team found fat-activated neurons in mouse brains that are located in the caudal nucleus of the solitary tract (cNST) of the brainstem
.

When the researchers blocked these neurons, the mice's preference for fat was
also lost.
The next step for the team is to find pathways
to deliver signals to cNST neurons.

In previous studies of sugar molecules, Professor Zuker's team found that a cluster of vagus nerves (the main nerves between the gut and the brain) can transmit signals of sugar to the brain
.

In the latest study, when the research team cut off the vagus nerve, the cNST neurons could not be activated, indicating that it was the vagus nerve that connected the intestine to the brain
.
▲ The green fluorescent marker in the picture is the fat-feeling cells in the vagus ganglia, which transmit signals from the intestine to the brain
through the brain-intestine axis.

(Image source: Li Mengtong/Zuker Lab/Zuckerman Institute of Columbia University)
Sugar and fat are both activated by the vagus nerve, so is there a difference in the specific pathways between the two? Next, the research team conducted a comparative study and identified two parallel pathways
.

"One pathway is activated by all nutrients ,including sugars, fats, and amino acids; the other is activated only by fat, and the two pathways work with different gut hormones
.
"
Dr.
Li Mengtong introduced
.
To the surprise of the team, blocking either of the two pathways was enough to erase the brain's preference for fat, indicating that both pathways are essential for fat preference
.

At the same time, the first universal nutritional pathway is necessary
for the preference of sugar molecules.
In gut endocrine cells, the team also found receptors for two types of sugars or fats: SGLT1 is the receptor preferred by sugar molecules, and GPR40/GPR120 is the receptor
for fat preference.

Notably, both pathways require the use of GPR40 and GPR120 receptors
to drive preference for fat.
The GPR40/GPR120 receptor in the gut activates the brain-gut axis, causing the brain to develop a craving for fat (Image: References [1])
From this, the study reveals intestinal receptors and brain-to-gut pathways that are critical to sugar and fat preferences, a finding that also guides disease treatment and our
lifestyles.
"Excessive intake of foods high in sugar and fat can lead to a range of metabolic diseases
such as obesity and diabetes.

Our research suggests that intervening in this pathway may be helpful in treating these diseases," dr.
Li Mengtong said.


Long-term excessive intake of these high-sugar and high-fat foods may make us 'addicted', thereby increasing the risk
of diabetes and obesity.

References
:[1] Li, M.
, Tan, HE.
, Lu, Z.
et al.
Gut-Brain Circuits for Fat Preference.
Nature (2022).
https://doi.
org/10.
1038/s41586-022-05266-z[2] Cravings for fatty foods traced to gut-brain connection.
Retrieved Sept 7th, 2022 from