Brain: "I want to lose weight", intestines: "No, you don't want to"! Nature reveals the secrets of fat addiction

In the era of rapid acceleration of the pace of life, high-sugar and high-fat foods often become people's favorites, even in the loss of friends, most of them still can't control the desire for
calories.

The study found that in multiple countries, there have been catastrophic increases in the consumption of high-sugar and high-fat processed foods, and these dietary changes have been linked to increased malnutrition, including metabolic disorders and overnutrition
.

On September 7, 2022, the team of Professor Charles S.
Zuker of Columbia University published a research paper in Nature revealing that the preference for high-fat foods is due to the presence of the gut-brain axis, and by understanding this biological mechanism, interfering with the gut-to-brain pathway will make human intervention possible
with overeating and fighting obesity, diabetes and cardiovascular disease.

Sugar and fat are essential nutrients, and animals have evolved 38 taste signaling pathways to detect and respond to stimuli
from sweetness and fat.

Direct attraction to fat relies on the TRPM5 channel expressed in taste receptor cells, but if the development of fat preference is not taste-induced, but mediated by ingestion, it should be independent of TRPM5 function
.

As predicted, animals with TRPM5 knockout were still able to develop behavioral preferences
for fat.

Through behavioral monitoring, it was found that over time, the dietary preferences of mice gradually changed from artificial sweeteners to fat, and the perception of fat caused a strong appetite and a response
to satisfaction.

So, how do fats activate brain circuitry? First, using single-cell data and animal experiments, the researchers determined that fat activates vagus neurons, transmitting fat signals from the gut to neurons in the isolated bundle tail nucleus (cNST) in the brainstem
.

Using Fos as a signal of neural activity, fat induces strong bilateral activation of cNST, cNST acts as a junction point for endoceptive signals, transmits information from the intestinal-brain axis to the brain, and experimentally confirms that the development of
fat preference is eliminated when this gut-to-brain pathway gene is silenced.

Figure 1: Development of
fat preference.

a) depicts the field of behavior of mice; b) Graph of preference for fat and sweetness; c) Schematic diagram of fat stimulation Fos induction; d) Quantification
of fos-positive neurons.

In addition, by comparing the pathways that drive fat and sugar preferences between the gut and the brain, the researchers found two parallel systems, one is a universal sensor of essential nutrients, which responds to intestinal stimuli of sugars, fats, and amino acids, while the other is activated
only by fat stimuli.

So how does the gut transmit these nutritional signals to the vagus nerve? Experimental data showed that blocking CCK (cholecystin) signaling eliminates all reactions of vagus nerve sugar/fat neurons, that is, CCK is a transmitter
that mediates intestinal-brain axis trophic sensing.

In addition, by using single-cell RNA-seq maps and the CRISPR/Cas9 system, vagus clusters expressing Trpa1 (transient receptor potential localization protein 1) respond
selectively to intestinal transmission of fat.

Fats in the diet, once ingested and digested, are thought to be perceived by many hypothetical intestinal receptors, including fatty acid translomase CD36 and G protein-coupled receptors GPR40 and GPR120, one or more of these receptors may be used to transmit fat preferences
through the gut-brain axis.

Knockout of all possible combinations using CRISPR-Cas9 found that GPR40 and GPR120 are necessary mediators
for intestinal fat signaling to the vagus nerve.

In GPR40/GPR120 mutants, the innate response to fat stimulation is not affected, illustrating the fundamental difference
between taste and gut-brain pathways.

Figure 2: Selective loss
of fat reactions in GPR40/GPR120 double knockout and CD36/GPR40/GPR120 triple knockout.

Based on the above research, the researchers showed that genetic or pharmacological blockade of sugar and fat to brain signals at any of the four stages after ingestion can inhibit the development of nutritional preferences and help address human health crises, as follows:

(1) by preventing sugar or fat from binding to the corresponding intestinal receptors;

(2) By blocking activated intestinal cells from sending signals to vagus nerve cells;

(3) by silencing vagus neurons activated by sugar or fat and preventing their signals from being transmitted to the brain;

(4) The presence of gut sugars or fats is transmitted to the rest of the brain by blocking cNST neurons that receive gut-brain signals
.

In short, the article sheds light on the fundamental difference between "like" and "want" and proposes new strategies
to change the brain's preference for nutrition.

Preference for sweets and fats is the innate attraction of appetite stimulation and is the result of activation of
the taste system.

The preference for sugar and fat, on the other hand, is the result of the regulation of
the gut-brain axis.

References:

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

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