February 26, 2024

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Fasting activates specific neurons in the brain and enhances liver autophagy

Fasting activates specific neurons in the brain and enhances liver autophagy



 

 

Scientists discover for the first time that fasting activates specific neurons in the brain and enhances liver autophagy.

The reasons why fasting is good for your health have come a long way.

 

Recently, a research team led by Jens Claus Brüning of the Max Planck Institute for Metabolism in Germany published important research results in the famous journal “Cell Metabolism” [1].

 

They found that after a short period of fasting, gastrin secreted from the gastrointestinal tract enters the brain, activates AgRP neurons in the hypothalamus, promotes the release of corticosterone hormones, and then enhances liver autophagy (which can clear harmful molecules), and Promote liver lipid and glucose metabolism remodeling .

If the activation of AgRP neurons is inhibited , the enhancement of autophagy in the liver is also inhibited.

 

For a long time, scientists believed that liver cells directly sense the lack of energy and then automatically initiate the autophagy program.

However, the research results of Brüning’s team show that the brain plays a crucial role in fasting-induced autophagy .

 

Fasting activates specific neurons in the brain and enhances liver autophagy

Screenshot of paper homepage

 

The hypothalamus is a key center for regulating energy balance.

 

Because neurons in the arcuate nucleus of the hypothalamus (ARH) are exposed to an incomplete blood-brain barrier, they are sensitive to subtle changes in peripheral circulating signals.

Among them, two anatomically adjacent but functionally distinct populations of neurons—AgRP neurons and POMC neurons—are critical for sensing and integrating metabolic signals that not only regulate food intake and energy expenditure, but also Can regulate whole body glucose balance and protein homeostasis.

 

Previous studies have found that the activation of AgRP neurons can promote food intake under starvation conditions .

In addition, autophagy, which can decompose intracellular proteins, lipids and nucleic acids, can also participate in the regulation of energy balance under the condition of food scarcity .

However, autophagy has long been viewed as a cell-autonomous process . Brüning’s team wondered whether there was an interaction between fasting-activated AgRP neurons and hepatic autophagy during energy deprivation .

 

They used a short-term food deprivation model in which mice were given no food for the first 4-6 hours after entering a dark cycle (in short, the mice lost their breakfast) .

They found that by the fourth hour of the dark cycle, 47% of the AgRP neurons in the brains of fasted mice were activated, compared with 12% of the AgRP neurons in the normally fed mice; At one hour, the number of activated AgRP neurons increased to 59 percent in the fasted mice, while it dropped to 8 percent in the normally fed mice .

 

Fasting activates specific neurons in the brain and enhances liver autophagy

Short-term fasting is sufficient to activate AgRP neurons

 

Subsequently, Brüning’s team activated AgRP neurons in a controlled manner with the help of optogenetics and observed changes in mouse liver autophagy.

 

They found that after 2 hours or 4 hours of light stimulation, gene expression in the mouse liver changed dramatically, and the autophagy regulation and catabolic amino acid metabolism pathways were the most enriched .

Quantitative analysis found that the expression of genes related to autophagy, lipid metabolism, and glucose production was upregulated .

In addition, they looked at changes in several autophagy markers and found that they did increase in a time-dependent manner .

 

With the help of transmission electron microscopy, it can be seen that after 4 hours of light stimulation, the number of autophagic vacuoles in hepatocytes of mice expressing photoreceptor (ChR2) increased 3-fold compared with mice not expressing photoreceptor (ChR2) .

 

These findings above indicate that short-term fasting can activate AgRP neurons, and the activation of AgRP neurons will increase the level of hepatic autophagy.

Subsequent research found that, in a natural state, fasting leads to increased levels of gastrin (Ghrelin) secreted from the gastrointestinal tract, which enters the brain and activates AgRP neurons .

 

Fasting activates specific neurons in the brain and enhances liver autophagy

Autophagy increases in a visible way

 

The next question is: how AgRP neurons regulate hepatocyte autophagy.

 

Mechanistically, AgRP neurons activated by gastrin secrete neuropeptide Y (NPY), and neuropeptide Y acts on neurons expressing NPY1R downstream, inhibiting the activity of NPY1R neurons, thereby releasing the effect of NPY1R neurons on The inhibitory effect of CRH neurons promotes the secretion of corticosterone from CRH neurons.

Corticosterone enters the liver through circulation and binds to glucocorticoid receptors (GR), thereby realizing the expression of genes related to hepatocyte autophagy, glucose metabolism and lipid metabolism. adjustment .

 

Fasting activates specific neurons in the brain and enhances liver autophagy

Mechanism diagram

 

At the end of the study, Brüning’s team compared the activity of this signaling pathway in young and aged mice. Unfortunately, gastrin- or fasting-induced AgRP neuron-hepatic autophagy The body is greatly weakened .

This means that fasting may not have the health benefits found in this study for older adults.

 

In general, Brüning’s team has opened up a complete signaling pathway for fasting to promote liver autophagy and metabolic remodeling, giving us a more complete and in-depth understanding of the mechanism by which autophagy promotes health.

Future interventions developed around AgRP neurons and their downstream signaling pathways may help extend the healthspan of animals.

 

 

 

 

 

 

 

 

references:

[1]. Chen W, Mehlkop O, Scharn A, et al. Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation. Cell Metab. 2023;35(5):786-806.e13. doi:10.1016/ j.cmet.2023.03.019

Fasting activates specific neurons in the brain and enhances liver autophagyFasting activates specific neurons in the brain and enhances liver autophagy

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