​NCB | Lin's team revealed the principle of "warm babies" - brown fat fever - under nerve stimulation

Editor's note The Lin Shengcai team of Xiamen University has made a series of outstanding original work on glucose perception and metabolic balance regulation.
Compared with this, the readers are more familiar with it ("Collector's Edition" "Must-Read" ReviewYin and Yang The golden mean of economics-AMPK and mTORC1 nutrition perception and cell growth regulation), but in fact, a series of pioneering work has been done in the field of fat metabolism.

In 2018, the Cell Metabolism cover paper published the mechanism of AIDA in slowing down fat absorption and synthesis (Cell Metabolism coverLin Shengcai's team revealed the mechanism of "waste gene"-expert comments), and proposed "wasteful gene-pro-wasteful" for the first time Concept; in 2020, Nature Communications published the most toxic oncogene SRC directly phosphorylates the key enzyme of fat synthesis LIPIN1 and promotes its activity, providing evidence of obesity and cancer (Lin Shengcai’s group found that the oncogene Src regulates the metabolic enzyme lipoin- 1 Enhance lipid synthesis, leading to the progression and deterioration of breast cancer).

Lin Shengcai’s team just published their work on Nature Cell Biology and discovered that AIDA can be directly plugged into the heat-generating machine UCP1, which inherits the signal from sympathetic nerves to brown fat’s heat-generating pathways that people have long been expecting to reveal.
This is of great significance! Responsible Editor | Enzyme Beauty has a variety of nervous systems, among which the sympathetic nervous system can mobilize the potential of many organs of the body to adapt to changes in the environment when the environment changes drastically.

Sympathetic nerve excitement can stimulate many emergency responses, such as walking in the dark at night, being yelled at by others, people's rapid call and heart rate will accelerate, blood flow will increase, blood sugar will increase, and so on.

The cold is also such a stimulus that can cause an emergency response.

For many people, no matter how cold the weather is, they are unwilling to wear more clothes.
Only warm babies are their life-sustaining artifacts.In mammals, there is a natural "warm baby", which is brown adipose tissue.

Under cold stimulation, brown adipose tissue will receive instructions from the sympathetic nervous system to quickly and efficiently use nutrients in the body to generate heat in a non-shivering thermogenesis way [1].

Norepinephrine is the most important signal molecule produced by the sympathetic nervous system under cold stimulation.

Norepinephrine binds to the adrenergic receptors of brown fat cells, thereby activating the downstream protein kinase A (PKA).

PKA promotes thermogenesis by regulating a variety of intracellular activities, including enhancing lipolysis to mobilize stored triglycerides [2], increasing the secretion of specific adipokines [3], and enhancing the transcription of thermogenic genes including UCP1 Expression and so on [4].

UCP1 is a transmembrane channel protein that is specifically and highly expressed in brown fat and is located in the inner mitochondrial membrane.
It is the final effector molecule in the thermogenesis of brown fat.

When UCP1 is activated, the mitochondrial transmembrane proton gradient originally used to produce ATP "leaks" due to the uncoupling effect of UCP1, that is, enters the mitochondrial matrix from the mitochondrial membrane space, and "by the way" generates a lot of heat.

In recent years, a large number of studies have explored the transcriptional regulation mechanism of UCP1, and discovered many regulatory mechanisms that target the abundance of UCP1 mRNA and protein as the ultimate target.

However, it is worth noting that the UCP1 protein level in brown fat at room temperature is already extremely high (reaching 5%-10% of the total mitochondrial protein level), but its thermogenic activity remains at a low level [5], similar to a Lurker.

Within a few hours of acute cold stimulation, the UCP1 protein level of brown adipose tissue does not increase significantly [6], but its thermogenic activity explodes rapidly.

Therefore, some other mechanisms independent of the regulation of UCP1 protein abundance are the key to the activation of brown adipose tissue under acute cold stimulation.

Although early studies have shown that fatty acids, nucleotides, and reactive oxygen species are important molecules in the regulation of UCP1 activity [7-10], there is no report on whether there is a direct effector protein that can connect sympathetic nerve signals with acute cold stress response.
The activation of UCP1 is linked.

On March 4, 2021, the research team of Professor Lin Shengcai and Professor Lin Shuyong of Xiamen University published an online article titled AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1 in Nature Cell Biology.
Under stimulation, a protein named AIDA mediates the regulation mechanism of brown fat thermogenic activity.

AIDA was first identified and named by the team of Professor Lin Shengcai.

In 2007, the team of Professor Lin Shengcai and the team of Academician Meng Anming discovered the function of AIDA in the development of zebrafish axis [11].

In 2018, Professor Lin Shengcai's team discovered the function of AIDA in mammals for the first time, that is, the AIDA-mediated degradation of the endoplasmic reticulum pathway degrades key enzymes in the fat synthesis pathway, while limiting the absorption of dietary fat in the intestinal tract, which is an inherent defense Obesity [12].

And this result reveals the specific function of AIDA in brown adipose tissue.

These work introduced AIDA into an important part of lipid stress metabolism, including lipid absorption and lipid-dependent thermogenesis.

(Luo, 2018 Cell Metabolism cover: The ancient Egyptian princess Aida and the ERAD system-the samurai Radamès and the cat Bast join forces to fight against fat accumulation.
The
idea comes from Verdi’s opera Aida of the same name .
) In this latest study, the team found that acute cold stimulation , AIDA whole body knockout, fat-specific knockout, or brown fat-specific knockout mice all exhibited a faster rate of body temperature drop and a decrease in thermogenesis. Through a large number of mechanistic studies, the team found that cold stimulation activates the adrenergic signaling pathway of brown fat through the sympathetic nervous system.
At this time, PKA phosphorylates the 161th serine group of AIDA and transfers the phosphorylated AIDA to the inner and outer mitochondrial membranes.
The gap, combined with the transmembrane uncoupling protein UCP1 located in the inner mitochondrial membrane, promotes the oxidative modification of the cysteine ​​group of UCP1 and activates the uncoupling activity of UCP1, thereby promoting thermogenesis of brown adipose tissue ( figure 1).

If the brown adipocytes of AIDA-deficient mice are supplemented with AIDA that cannot be phosphorylated, it will not restore the mice's ability to produce heat under acute cold stimulation as the wild-type AIDA can be supplemented.

Previous studies have found that the activity of UCP1 is not essential in mice in a cold environment after gradual cooling and adaptation [13].

In response to this, the team also found that the indicators of AIDA knockout mice did not show obvious abnormalities in the cold environment after the gradual cooling and adaptation.

This further indicates that the remodeling of the body's thermoregulatory system by acute cold stimulation and gradual adaptation to the cold environment is through different mechanisms.

Figure 1: AIDA directly connects sympathetic nerves and adaptive thermogenesis through UCP1.
In addition, the adaptive thermogenesis of brown fat is extremely important for hibernating animals.
The earliest brown adipose tissue was found in hibernating mammal marmots [ 14].

In the study, it was found that the 161th serine of AIDA and its vicinity are highly conserved in mammals.
Therefore, the research team also initially explored the conservation of the PKA-AIDA-UCP1 signaling pathway in a variety of hibernating species.

At the same time, the team found that in the AIDA homologous protein sequence of Amphioxus, the existing species closest to vertebrates in evolution, the corresponding group of serine 161 was replaced by proline, and the ability to be phosphorylated by PKA was also lost.
, But as long as the corresponding proline in AIDA of Amphioxus is replaced with serine, the communication between PKA and AIDA of Amphioxus can be connected.

The significance of this in evolutionary biology is worthy of further exploration.

Original link: https://doi.
org/10.
1038/s41556-021-00642-9 Plate maker: 11 Lin Shengcai's team related work: Nat Comm | Lin Shengcai's group found that the oncogene Src regulates the metabolic enzyme lipin-1 to enhance lipid synthesis , Leading to the progression and deterioration of breast cancer; Cell MetabolismLin Shengcai’s team penetrates the glucose sensing pathway-the role and mechanism of cation channel protein TRPV mediating glucose-sensing AMPK activation; Cell Res coverLin Shengcai’s team fully displays the AMPK air conditioning control map; carbohydrate The compound is not a "scourge"! Professor Lin Shengcai Cell Metabolism published a review article Interpretation of Glucose Metabolism——Experts Interpretation Comments; Lin Shengcai's group reveals the molecular mechanism of the key steps of lipid synthesis; subversive discovery: Lin Shengcai's group Nature cracks the new mechanism of glucose perception.
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