"Parking space grabbing" in the body! IgG grabs the "parking space" of insulin and causes obesity?

Table of contents:
1. Introduction: Obesity’s hidden enemy

2. Understanding insulin resistance

3. Immunoglobulin G (IgG): From "special forces" to "troublemakers"

4. White fat and brown fat: the dual nature of fat

5. IgG’s “cross-border behavior”

6. The "Parking Crisis" of Insulin Receptors

7. New hope: the dawn of targeted therapy

8. Future Outlook

1. Introduction: The hidden enemy of obesity—immunoglobulin G?

Obesity is a major challenge to global health. We know that obesity is closely related to diseases such as diabetes and high blood pressure, but sometimes, the immune system will quietly add fuel to the fire?

In recent years, scientists have been studying obesity: What causes our own insulin resistance? In other words, insulin is clearly "working hard" in our body, but the cells are unwilling to listen to its command, resulting in increased blood sugar.

Recently, the team of Professor Qiang Li and Professor Wang Liheng from Peking University published a breakthrough study in the journal Cell Metabolism: Immunoglobulin G (IgG for short) is what we usually think of as an antibody. This antibody accumulates in large quantities in white adipose tissue during the formation of obesity, and can directly bind to the insulin receptor (IR for short), occupying the working space of insulin, thereby causing a series of metabolic problems such as insulin resistance. At the same time, the team also further discovered that after interfering with the accumulation of immunoglobulin G, adipose tissue can regain health, thereby reversing this metabolic disorder.

This is like a "parking space grab" battle in a parking lot. Insulin should have its own exclusive parking space, but IgG forcibly occupies it, resulting in insulin having nowhere to park (parking space) and being unable to work normally (how can it work if the car hasn't stopped yet). This discovery is really shocking and also provides a new direction for the treatment of obesity and metabolic diseases in the future.

2. Understanding insulin resistance

Insulin resistance (IR) refers to the poor response of cells to insulin's "instructions", which results in insulin's inability to effectively help cells absorb glucose, causing blood sugar levels to rise. Insulin resistance is the core problem of type 2 diabetes, obesity, and metabolic syndrome.

1. Simply put - insulin is like the "key" and cells are the "door"

A. Under normal circumstances: Insulin is the "key" that can open the "door" of cells, allowing glucose to enter cells smoothly and provide energy for the body.

B. When insulin resistance occurs: the "door lock" of the cell is like rusted, and the key cannot be turned when inserted, and the door cannot be opened. In this way, glucose cannot enter the cell, and sugar will accumulate more and more in the blood outside the door, and blood sugar will rise.

2. It’s also like the express delivery service around you

A. Under normal circumstances: Insulin is like a courier, it is responsible for delivering "sugar" into cells (cells).

B. When insulin resistance occurs: The security guards at the gate of the community become alert and will not let the couriers enter the community no matter how they explain. This causes sugar to accumulate in the blood (outside the community), eventually leading to high blood sugar.

At this time, we need these couriers again, so the body sends out more couriers (secreting more insulin) to try to deliver the sugar into the cells (communities) again. This repeated process makes the pancreas more and more tired and forms diabetes.

3. Consequences of insulin resistance

We know that: the increase of blood sugar will increase the risk of diabetes. The overload of the pancreas will cause the failure of pancreatic beta cells (too tired) for a long time. The accumulation of fat will form obesity, especially the "beer belly" - abdominal obesity. These three factors will increase the risk of high blood pressure, fatty liver, and arteriosclerosis, which will affect cardiovascular health.
This is why controlling insulin resistance is the key to preventing metabolic diseases such as obesity and diabetes!

3. Immunoglobulin G (IgG): From "special forces" to "troublemakers"
Immunoglobulin G is a "special soldier" in the human body, but sometimes it is also a "naughty boy" or even a "troublemaker". Before we take a closer look at how IgG interferes with insulin, let's first look at its job.

1. Normal duties of IgG

We know that IgG is the most abundant immunoglobulin in our body. Its main functions are:

A. Identify and eliminate pathogens (such as bacteria and viruses) to protect the body from infection.

B. Maintain long-term immune memory and help the body resist "some old friend" viruses, such as the chickenpox virus.

C. It is the only antibody that can be passed through the placenta to the fetus, giving the newborn immune protection early in life. It is like the first painless vaccination given by the mother to the baby.

It can be said that IgG is an "elite soldier" of the immune system, protecting our health at all times.

2. Four major types of IgG

We also know that there are many members of the immunoglobulin G (IgG) family, mainly four types:

IgG1: The strongest "pathogen killer", accounting for more than 60% of the total IgG.

IgG2: Mainly fights against the outer shell of bacteria, similar to a "battering ram".

IgG3: has the strongest attack power, but a shorter survival time, just like a "rocket".

IgG4: Often associated with chronic inflammation and autoimmune diseases, it is like an "invisible warrior."

However, in the state of obesity, these "elite soldiers" will also become "naughty boys and troublemakers", accumulate abnormally in the fat tissue, and huddle together to "grab the parking space for insulin", thus interfering with the normal work of insulin!

[The image is from this paper. The study injected IgG from fat mice into lean mice, which also accumulated IgG in the white fat of the lean mice and damaged the mice's insulin sensitivity.]

4. White fat and brown fat: the dual nature of fat

Now we know that there are four types of immunoglobulin G, or IgG for short, with different effects. In the field of fat, let's also look at the classification of fat, because not all fat is "bad"!

1. White fat (WAT): the body’s “energy storage tank”

White fat is our most common form of fat and is responsible for storing energy. Its main functions are:

--Store excess calories for future use.

-- Secretes hormones (such as leptin and adiponectin) that affect appetite and metabolism.

--Padding and supporting organs and acting as a cushion, such as the buttocks.

However, when we have too much white fat, especially when it accumulates in the abdomen (such as a beer belly), it can cause obesity, insulin resistance and metabolic problems.

2. Brown fat (BAT): the body’s “fat burning engine”

In contrast, brown fat acts like a calorie burner in the body:

--Can burn fat to generate heat and help regulate body temperature.

--Contains a large number of mitochondria (the "power plants" of cells), making it easier to consume fat.

--Helps increase insulin sensitivity and improve metabolic health.

Children and slender people have more brown fat in their bodies. People who are a little fatter have less brown fat in their bodies. This is why fatter people are more likely to be afraid of cold, because their metabolism is slower - burning fat to produce less heat.

5. IgG’s “out-of-bounds behavior”: Why does it run into the fat?

Normally, immunoglobulin G, or IgG, should patrol the blood, but in obesity, it can accumulate in white adipose tissue and cause insulin resistance.

In simple terms:

--Under normal circumstances, the "express delivery" IgG should be sent to the blood to perform immune tasks.

--However, in the obese state, the "courier" responsible for transporting IgG - that is, the receptor (FcRn) responsible for IgG recycling - has problems, and as a result, IgG is mistakenly transported to the white adipose tissue, where it accumulates in large quantities.

That is, "during the development of obesity, IgG accumulates mainly in adipose tissue, triggering insulin resistance and macrophage infiltration."

6. The "Parking Crisis" of Insulin Receptors

What's worse is that IgG does not just accumulate passively, it also directly occupies the "parking space" of the insulin receptor, making it impossible for insulin to work, thus hindering the effect of insulin.

Let me give you another analogy:

--Under normal circumstances, the "VIP car" of insulin should be parked in the exclusive VIP parking space of the insulin receptor (IR), and then send instructions to the cells to allow the cells to absorb glucose and lower blood sugar.

--However, the clustered IgGs occupy all the "parking spaces", leaving the insulin with nowhere to park and work, ultimately making the cells unable to receive insulin signals, causing blood sugar to soar and forming insulin resistance.

[Image from this paper: IgG competes with insulin for binding to the insulin receptor. The CH3 domain in the Fc segment of IgG can bind to the IgLD1 domain of the insulin receptor. The interaction between the Fc-CH3 domain and the extracellular domain of the insulin receptor blocks insulin signaling and adipocyte function, causing insulin resistance]

7. New hope: Improving obesity and diabetes through targeted intervention of IgG!

Since IgG is an important factor causing insulin resistance, scientists began to think: If the accumulation of IgG can be reduced, can obesity and metabolic diseases be improved?

Indeed, the study found two important breakthroughs:

Ⅰ. Knock out the FcRn gene (the receptor responsible for IgG recycling) → IgG will no longer accumulate, insulin sensitivity will be restored, and obesity symptoms will be alleviated!

Ⅱ. Using antisense oligonucleotides (ASO) to inhibit FcRn → Blood glucose levels and insulin resistance in obese mice were improved!

Imagine that if FcRn is a courier sorting center, then antisense nucleotides (ASOs) are like a "temporary stop order" that can temporarily shut down the sorting center so that IgG cannot be mistakenly sent to adipose tissue. This method can reduce the accumulation of IgG without affecting the normal production process of IgG.

That is, "targeting FcRn can avoid excessive accumulation of IgG without damaging its production process."

[Image from this paper: FcRn may be a potential therapeutic target for obesity. Researchers designed antisense oligonucleotides (ASOs) targeting the Fcgrt gene encoding FcRn to inhibit its mediated IgG accumulation. Experiments showed that ASOs significantly reduced plasma IgG levels. Although the weight and fat composition of mice did not change significantly, glucose tolerance and insulin sensitivity were significantly improved.]

8. Future Outlook

This groundbreaking research has brought us a new understanding: obesity is not just a simple problem of eating too much and moving too little, but an imbalance in the immune system also plays an important role. Through this discovery, we have seen a new direction for the treatment of obesity and metabolic diseases:

Ⅰ. Precision treatment: Targeted drugs for IgG accumulation may be developed in the future

II. Personalized plan: Develop treatment strategy based on the patient's immune status

III. Preventive medicine: Early prevention of obesity by monitoring immune indicators

IV. Combination therapy: combining immunomodulation with traditional treatment regimens

This not only shows that obesity is not just a problem of eating more and exercising less, but also a problem of the immune system! Immunoglobulin G "grabs" the "parking space" of the insulin receptor, leading to obesity and insulin resistance. But this process seems to be reversible.

This opens up a new path for the treatment of obesity and diabetes. Perhaps in the near future, we will be able to help more people get rid of obesity and diabetes by regulating the immune system!

References:

Yu et al., FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology, Cell Metabolism (2024), https://doi.org/10.1016/j.cmet.2024.11.001