Science: Obesity also has "sequelae"? Scientists have found that even if weight loss is successful, obesity still affects innate immunity through epigenetics, promoting the release of pro-inflammatory cytokines

*For medical professionals only

Singularity Cake has repeatedly talked about the harm of obesity, and I believe everyone has kept it in mind
.
There are countless diseases associated with obesity, not only metabolic and cardiovascular diseases, but also cancer
.

In such a situation, losing weight is certainly a preferred strategy worth giving a thumbs up, and it is not too late to make amends
.

However, the harm of obesity is also really serious, and a paper recently published in the journal Science [1] revealed a "sequelae"
of obesity.
Even after successful weight loss, obesity still affects innate immunity through epigenetics, promoting the expression of pro-inflammatory cytokines
by macrophages.
These macrophages travel through the body and become accomplices in age-related macular degeneration (AMD) in the eye
.

Thesis title map

Before starting the research, let's briefly understand the age-related
macular degeneration of the retina (AMD).

AMD is the main cause of irreversible blindness worldwide, although some risk gene loci have been found, but there is no clear disease-causing gene mutation, so we can think that environmental factors play an important role
in the pathogenesis of AMD.

In the early days of AMD, one of the more obvious symptoms was the formation of insoluble extracellular deposits called drusen in the subretinal pigment epithelium, which contained various lipids, proteins, trace elements and various inflammatory factors
.
This is definitely the focus of the immune system, so there will also be microglia that reside in the retina and macrophages and monocytes that come from abroad to reinforce
.

However, like other neurodegenerative diseases, AMD's inflammation, immunity and other systems are dysbalanced, and macrophages cannot remove the drusen in time, which will further trigger more serious pathological reactions, eventually causing tissue damage and leading to advanced AMD
.

Advanced AMD can be divided into neovascular AMD (nAMD) and non-neovascular AMD, 80% of which will develop vision loss are nAMD, in nAMD there will be abnormal vascular growth of the choroid under the macula, this symptom is called choroidal neovascularization (CNV).

Subsequent various serious pathological manifestations and even blindness can be said to be the pot
of CNV.

In addition to the local immune response, the progression of AMD is also affected
by systemic inflammation.
Of all the risk factors that can be intervened, obesity is the second most dangerous factor
after smoking.
For every 0.
1% increase in the waist-hip ratio, the risk of late AMD increases by 75%, which is really scary
.

So can losing body fat reverse the decline?

The mice have come to suffer for us again
.
This experimental design can be said to be very miserable, first let male mice enjoy 11 weeks of 60% high-fat diet induced obesity, and then return to 10% of the regular diet for 9 weeks to lose weight
.

Said to be a regular diet, I think this is a fat reduction meal, otherwise 3 times fat, how can it be said that thin will be thin back to normal? In short, after these twenty weeks, the mice gained weight and thin, and finally returned to the same level as the control group mice who had been eating fat-reducing meals, and the indicators such as insulin and glucose tolerance were basically the same
.

Experimental process

Finally, the researchers used laser to induce choroidal neoangiogenesis in the eyes of mice, and did quantitative analysis two weeks later, and the results showed that the CNV production of lean mice was 40% more than that of control mice!

The researchers also tried transplanting fat tissue from lean mice into regular mice, and found that this also caused more CNV
.

Mouse: It was the memory of dead fat that was attacking me

Analyzing adipose tissue from obese, lean, and normal mice, the researchers found that adipose tissue macrophages (ATMs) were somewhat eccentric
.

In obese mice, macrophages gather around dead fat cells to form a corona-shaped macrophage syncytia, a phenomenon that persists
in lean mice.
And in lean mice, the number of pro-inflammatory ATMs also increased threefold.

Coronal structures formed by aggregation of macrophages

From top to bottom, obese mice, normal mice, and lean mice were followed

The researchers transplanted bone marrow from lean mice into normal mice and found that this could still promote the production
of CNV.
Obviously, myeloid cells are behind everything
.

After analyzing the gene expression of ATM, the reason gradually became clear
.
The chromatin structure of these macrophages has changed somewhat, and some positions remain open, making genes easier to express — coincidentally, a series of genes
involved in angiogenesis, cytokine production, and inflammation.

In simple terms, in the obese state, high levels of stearic acid in adipose tissue act through toll-like receptors (TLR4) to unfold chromatin and recruit activating protein-1 (AP-1) transcription factors, resulting in epigenetic alterations
in macrophages.
These cells exhibit a pro-inflammatory phenotype and express more pro-inflammatory cytokines
such as tumor necrosis factor (TNF), interleukin 1-β, and interleukin 6.
When they enter the eye, they promote pathological inflammation and accelerate AMD progression
.

This is true
even after the weight returns to normal.

Mechanism diagram

However, the singularity cake, as a representative of fat/continuous fat, is still relatively stable, after all, there is nothing to do, ahahah, and still young (probably).

Don't panic, readers, you say that you are fat all day, I see that there are few really fat people at all!

Resources:

[1]Kevin D.
Mangum,Katherine A.
Gallagher,Obesity confers macrophage memory, Science, 379, 6627, (28-29), (2023).
doi/10.
1126/science.
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The author of this article Dai Siyu