*For medical professionals only
Every time I see this kind of paper about a gene saying goodbye to getting fat, my first reaction is "what a good thing in a dream", and the second reaction is "human beings, you really can't evolve"...
Recently, a scientific team from the University of California, Irvine published a paper in Nature Communications [1], they found a negative regulator of the classical metabolic regulatory pathway AMPK SAPS3, inhibition of SAPS3 can effectively avoid various metabolic problems caused by high-fat diet to mice, and even "enjoy" a high-fat meal with 45% fat content will not gain weight at all.
Let's just say, why did this kind of thing stay in the genome in the first place?
Thesis title map
First of all, AMPK, which is adenylate-activated protein kinase, which senses metabolic homeostasis in cells and the whole organism, regulates the metabolism of glucose and fatty acids, and affects energy production. There are many physiological processes associated with AMPK, which can be related to metabolic diseases such as diabetes, as well as cancer and aging, but today we will only discuss the function of its energy metabolism part.
When AMPK is activated, it promotes energy production, which increases the "burning" of fats and sugars. However, contrary to our wishes, this generally occurs when the body is short of energy, and when the body has sufficient or even excess intake, AMPK is not proactive.
Various features of AMPK[2]
What dampened AMPK's enthusiasm for work?
The researchers found that by altering the supply of glucose could affect the activity of AMPK, by analyzing the specific complex that binds to AMPK in this process, the researchers found a target, SAPS3. SAPS3 is a catalytic subunit of the PP2A protein phosphatase family, which can assist in the dephosphorylation of AMPK and is the key to inhibiting AMPK activity.
So suppressing SAPS3, can it keep AMPK working?
The researchers knocked out the mice's SAPS3 and gave them a high-fat meal whose calorie source was 45 percent fat. Surprisingly, after eating like this for 16 weeks, the mice seemed to eat air, and the weight gain was completely invisible, basically the same as the control group that ate standard rat food.
The metabolic indexes such as blood sugar, insulin tolerance, and liver fat that knocked out SAPS3 were not impaired by the high-fat diet. The SAPS3 knockout itself also poses no health problems.
So, why, why hasn't this thing evolved?
Is this fat, I don't think it's fat
Because the liver has a huge amount of energy in regulating energy metabolism, the researchers also tried to knock out only SAPS3 in the liver of mice, which is enough to reduce the negative effects of high-fat diet.
Finally, the researchers systematically examined the effects of SAPS3 knockout on metabolism and gene expression.
Interestingly, when mice were eating a normal diet, it almost didn't matter whether SAPS3 was present or not. When mice eat a high-fat diet, SAPS3 shines, and knocking out SAPS3 can reverse the metabolic and transcriptional changes induced by high-fat diet, including fatty acid synthesis, glucose uptake and glycolysis levels.
Up-regulated and down-regulated genes after knocking out SAPS3
Finally, although it is understandable that in the old era when food resources were still scarce, the biological mechanism of SAPS3 that can store excess calories in time for later use is understandable, but modern society is advancing too fast! We are already materially rich! No need anymore! Thank you!
Resources:
[1] Yang, Y., Reid, M.A., Hanse, E.A. et al. SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice. Nat Commun 14, 1368 (2023). https://doi.org/10.1038/s41467-023-36809-1
[2] Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016 Apr 1;48(4):e224. doi: 10.1038/emm.2016.16. PMID: 27034026; PMCID: PMC4855276.
The author of this article 丨 Dai Siyu