June 18, 2024

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Why is the kidney the key to Metformin’s anti-obesity effects?

Why is the kidney the key to Metformin’s anti-obesity effects?



Why is the kidney the key to Metformin’s anti-obesity effects?

Metformin  has the effect of lowering blood sugar by inhibiting the production of glucose in the liver.

It is the first-line drug for the treatment of type 2 diabetes and one of the most commonly prescribed drugs in the world. Hundreds of millions of people around the world are taking Metformin.

As an old drug, people’s research on Metformin has never stopped, and the research enthusiasm is also increasing day by day, and Metformin is always refreshing our understanding of it, and continues to bring people one surprise after another.

In recent years, many studies have shown that in addition to its hypoglycemic effect, Metformin also has the effect of losing weight .

But until now, exactly how Metformin regulates weight loss was not well understood.

In April 2023, the team of Tony KT Lam of the Toronto General Hospital Research Institute published a paper entitled: Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake in the Cell sub-journal Cell Metabolism and body weight research paper.

The study found that the kidney is the key to Metformin’s fight against obesity .

Specifically, Metformin increases the level of GDF15 in the blood by up-regulating the synthesis of GDF15 protein in the kidney, and GDF15 acts on GFRAL in the area postrema (AP) of the brain , thereby Reduce food intake and achieve weight loss.

This study reveals a previously unknown new function of the kidney and suggests that the kidney may serve as a target for Metformin, opening up exciting new avenues for the treatment of obesity and the debilitating and devastating diseases it brings.

Why is the kidney the key to metformin's anti-obesity effects?

On December 9, 2019, researchers from McMaster University in Canada published a research paper entitled: Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss in the journal Nature Metabolism [2] .

The study found that Metformin can induce an increase in the level of GDF15 in the blood , thereby regulating specific areas of the brain, inhibiting the desire to eat high-fat diets, reducing hunger, and achieving weight loss.

However, this study did not clarify which organ helps Metformin regulate the expression of GDF15 to achieve weight loss. Understanding how Metformin works is key to understanding how food intake and weight are controlled in the body.

Why is the kidney the key to metformin's anti-obesity effects?

On December 25, 2019, researchers from the University of Cambridge published a research paper entitled: GDF15 mediates the effects of Metformin on body weight and energy balance in the journal Nature [3] .

The paper describes and analyzes a large amount of data from clinic, cells, organoids and mice in detail, and for the first time determines the tissue source of GDF15 that responds to Metformin in vivo – the distal small intestine and colon , revealing that GDF15 regulates the effect of Metformin on body weight Molecular mechanisms that play an important role in the beneficial effects on energy and energy balance.

Why is the kidney the key to metformin's anti-obesity effects?

On the basis of the above studies, Tony Lam’s team speculated that the small intestine should be responsible for Metformin’s ability to induce weight loss, because Metformin causes blood sugar changes through the gut, which is why it can effectively treat type 2 diabetes .

However, follow-up experiments proved that the speculation was wrong. In the rat model, when GDF15 was inhibited from the small intestine, Metformin could still induce a significant increase in the level of GDF15 in the blood, as well as a decrease in food intake and body weight.

According to previous studies, GDF15 is expressed in both the distal gut and the kidney.

The research team found that only by inhibiting the production of GDF15 in the kidney can the Metformin-induced increase in the level of GDF15 in the blood be blocked and its effect on food intake and Weight reducing effect.

This latest study shows that the kidney also performs a new function that we did not know before.

In addition to regulating blood pressure, red blood cell production and bone mineralization, the kidney is also involved in the regulation of energy balance in the body .

By linking the kidney to weight loss, this work also lays the groundwork for new, more targeted treatments to address the obesity epidemic.

Why is the kidney the key to metformin's anti-obesity effects?Metformin’s pathway of action in the body

In addition to using animal models, the research team worked with nephrologists to conduct experiments using existing human clinical data.

They analyzed GDF15 levels in 360 human kidney biopsies and found a correlation with GDF15 levels in the patients’ blood.

The experimental data, although preliminary, support the idea that GDF15 from the kidney contributes to GDF15 levels in the blood.

Overall, the study found that Metformin increased blood GDF15 levels in male rats fed a high-fat diet by upregulating GDF15 synthesis in the kidneys .

Importantly, kidney-specific downregulation of GDF15 and brain Area Postrema (AP) -specific downregulation of GFRAL abolished the ability of Metformin to reduce food intake and body weight.

These findings reveal the kidney as a target of Metformin, which regulates energy homeostasis through the renal GDF15-dependent area posterior (AP) axis of the brain.

Professor Tony Lam said that further research will be carried out at the Toronto General Hospital Research Institute to translate this laboratory discovery into clinical application to help obese patients, understanding that Metformin works through the kidneys will contribute to obesity and its debilitating and devastating effects Treatment of diseases opens exciting new avenues.

 

 

 

 

Paper link :
1. https://doi.org/10.1016/j.cmet.2023.03.014
2. https://www.nature.com/articles/s42255-019-0146-4
3. https://www.nature.com/articles/s41586-019-1911-y

Why is the kidney the key to Metformin’s anti-obesity effects?

(source:internet, reference only)


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