It is the underlying cause of obesity and insulin resistance?

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Nature Sub-Journal: It is the underlying cause of obesity and insulin resistance?

Nature Sub-Journal: It is the underlying cause of obesity and insulin resistance? Scientists will take you to find out!

At present, there are about 500 million obese people and 1 billion overweight people in the world. Severe metabolic disorders have become an urgent health challenge.

There are many health problems caused by obesity, such as: various three highs, such as high blood fat, high blood sugar, high uric acid, and high blood pressure; obesity often causes fatty liver; leading to apnea syndrome. For example, some people sleep and snore at night, obesity will affect it; it will also affect the joints, such as the spine and knee joints, which increase the chance of inflammation.

Understanding the factors that cause obesity plays a vital role in the research of the scientific community and the treatment of obese patients by clinicians. Only because of the reasons can we further develop effective drugs or treatment methods to prescribe the right medicine to the patients, so that the treatment can be real. Efficient effect.

Recently, scientists have carried out a more in-depth study on this and made a new discovery…

The main causes of insulin resistance are abnormal fat metabolism, abnormal fat distribution, and excessive accumulation. The mechanism of obesity-induced insulin resistance is related to the increase in fat cell-derived hormones and cytokines, such as free fatty acids, tumor necrosis factor, leptin, resistin, plasminogen activator inhibitor, etc., and the lack of adiponectin.

Changes in the secretion of these adipocytokines not only affect energy storage and release in the form of fat, but also involve tissue sensitivity to insulin, low-grade inflammation, and abnormal blood coagulation.

Recently, a group of scientists from Monash University discovered the underlying causes of obesity and insulin resistance.

They found through experiments that the intestinal lymphatic dysfunction is a potential cause of obesity and insulin resistance, as well as a therapeutic target for both. This is the first time in history.

They published the results of this research in an article titled “Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity” in the journal Nature Metabolism:

Nature Sub-Journal: It is the underlying cause of obesity and insulin resistance?

This very groundbreaking study found that a high-fat diet can cause mesenteric lymphatic dysfunction, which in turn leads to the accumulation of abdominal fat, which ultimately forms a very destructive cycle.

It is worth noting that the study also provides evidence that intervening this cycle by inhibiting pathways related to lymphatic dysfunction may be a way to treat obesity and related metabolic diseases.

Studies have shown that treatment of the mesenteric lymphatic system with lymphatic-targeted COX-2 inhibitors can normalize the structure of lymphatic vessels, prevent weight gain, and reverse the glucose tolerance and hyperinsulinemia associated with type 2 diabetes.

Visceral adipose tissue (VAT) wraps the mesenteric lymphatic vessels and lymph nodes, and transports lymph fluid from the intestine and mesenteric through it.

Whether the mesenteric lymphatic vessels contribute to the inflammation, metabolism and insulin resistance of adipose tissue is unclear.

In experiments, scientists found that obesity is related to severe and progressive sexual dysfunction of the mesenteric lymphatic system in mice and humans. They found that lymphatics from mice and humans on a high-fat diet (HFD) stimulated the growth of lymphatic vessels, resulting in the formation of high-branched mesenteric lymph vessels, which “leaked” HFD-lymphatic vessels into VAT, thereby promoting insulin resistance. .

Mesenteric lymphatic dysfunction is regulated by COX-2 and vascular endothelial growth factor (VEGF)-C-VEGF receptor (R)3 signals.

Targeted inhibition of COX-2 using glyceride prodrugs can reverse mouse mesenteric lymphatic dysfunction, visceral obesity and inflammation, and restore blood sugar control. Therefore, through experiments, they can finally conclude that targeting obesity-related mesenteric lymphatic dysfunction is a potential treatment option for the treatment of metabolic diseases.

Leading the research is a team of researchers from the Monash Institute of Pharmaceutical Sciences in Melbourne, including Associate Professor Natalie Trevaskis, Professor Chris Porter, and postdoctoral researcher Enyuan Cao. They are engaged in research, development, and marketing of the treatment of devastating diseases with a US clinical firm. A collaboration with PureTech Health, a clinical-stage biotherapeutic company for highly differentiated drugs.

Preclinical models show that a high-fat diet stimulates the formation of new mesenteric lymph vessels, which grow in a highly disordered pattern.

These tortuous branch blood vessels tend to leak lymph fluid rich in intestinal fat metabolites and pro-inflammatory mediators into the abdominal visceral fat tissue, triggering insulin resistance.

Associate Professor Trevaskis said: “In this study, we were able to explain for the first time from a biological point of view why the accumulation of fat in the abdomen is more important to the formation of metabolic diseases, which is more likely to cause type 2 diabetes than the accumulation of fat in other parts. And other metabolic diseases.

A high-fat diet leads to dysfunction of the mesenteric lymphatic vessels, which in turn promotes more fat deposits and insulin resistance around the abdomen. The results of in vitro experiments using clinical samples show that these principles and observations are also applicable to humans. “

The key to the success of this research is that the scientists used PureTech’s GlyphTM drug technology platform, which was specifically designed for small molecule drugs to directly enter the mesenteric lymphatic system after oral administration. GlyphTM prodrug technology was originally developed by the MIPS team and licensed to PureTech in 2017. Scientists from MIPS and PureTech have since been collaborating to further develop the platform.

In the current study, the use of lymphatic targeting technology is the key to intervening in the cycle of mesenteric lymphatic dysfunction leading to abdominal fat accumulation, because it transports COX-2 inhibitors directly to the place where it is needed in the mesenteric lymph.

Professor Chris Porter said: “By using the GlyphTM technology platform, we now have pre-clinical evidence that intervening in this cycle by targeting the pathways related to mesenteric lymphatic dysfunction may provide a new approach for obesity and related metabolic diseases. treatment method.”

Dr. Joseph Bolen, Chief Scientific Officer of PureTech, said: “The striking thing about this study is that when the messy lymphatic structure in the mouse is directly transported to the mesenteric lymphatic vessels through our Glyph technology platform, COX-2 inhibits The agent can effectively recombine these disordered lymphatic structures.

While those lymphatic structures were recombined, it was accompanied by a significant reduction in body weight and a significant decrease in insulin resistance.

We look forward to continuing the long-term cooperative relationship with the Monash University team, establishing a cooperative relationship based on this exciting research, and advancing the new potential treatment methods of the technology platform in the treatment practice. “