Nature Sub-Journal: Is this the root cause of obesity and insulin resistance?

Currently, there are approximately 500 million obese people and 1 billion overweight people in the world

There are many health problems caused by obesity, such as: various three highs, such as hyperlipidemia, hyperglycemia, hyperuric acid, and hypertension; obesity often leads to fatty liver; leads to apnea syndrome

Understanding the factors that lead to obesity plays a vital role in the research of the scientific community and the treatment of obese patients by clinicians

Recently, scientists have conducted more in-depth research on this and have made new discoveries.

The main causes of insulin resistance are abnormal fat metabolism, abnormal fat distribution, and excessive accumulation

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

Recently, a team of scientists at Monash University discovered the underlying causes of obesity and insulin resistance

They found through experiments that intestinal lymphatic dysfunction is a potential cause of obesity and insulin resistance, as well as a therapeutic target for both

They published an article titled "Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity" in the journal Nature Metabolism

This pioneering study found that a high-fat diet can lead to mesenteric lymphatic dysfunction, which in turn leads to abdominal fat accumulation, which ultimately forms a very destructive cycle

It is worth noting that the study also provides evidence that intervening this cycle by inhibiting lymphatic dysfunction-related pathways 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 wraps the mesenteric lymphatic vessels and lymph nodes, and transports lymph fluid from the intestine and mesenteric

Whether the mesenteric lymphatic vessels are involved in the inflammation, metabolism and insulin resistance of adipose tissue is still unclear

In experiments, scientists found that obesity is associated with severe progressive sexual dysfunction in the mesenteric lymphatic system in mice and humans

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

Targeting inhibition of COX-2 with glycerol prodrugs can reverse mouse mesenteric lymphatic dysfunction, visceral obesity and inflammation, and restore blood sugar control
.
Therefore, through experiments, they finally concluded that obesity-related mesenteric lymphatic dysfunction is a potential treatment option for metabolic diseases
.
 

Leading the study were researchers from the Monash Institute of Pharmaceutical Sciences in Melbourne, including Associate Professor Natalie Trevaskis, Professor Chris Porter and postdoctoral researcher Enyuan Cao
.
They cooperated with an American clinical company to engage in the research, development and marketing of treatments for fatal diseases
.
Cooperate with PureTech Health (a clinical-stage biotherapeutic company that develops 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 to 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 abdominal fat is more important for the formation of metabolic diseases, and it is more likely to cause the accumulation of fat in type 2 diabetic patients than other parts of the body
.
Other metabolic diseases
.

A high-fat diet leads to mesenteric lymphatic dysfunction, which in turn promotes fat deposition around the abdomen and insulin resistance
.
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 scientists use PureTech's GlyphTM drug technology platform, which is 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 been collaborating to further develop the platform
.
 

In the current study, the use of lymphatic targeting technology is the key to intervening the cycle of mesenteric lymphatic dysfunction that causes 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 preclinical evidence that by targeting pathways related to mesenteric lymphatic dysfunction to intervene in this cycle, it may provide a new way for obesity and related metabolic diseases
.
Therapeutic Method
.
" 

Dr.
Joseph Bolen, Chief Scientific Officer of PureTech, said: "The amazing 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 this drug.
Effectively reorganize these disordered lymphatic structures
.

When these lymphatic structures are reorganized, body weight is significantly reduced and insulin resistance is significantly reduced
.

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 this technology platform in the treatment practice
.
" 

Is this the underlying cause of obesity and insulin resistance?