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Written by Enyuan Cao and Sifei Han, edited by Sifei Han | xi Compared with subcutaneous fat accumulation, abdominal obesity (fat accumulation around the internal organs) is more likely to cause metabolic syndrome such as type II diabetes
.
This phenomenon and the risk factors of abdominal obesity have long been widely recognized, but the specific principles are not very clear
.
On September 21, 2021, Dr.
Enyuan Cao (first author and joint communication), Professor Christopher Porter and Associate Professor Natalie Trevaskis of the Institute of Pharmaceutical Sciences (MIPS), Monash University, Melbourne, Australia, published in Nature Metabolism The paper Messengeric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity, revealing that mesenteric lymphatic dysfunction is one of the important causes of pathological phenomena such as abdominal obesity and insulin resistance, and it has successfully corrected lymphatics with lymphatic-directed prodrugs.
Dysfunction, which greatly improves the pathological indicators related to metabolic syndrome, is expected to have a profound impact on further medical research and drug development
.
The human lymphatic system plays a vital role in body fluid balance and immune protection; disorders of the structure and function of the lymphatic system often cause or aggravate cancer, autoimmune and inflammatory diseases, cardiovascular and cerebrovascular diseases, and neurodegenerative diseases.
One
.
The lymphatic system is also closely related to fat metabolism.
For example, in patients with lymphedema (caused by the obstruction of lymphatic drainage) and genetically modified mice with abnormal lymphatic systems, adipose tissue collects in weak parts of the lymphatic vessels (lymphatic leakage sites) , Showing that obesity is related to impaired lymphatic system function
.
In the human abdominal cavity, the mesenteric adipose tissue wraps the mesenteric lymph vessels and lymph nodes
.
However, for the human mesenteric lymphatic system, the main absorption channel of lipid nutrients in the diet, it is unclear whether the mesenteric lymphatic system is related to the deposition of mesenteric fat tissue, inflammation and metabolism, and insulin resistance
.
This newly published study shows that the function of mesenteric lymphatic vessels is closely related to glucose and lipid metabolism and immune balance
.
In mice fed high-fat-induced mice and patients with obesity and insulin resistance, the mesenteric lymphatic vessels were severely dysfunctional
.
It is specifically manifested in severe abnormal lymphatic hyperplasia and leakage of lymphatic fluid containing high concentrations of lipids.
The leaked lymph fluid leads to the abnormal expression of a large number of adipogenesis and related metabolic genes.
The fat cells enlarge and excessively release fatty acids, which seriously reduces internal organs.
The sensitivity of adipose tissue to insulin
.
The researchers then demonstrated that pro-inflammatory cyclooxygenase 2 (COX-2) and vascular epithelial growth factor C (VEGF-C) signaling play a key role in mesenteric lymphatic dysfunction
.
High-fat lymph fluid that absorbs a large amount of lipid components from the intestine is rich in a large amount of VEGF-C, which leads to abnormal lymphatic hyperplasia and lymphatic leakage; similar to the direct blocking of epidermal growth factor receptor 3 (VEGFR-3), Blocking VEGF-C can effectively restore lymphatic function and improve the tolerance of experimental animals to oral glucose
.
The researchers next used a new type of lymphatic targeting prodrug to improve mesenteric lymphatic dysfunction
.
The lipid-derived prodrug (Cele-Pro) using COX-2 inhibitor celecoxib can increase the concentration of the drug in the lymph fluid by more than 10 times, which is extremely effective in reversing mesenteric lymphatic dysfunction and improving obesity and Blood sugar control
.
This is mainly due to the COX-2 lymphatic targeting inhibition while completely removing a large amount of VEGF-C in the high-fat lymphatic fluid, reversing lymphangiogenesis and lymphatic leakage
.
The study also determined that compared with intestinal macrophages and lymphatic endothelial cells, the main source of pathological VEGF-C is macrophages in visceral adipose tissue
.
In addition, COX-2 lymphatic targeting inhibition reduces immune cell aggregation caused by high-fat feeding and lipid metabolites in lymph fluid
.
In order to further confirm that the improvement of blood sugar control is the result of the recovery of mesenteric lymphatic function, studies have shown that there is no change in systemic metabolism and energy expenditure
.
The data shows that the therapeutic benefit of COX-2 lymphatic targeted inhibition is not to change the systemic metabolic function, but to restore intestinal lymphatic function
.
In summary, this study found that mesenteric lymphatic dysfunction leads to metabolic abnormalities such as abdominal fat deposition and insulin resistance, demonstrating the potential of targeted recovery of mesenteric lymphatic function as a potential treatment strategy for obesity and related metabolic diseases
.
The research lasted for eight years and was led by the Monash University Institute of Pharmaceutical Sciences (MIPS), Dr.
Enyuan Cao, Prof.
Christopher Porter, Associate Prof.
Natalie Trevaskis in Melbourne, Australia, and other teams.
A laboratory, clinical medicine team and PureTech Health (a biotechnology company) jointly completed the project
.
The lymphatic-directed drug technology platform has applied for patents in multiple countries and is currently in clinical-oriented joint development with PureTech Health in Boston, USA
.
Original link: https://doi.
org/10.
1038/s42255-021-00457-w Platemaker: Instructions for reprinting on the 11th [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
.
This phenomenon and the risk factors of abdominal obesity have long been widely recognized, but the specific principles are not very clear
.
On September 21, 2021, Dr.
Enyuan Cao (first author and joint communication), Professor Christopher Porter and Associate Professor Natalie Trevaskis of the Institute of Pharmaceutical Sciences (MIPS), Monash University, Melbourne, Australia, published in Nature Metabolism The paper Messengeric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity, revealing that mesenteric lymphatic dysfunction is one of the important causes of pathological phenomena such as abdominal obesity and insulin resistance, and it has successfully corrected lymphatics with lymphatic-directed prodrugs.
Dysfunction, which greatly improves the pathological indicators related to metabolic syndrome, is expected to have a profound impact on further medical research and drug development
.
The human lymphatic system plays a vital role in body fluid balance and immune protection; disorders of the structure and function of the lymphatic system often cause or aggravate cancer, autoimmune and inflammatory diseases, cardiovascular and cerebrovascular diseases, and neurodegenerative diseases.
One
.
The lymphatic system is also closely related to fat metabolism.
For example, in patients with lymphedema (caused by the obstruction of lymphatic drainage) and genetically modified mice with abnormal lymphatic systems, adipose tissue collects in weak parts of the lymphatic vessels (lymphatic leakage sites) , Showing that obesity is related to impaired lymphatic system function
.
In the human abdominal cavity, the mesenteric adipose tissue wraps the mesenteric lymph vessels and lymph nodes
.
However, for the human mesenteric lymphatic system, the main absorption channel of lipid nutrients in the diet, it is unclear whether the mesenteric lymphatic system is related to the deposition of mesenteric fat tissue, inflammation and metabolism, and insulin resistance
.
This newly published study shows that the function of mesenteric lymphatic vessels is closely related to glucose and lipid metabolism and immune balance
.
In mice fed high-fat-induced mice and patients with obesity and insulin resistance, the mesenteric lymphatic vessels were severely dysfunctional
.
It is specifically manifested in severe abnormal lymphatic hyperplasia and leakage of lymphatic fluid containing high concentrations of lipids.
The leaked lymph fluid leads to the abnormal expression of a large number of adipogenesis and related metabolic genes.
The fat cells enlarge and excessively release fatty acids, which seriously reduces internal organs.
The sensitivity of adipose tissue to insulin
.
The researchers then demonstrated that pro-inflammatory cyclooxygenase 2 (COX-2) and vascular epithelial growth factor C (VEGF-C) signaling play a key role in mesenteric lymphatic dysfunction
.
High-fat lymph fluid that absorbs a large amount of lipid components from the intestine is rich in a large amount of VEGF-C, which leads to abnormal lymphatic hyperplasia and lymphatic leakage; similar to the direct blocking of epidermal growth factor receptor 3 (VEGFR-3), Blocking VEGF-C can effectively restore lymphatic function and improve the tolerance of experimental animals to oral glucose
.
The researchers next used a new type of lymphatic targeting prodrug to improve mesenteric lymphatic dysfunction
.
The lipid-derived prodrug (Cele-Pro) using COX-2 inhibitor celecoxib can increase the concentration of the drug in the lymph fluid by more than 10 times, which is extremely effective in reversing mesenteric lymphatic dysfunction and improving obesity and Blood sugar control
.
This is mainly due to the COX-2 lymphatic targeting inhibition while completely removing a large amount of VEGF-C in the high-fat lymphatic fluid, reversing lymphangiogenesis and lymphatic leakage
.
The study also determined that compared with intestinal macrophages and lymphatic endothelial cells, the main source of pathological VEGF-C is macrophages in visceral adipose tissue
.
In addition, COX-2 lymphatic targeting inhibition reduces immune cell aggregation caused by high-fat feeding and lipid metabolites in lymph fluid
.
In order to further confirm that the improvement of blood sugar control is the result of the recovery of mesenteric lymphatic function, studies have shown that there is no change in systemic metabolism and energy expenditure
.
The data shows that the therapeutic benefit of COX-2 lymphatic targeted inhibition is not to change the systemic metabolic function, but to restore intestinal lymphatic function
.
In summary, this study found that mesenteric lymphatic dysfunction leads to metabolic abnormalities such as abdominal fat deposition and insulin resistance, demonstrating the potential of targeted recovery of mesenteric lymphatic function as a potential treatment strategy for obesity and related metabolic diseases
.
The research lasted for eight years and was led by the Monash University Institute of Pharmaceutical Sciences (MIPS), Dr.
Enyuan Cao, Prof.
Christopher Porter, Associate Prof.
Natalie Trevaskis in Melbourne, Australia, and other teams.
A laboratory, clinical medicine team and PureTech Health (a biotechnology company) jointly completed the project
.
The lymphatic-directed drug technology platform has applied for patents in multiple countries and is currently in clinical-oriented joint development with PureTech Health in Boston, USA
.
Original link: https://doi.
org/10.
1038/s42255-021-00457-w Platemaker: Instructions for reprinting on the 11th [Original article] BioArt original article, personal forwarding and sharing are welcome, reprinting without permission is prohibited, all published The copyright of the work is owned by BioArt
.
BioArt reserves all statutory rights and offenders must be investigated
.
