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Possible ways to combat obesity by mobilizing the lymphatic system

New model shows enhancing lymph vessel formation in fat tissue has beneficial anti-inflammatory and metabolic effects
lymphatic system

Scientists’ search for ways to combat obesity continues. Recently, investigators have been exploring whether they can engage the lymphatic system to help regulate obesity-induced inflammation of fat (also called adipose) tissue and restore systemic metabolic fitness.

Texas A&M College of Medicine researchers report that augmenting lymphatic vessel formation in obese adipose tissue reduced obesity-associated immune accumulation and improved metabolic responsiveness, according to research published in The American Journal of Pathology, published by Elsevier. This suggests a new approach to improving some obesity-associated metabolic abnormalities.

In obesity, adipose tissue expands and becomes dysfunctional, leading to the appearance of a cluster of medical issues known as metabolic syndrome, which includes increased blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol or triglyceride levels.

The adipose tissue found in obesity exhibits symptoms of chronic inflammation, including hypoxia, immune cell accumulation and fibrosis, leading to spilling over of pro-inflammatory substances and excess lipids into the circulation. This allows fat to circulate and be deposited in other tissues that are less well-equipped to safely store it.

“Adipose tissue inflammation is at the root of the epidemic of obesity’s metabolic syndrome,” said lead investigator Joseph M. Rutkowski, PhD, of the Division of Lymphatic Biology and Department of Medical Physiology at the College of Medicine. “Reducing inflammation in animal models has worked to improve metabolism, but this approach has not translated well to humans.”

Normally, the primary function of the lymphatic system is to transport lymph, a fluid containing infection-fighting white blood cells, throughout the body via lymphatic vessels. Lymphatic vessels are similar to the circulatory system’s veins and capillaries. The lymphatic vasculature and lymphatic endothelial cells in tissues are essential for maintaining tissue balance through the uptake and transport of peripheral fluid, large molecules and immune cells.

Tissue inflammation is often accompanied by the formation of new lymph vessels, a process known as lymphangiogenesis. Although obesity seems to inhibit lymphangiogenesis and reduce lymphatic function in adipose tissue, the goal of this research was to determine whether artificially enhancing the lymph system in obese adipose tissue can be beneficial.

“Understanding the mechanisms of adipose inflammation and how to regulate it sheds light on the biology of our current obesity problem,” Rutkowski said. “We hypothesized that increasing lymphangiogenesis in adipose tissue would help to reduce obesity-associated adipose inflammation.”

The investigators developed a new transgenic animal model to test their hypothesis. The model allows for activation of vascular endothelial growth factor receptor-3 (VEGFR-3), a receptor known to regulate lymphangiogenesis, by elevating expression of its ligand vascular endothelial growth factor (VEGF-D) from fat cells.

“We demonstrated that augmenting VEGF-D signaling specifically in adipose tissue induces lymphangiogenesis and improves glucose and lipid homeostasis during obesity,” Rutkowski said.

These findings might help identify a potential new target for treating metabolic syndrome associated with obesity.

“The studies showed that despite equivalent weight gain, the animal models with elevated lymphangiogenesis demonstrate reduced systemic insulin resistance, liver lipid deposition and adipose immune accumulation when compared to controls,” Rutkowski added. “We still have more mechanistic work to do, but the phenotype is exciting.”

Adapted from a story posted on Elsevier.

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