Lymphatic Valve Dysfunction in Western Diet-Fed Mice: New Insights Into Obesity-Induced Lymphedema.
Study Goal
The researchers aimed to determine whether Western Diet-induced obesity causes lymphatic valve dysfunction and whether this dysfunction results from the diet itself or the metabolic changes it induces.
Results Summary
The study found that Western Diet-induced obesity led to lymphatic valve dysfunction in mesenteric lymphatics, characterized by back-leak of pressure and higher adverse pressure required for valve closure. PAI-1 deficient mice were protected from these effects, suggesting metabolic alterations play a key role.
Population
C57BL/6J (WT) mice
Effective Dosage
Not specified
Duration
14 weeks
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
obesity | increase | secondary lymphedema | Clinical studies | - | significantly increases the risk for developing | #1 |
obesity and metabolic syndrome | increase | lymphatic structural abnormalities and lymphatic dysfunction | animal-models | - | have been linked to | #2 |
western diet | increase | obesity | C57BL/6J (WT) mice | - | induced | #3 |
western diet | increase | plasma glucose and cholesterol levels | C57BL/6J (WT) mice | - | elevated | #4 |
diet-induced obesity | no change | function of lymphatic valves in popliteal lymphatics | C57BL/6J (WT) mice | - | was not affected by | #5 |
diet-induced obesity | increase | mesenteric lymphatic valves | C57BL/6J (WT) mice | - | significant back-leak of pressure was observed in | #6 |
diet-induced obesity | increase | valve closure | C57BL/6J (WT) mice | - | required significantly higher adverse pressure to trigger | #7 |
western diet | decrease | metabolic dysfunction | globally deficient PAI-1 mice | - | were significantly protected against | #8 |
western diet | no change | mesenteric lymphatic valves | globally deficient PAI-1 mice | - | displayed fully functional, competent | #9 |
A two-way connection between obesity and lymphatic dysfunction has now been established. Clinical studies have demonstrated that obesity significantly increases the risk for developing secondary lymphedema. Using animal-models, obesity and metabolic syndrome have been linked to different aspects of lymphatic structural abnormalities and lymphatic dysfunction, including impaired contractility, impaired flow-mediated responses, impaired fluid transport, as well as increased permeability, and abnormal dendritic cell migration among others. Dysfunction of lymphatic valves is a main form of lymphatic dysfunction, known to result in severe edematous phenotypes; however, the extent of lymphatic valve deficiency in secondary lymphedema, including obesity-induced lymphedema, remains unknown. Therefore, the aims of the present study were 1) to determine whether western diet-induced obesity results in lymphatic valve dysfunction, and 2) to determine whether lymphatic valve dysfunction in western diet-induced obesity results from the diet itself, or as a consequence of the metabolic alterations induced by the diet. First, we quantitatively assessed and compared valve function in isolated popliteal and mesenteric collecting lymphatic vessels from control and western diet-induced obese C57BL/6J (WT) mice. Feeding a western diet for 14 weeks induced obesity and elevated plasma glucose and cholesterol levels when compared to controls. The function of lymphatic valves in popliteal lymphatics was not affected by diet-induced obesity; however, significant back-leak of pressure was observed in mesenteric lymphatic valves. Dysfunctional, leaky valves from obese animals also required significantly higher adverse pressure to trigger valve closure. Importantly, when subjected to treatment with a western diet, globally deficient PAI-1 mice were significantly protected against metabolic dysfunction and displayed fully functional, competent mesenteric lymphatic valves. In conclusion, our findings show for the first time that, in association with the metabolic alterations induced by the western diet, lymphatic valve dysfunction can be a critical component of obesity-induced lymphedema.