Dataset Information

Regulation of Lymphatic Function in Obesity.

ABSTRACT: The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphatic function. Obesity-induced pathologic changes in the lymphatic system result, at least in part, from the accumulation of inflammatory cells around lymphatic vessel leading to impaired lymphatic collecting vessel pumping capacity, leaky initial and collecting lymphatics, alterations in lymphatic endothelial cell (LEC) gene expression, and degradation of junctional proteins. These changes are important since impaired lymphatic function in obesity may contribute to the pathology of obesity in other organ systems in a feed-forward manner by increasing low-grade tissue inflammation and the accumulation of inflammatory cytokines. More importantly, recent studies have suggested that interventions that inhibit inflammatory responses, either pharmacologically or by lifestyle modifications such as aerobic exercise and weight loss, improve lymphatic function and metabolic parameters in obese mice. The purpose of this review is to summarize the pathologic effects of obesity on the lymphatic system, the cellular mechanisms that regulate these responses, the effects of impaired lymphatic function on metabolic syndrome in obesity, and the interventions that may improve lymphatic function in obesity.

SUBMITTER: Kataru RP

PROVIDER: S-EPMC7242657 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Regulation of Lymphatic Function in Obesity.

Kataru Raghu P RP Park Hyeong Ju HJ Baik Jung Eun JE Li Claire C Shin Jinyeon J Mehrara Babak J BJ

Frontiers in physiology 20200515

The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphati ...[more]

PMID: 32499718

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Project description:Key pointsObesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells.AbstractAlthough previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, including VEGFR-3 and Prox1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity-induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications.

Project description:Background Pathophysiological mechanisms that connect obesity to cardiovascular disease are incompletely understood. FSP27 (Fat-specific protein 27) is a lipid droplet-associated protein that regulates lipolysis and insulin sensitivity in adipocytes. We unexpectedly discovered extensive FSP27 expression in human endothelial cells that is downregulated in association with visceral obesity. We sought to examine the functional role of FSP27 in the control of vascular phenotype. Methods and Results We biopsied paired subcutaneous and visceral fat depots from 61 obese individuals (body mass index 44±8 kg/m2, age 48±4 years) during planned bariatric surgery. We characterized depot-specific FSP27 expression in relation to adipose tissue microvascular insulin resistance, endothelial function and angiogenesis, and examined differential effects of FSP27 modification on vascular function. We observed markedly reduced vasodilator and angiogenic capacity of microvessels isolated from the visceral compared with subcutaneous adipose depots. Recombinant FSP27 and/or adenoviral FSP27 overexpression in human tissue increased endothelial nitric oxide synthase phosphorylation and nitric oxide production, and rescued vasomotor and angiogenic dysfunction (P<0.05), while siRNA-mediated FSP27 knockdown had opposite effects. Mechanistically, we observed that FSP27 interacts with vascular endothelial growth factor-A and exerts robust regulatory control over its expression. Lastly, in a subset of subjects followed longitudinally for 12±3 months after their bariatric surgery, 30% weight loss improved metabolic parameters and increased angiogenic capacity that correlated positively with increased FSP27 expression (r=0.79, P<0.05). Conclusions Our data strongly support a key role and functional significance of FSP27 as a critical endogenous modulator of human microvascular function that has not been previously described. FSP27 may serve as a previously unrecognized regulator of arteriolar vasomotor capacity and angiogenesis which are pivotal in the pathogenesis of cardiometabolic diseases linked to obesity.

Dataset Information

Regulation of Lymphatic Function in Obesity.

Publications

Regulation of Lymphatic Function in Obesity.

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