Abstract

The Lymphatic System in Obesity, Insulin Resistance, and Cardiovascular Diseases

Xinguo Jiang1,2*†, Wen Tian1,2†, Mark R. Nicolls1,2 and Stanley G. Rockson2*. Frontiers in Physiology. November 2019, Volume 10.

Obesity, insulin resistance, dyslipidemia, and hypertension are fundamental clinical manifestations of the metabolic syndrome. Studies over the last few decades have implicated chronic inflammation and microvascular remodeling in the development of obesity and insulin resistance. Newer observations, however, suggest that dysregulation of the lymphatic system underlies the development of the metabolic syndrome. This review summarizes recent advances in the field, discussing how lymphatic abnormality promotes obesity and insulin resistance, and, conversely, how the metabolic syndrome impairs lymphatic function. We also discuss lymphatic biology in metabolically dysregulated diseases, including type 2 diabetes, atherosclerosis, and myocardial infarction.

Main findings

• There is increasing evidence that dysfunction of the lymphatic vasculature is involved in the pathogenesis of obesity and obesity-associated dyslipidemia and low grade chronic inflammation (Harveyetal., 2005; Aspelund et al., 2016), presumably because the lymphatic system is important for immune homeostasis and lipid transport (Jiang et al., 2018). This review provides an overview of the interplay between the function of lymphatic system and presence of obesity and insulin resistance. We also discuss how the lymphatic system may be harnessed to treat T2D and cardiovascular diseases associated with obesity and insulin resistance.
• When energy intake is in surplus, about 70–80% of the excessive intake is stored as fat, and the remainder is converted into glycogen or protein or lost as heat; long-term positive energy balance ultimately leads to obesity (Oussaada et al., 2019). Genetic mediation of obesity can be monogenicorpolygenic. Monogenic mutation is relatively rare and primarily affects the genes involved in the leptin–melanocortin pathway, the central regulator of food intake and energy balance (Oussaada et al., 2019).
• Polygenic causation, however, is more common and accounts for >90% cases of childhood-onset obesity (Kleinendorst et al., 2018). Notably, common variants in certain loci within the fat mass and obesity-associated gene (FTO) have been linked to higher BMI in human populations.
• The lymphatic vasculature regulates both dietary lipid absorption and peripheral cholesterol removal. The intestinal lacteals are lymphatic vessels comprised of both capillary and collecting lymphatic elements.
• Lacteals possess a spontaneous contractile feature; they actively absorb and transport enterocyte-processed lipids to the systemic circulation in concert with contractile forces produced by adjacent smooth muscle cells controlled by the autonomic nervous system (Choe et al., 2015). It was recently revealed that lacteal function controls dietary lipid absorption and, consequently, body weight, supporting the concept that the lacteals are the gatekeepers of lipid intake from the environment.
• In peripheral tissues, the lymphatic vasculature is generally considered to be the only route for the return of lipoprotein to the blood circulation.
• Several lines of evidence support the notion that lymphatic functionality impacts the pathogenesis of obesity. In patients with lymphatic injury-induced (secondary) lymphedema, fat hypertrophy in the lymphedematous tissues is prominent, accompanying tissue swelling and fibrosis.
• Lymphatic dysfunction promotes obesity, and that improving lymphatic function inhibits the development of obesity and alleviates obesity-caused metabolic syndrome. Studies have also illustrated that obesity promotes lymphatic abnormalities, such as decreased initial lymphatic density, heightened lymphatic leakiness, impaired collecting lymphatic pumping, and diminished macromolecule transport; but those phenotypic and functional changes are reversible in response to dietary modificationand weight control.
• Severely obese individuals often develop acquired lymphedema of the extremities.
• high concentrations of leptin produced by adipose tissue maybe responsible for suppressing lymphatic vasculature in obese individuals. In summary, lymphatic dysfunction sensitizes individuals to develop obesity, and obesity worsens lymphaticfunction.
• Unhealthy microvas culature hampers insulin delivery to muscle and adipose tissue and affects glucose disposal and lipid homeostasis.
• Studies indicate that insulin signalling likely plays important roles in regulating both LEC metabolism and lymphangiogenesis;LEC insulin resistance diminishes lymphatic function, and exacerbate  sobesity and metabolic abnormality.
• The lymphatic pathology likely co-evolves with the pathogenesis of diabetes.
• The metabolic syndrome poses a significant risk for the development of cardiovascular diseases, such as atherosclerosis and its severe complication, myocardial infarction (MI) (Wilson et al., 2005; Mottillo et al., 2010). Following the revelation of the interplay between metabolic syndrome and lymphatic dysfunction, a multiplicity of research has shown that the lymphatic vasculature is also actively involved in the progression of atherosclerosis and development of MI (Aspelund et al., 2016).
• In atherosclerosis-prone Ldlr−/−; ApoB100+/+ mice, lymphatic dysfunction, mainly of the collecting lymphatic vessels, occurs before the onset, and during the progression, of atherosclerosis (Milasan et al., 2016), suggesting that lymphatic vascular abnormalities likely promote atherosclerosis.
• Targeting inflammation may, therefore, not only ameliorate tissue inflammation but also improve lymphatic function.
• Protective role of the lymphatic vasculature in promoting postMI recovery, downregulation of the LEC marker VEGFR3 alters cardiac lymphatic structure, increases lymphatic leakage, and raises MI-induced mortality.
• Promoting lymphatic function has the apparent capacity to reduce pathology in preclinical obesity and cardio vascular disease models. More in-depth study of lymphatic biology is therefore urgently needed.