Monash University researchers have shown for the first time that mesenteric (gut) lymphatic dysfunction is a potential cause of and therapeutic target for obesity and insulin resistance.
The groundbreaking study, published in Nature Metabolism, identified a profoundly damaging cycle in which a high fat diet promotes dysfunction of the mesenteric lymphatics, that in turn leads to accumulation of abdominal fat.
Notably, the study also provides evidence that intervening in this cycle by inhibiting the pathways associated with lymphatic dysfunction may be a treatment for both obesity and associated metabolic disease.
Treatment of the mesenteric lymphatic system with a lymph-targeted COX-2 inhibitor was shown to normalize the structure of the lymphatic vasculature, block weight gain and reverse glucose intolerance and hyperinsulinemia—conditions associated with type 2 diabetes.
Leading the study was a team of researchers from Melbourne’s Monash Institute of Pharmaceutical Sciences (MIPS) including Associate Professor Natalie Trevaskis, Professor Chris Porter and Post-Doctoral Research Fellow Enyuan Cao, in collaboration with PureTech Health, a US clinical-stage biotherapeutics company specializing in the discovery, development and commercialisation of highly differentiated medicines for devastating diseases.
As shown through pre-clinical models, a high-fat diet stimulated the formation of new mesenteric lymphatic vessels, which grew in a highly disorganized pattern. These tortuous, branching vessels tended to leak lymphatic fluid, which is rich in gut-derived lipid metabolites and pro-inflammatory mediators, into the visceral adipose tissue in the abdomen, triggering the promotion of insulin resistance.
Associate Professor Trevaskis said: “In this study we were able to uncover for the first time a biological reason behind why the accumulation of fat around the abdomen is correlated with higher rates of metabolic disease such as type 2 diabetes than accumulation of fat in other regions of the body.
“We were able to show that a high-fat diet leads to dysfunction of the mesenteric lymphatics, which in turn promotes more fat deposition around the abdomen and insulin resistance.”
“The results from ex vivo experiments using clinical samples suggest that these observations extend to humans as well.”
Central to the success of the study was the use of PureTech’s GlyphTM prodrug technology platform, which is specifically designed to enable the trafficking of small molecule drugs directly into the mesenteric lymphatic system following oral administration.
The GlyphTM prodrug technology was initially developed by the MIPS team and licensed to PureTech in 2017. MIPS and PureTech scientists have subsequently been working together to further develop the platform.
In the current study the use of the lymph targeting technology was key to the intervention of the cycle in which mesenteric lymphatic dysfunction leads to the accumulation of abdominal fat, since it trafficked the COX-2 inhibitor directly to where it was needed in the mesenteric lymphatics.
Professor Chris Porter said: “By harnessing the GlyphTM technology platform, we now have preclinical evidence that intervening in this cycle by targeted inhibition of the pathways associated with mesenteric lymphatic dysfunction may provide a novel treatment option for both obesity and associated metabolic disease.”
“What’s remarkable about this study is that the COX-2 inhibitor was able to meaningfully repattern the chaotic lymphatic structure in obese mice when it was delivered directly to the mesenteric lymphatics with our Glyph technology platform, and that repatterning was accompanied by a substantial decrease in both weight gain and insulin resistance,” said PureTech’s Chief Scientific Officer, Joseph Bolen, Ph.D.
“We look forward to continuing our long-standing partnership with the team at Monash to build on this exciting research and to identify and advance new potential treatment applications for this platform.”
Dietary lipids are transported to the circulation predominantly as chylomicrons via the intestinal lymphatic system, which drains into the subclavian vein1. Chylomicrons enter the intestinal lymphatic capillaries, or lacteals, through the open “button-like” vascular endothelial (VE)-cadherin junctions localized between adjoining lymphatic endothelial cells (LECs)2. The “zippering” of VE-cadherin junctions, through deletion of neuropilin1 and vascular endothelial growth factor receptor 1 (VEGFR1), prevents chylomicron uptake by lacteals and fat absorption protecting against diet-induced obesity and systemic glucose intolerance2.
Similar metabolic protection is achieved by deletion of vascular endothelial growth factor (VEGF)-C3, or of VEGF-C regulated Notch ligand delta like−4 (DLL4)4, both important for lacteal maintenance and remodeling5. On the other hand, mice heterozygous for the transcription factor prospero-related homeobox 1 (Prox1) important for LEC lineage commitment6 show defective, leaky lymphatic vessels and adult-onset obesity7.
Disruption of lymphatic vessel integrity8,9 and attenuation of VEGF-C induced lymphangiogenesis10 have been reported as pathophysiological phenotypes in mice models of obesity and type 2 diabetes (T2D). In humans, lymphatic dysfunction is associated with obesity, diabetes, and aging, which increases the risk of cardiovascular disease, lymphedema and age-related neurological decline11–15, but our knowledge of the mechanisms underlying lymphatic dysfunction and its link to disease remains limited.
The fatty acid transporter CD36/FAT is a transmembrane scavenger receptor widely expressed in tissues16 and cell types including endothelial cells17,18. CD36 recognizes long-chain fatty acids (FAs)16,19, lipoproteins20, pathogen-associated lipids21, in addition to non-lipid ligands22,23. Studies in rodents24,25 and people26,27 have shown that CD36 facilitates tissue uptake of non-esterified FAs, and that of FA released from very low-density lipoproteins (VLDL)28. CD36 deficient (Cd36−/−) mice have reduced FA uptake by peripheral tissues, and this reduction was recapitulated in mice with specific deletion of endothelial cell Cd36, highlighting its regulatory role in tissue FA uptake18.
There is little information on CD36 expression level or its role in the lymphatic endothelium. Although human dermal LECs were reported to express CD36 mRNA29, cutaneous lymphatic vessels were found to have low CD36 protein content30 and there is no evidence for CD36 expression in LECs of the small intestine. We had previously shown that Cd36−/− mice have reduced lipid secretion into the cannulated mesenteric lymph duct following duodenal lipid infusion, and at the time attributed this impairment to the defective generation of chylomicrons by enterocytes devoid of CD3631,32.
In this study, we show that CD36 is highly expressed in intestinal lymphatics (lacteals and submucosa) and that Cd36−/− mice have discontinuous VE-cadherin junctions in gut mucosa (lacteals) and submucosa lymphatic vessels. To understand the role of CD36 in LEC function, we generated a mouse with inducible Cd36 deletion in LECs (Prox1-CreERT2-tdTomatoCd36−/−, hereafter referred to as Cd36ΔLEC) and assessed VE-cadherin morphological status in gut lymphatics, lymph transport, and metabolic phenotypes.
Mechanistic studies with cultured LECs highlighted the importance of CD36 in the regulation of oxidative and glycolytic metabolism. Here, we show that inducible LEC CD36 deletion in adult mice causes leaky lymphatic vessels in the mesenteric region, accumulation of inflamed visceral adipose tissue, and spontaneous late-onset obesity. CD36 silencing in LECs inhibits fatty acid oxidation (FAO) and increases glycolytic rates. The switch in metabolic fuel associates with reduced VEGF-C signaling to VEGFR2/AKT, which impairs LEC migration, tube formation and monolayer integrity.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184948/
More information: Enyuan Cao et al, Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00457-w