Researchers identify potential cause and treatment for obesity and insulin resistance

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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 study, published today in the journal Nature Metabolism, identified a damaging cycle in which a high-fat diet promotes dysfunction of the mesenteric lymphatics, which in turn leads to the accumulation of abdominal fat.

The study provides preclinical 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 prodrug of the lymph-targeted COX-2 inhibitor was shown to normalise 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 specialising in the discovery, development and commercialisation of highly differentiated medicines for devastating diseases.

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.”

PureTech’s Glyph prodrug technology platform is specifically designed to enable the trafficking of small molecule drugs directly into the mesenteric lymphatic system following oral administration. 

The 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 Glyph 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.

“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.”

This research was conducted in collaboration with scientists from the University of Melbourne, University of Auckland and the University of South Australia.