World first: researchers identify potential cause and treatment for obesity and insulin resistance

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.

Professor John Windsor

The ground-breaking study, published in the prestigious journal 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 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 in collaboration with PureTech Health (Nasdaq: PRTC, LSE: PRTC), a US clinical-stage biotherapeutics company specialising in the discovery, development and commercialisation of highly differentiated medicines for devastating diseases and the University of Auckland.

As shown through pre-clinical models, a high-fat diet stimulated the formation of new mesenteric lymphatic vessels, which grew in a highly disorganised 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.

Monash University’s 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.”

These preclinical experiments were then repeated in clinical samples by researchers from the Surgical and Translational Research (STaR) Centre at the University of Auckland. Samples of small bowel and mesentery were provided by lean and obese patients undergoing surgery at the Auckland City Hospital. The samples were then processed and transported to MIPS for ex vivo experiments which suggest that the key observations made in the animal studies extend to humans as well.

Beyond just observing these changes the study went further to test a treatment designed to prevent the mesenteric lymphatic dysfunction and to find out whether this would result in a decrease in weight gain and insulin resistance. Central to the success of this treatment 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 the platform trafficked the COX-2 inhibitor directly to where it was needed in the mesenteric lymphatics.

Professor John Windsor, who directs the STaR Centre in Auckland, sees this as an excellent example of transdisciplinary research that is critical for the translation of key experimental findings to the clinical setting and potential patient benefit.

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

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