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Key Enzyme Involved in Regulatory Mechanism for Satiety Identified as Possible Therapeutic Target for Obesity Management
Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been found to play a key role in regulating satiety (also known as fullness). Researchers are currently investigating its potential as a therapeutic target for obesity management.

A group of researchers from Hong Kong Baptist University (HKBU) has found that membrane-type 1 matrix metalloproteinase (MT1-MMP), a proteolytic enzyme, is key in the regulatory mechanism of satiety (also known as fullness). This could serve as a new therapeutic drug target for the treatment of obesity.

Their findings were published in the internationally-renowned Nature Metabolismand have been featured in other high-impact journals, including Nature Reviews Endocrinology and Science Signaling.

According to the World Health Organization, worldwide obesity has nearly tripled since 1975, increasing the risk of cardiovascular diseases, diabetes, musculoskeletal disorders, and some cancers in people who suffer from this affliction.

The best way to address obesity is to regulate food consumption, which is an uphill battle for obese people as they have a higher tendency to lose their feeling of satiety, thus they might face difficulties in halting their consumption of food. Therefore, pinpointing a particular factor that controls body weight and understanding how it regulates our sense of satiety is essential for the creation of therapeutic approaches for obesity.

Led by Dr. Xavier Wong Hoi-leong, Assistant Professor of the Teaching and Research Division of the School of Chinese Medicine (SCM), and Professor Bian Zhaoxiang, Director of the Clinical Division of SCM and Tsang Shiu Tim Endowed Chair of Chinese Medicine Clinical Studies at HKBU, the team of researchers identified the proteolytic enzyme MT1-MMP, which regulates the mechanism of producing satiety signals in the brain.

Growth and differentiation factor 15 (GDF15) is a hormone that produces satiety signals by binding with the neuron receptor in the hindbrain called GDNF-family receptor α-like (GFRAL). Interrupting this binding process between GDF15 and GFRAL would affect GDF15’s ability to send satiety signals, which could then influence one’s food intake. With this focus in mind, the researchers investigated the effects of MT1-MMP on GFRAL and the overall effect on the satiety signals produced.

The researchers tested their hypothesis with a group of obese mouse models with depleted MT1-MMP in their satiety neurons and a control group of normal mice. Both groups of mice were fed a diet rich in fats, and after 16 weeks, the mice with depleted MT1-MMP ate 10 per cent less food, gained 50 per cent less weight, and had lower glucose and plasma insulin levels compared to the control group. The findings reflected that the depletion of MT1-MMP helped to reduce weight gain from a high-fat diet, so more research was conducted to properly understand the role of how MT1-MMP suppresses GDF15 in satiety signalling.

Further experiments were conducted in animal models and cell culture and it was found that cells with active MT1-MMP also had significantly less GFRAL and thus, less GDF15 signalling. This was due to MT1-MMP clipping GFRAL from the surface of the brain neurons, which blocks GDF15 from binding to GFRAL, reducing the number of satiety signals. This also blocks the neurons from transmitting the satiety signals produced by GDF15.

More research was also carried out to evaluate the potential of MT1-MMP as a therapeutic drug target, with an emphasis on the effects of its inhibition by drugs in the body. Experiments, where a specific neutralising antibody was used to inhibit MT1-MMP, were conducted, and it was found that food intake and body weight were reduced, while glucose tolerance was improved. The experimental findings suggest that MT1-MMP could open new avenues for drug development for the management of obesity.

Regarding his findings, Dr. Wong has reflected that his discovery shines light on the potential utility of MT1-MMP as a therapeutic target for obesity management, and a viable pharmacotherapy for this ailment could be in the form of drugs designed to inhibit MT1-MMP.

Source: Chow et al. (2022). Body weight regulation via MT1-MMP-mediated cleavage of GFRAL.Nature metabolism,4(2), 203-212.

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