Study uncovers fullness regulatory mechanism and drug target for obesity
Obesity is a global health epidemic that raises the risk of developing life-threatening conditions such as diabetes and heart disease, but despite its prevalence worldwide and in Hong Kong, there are few effective drugs on the market.
However, a new study led by researchers from HKBU has identified a promising potential drug target for the management of obesity, as they found that a proteolytic enzyme called membrane-type 1 matrix metalloproteinase (MT1-MMP) plays an important role in the regulatory mechanism that underpins the sensation of fullness, or satiety. The research findings were published in the journal Nature Metabolism.
Hunger games
To further explore the role of MT1-MMP, the research team 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, Tsang Shiu Tim Endowed Chair of Chinese Medicine Clinical Studies and Director of the Clinical Division of SCM at HKBU, generated an obesity mouse model by feeding a fat-rich diet to a group of transgenic mice with a depletion of MT1-MMP in their satiety neurons, as well as a control group of ordinary mice.
After 16 weeks, the mice with depleted MT1-MMP ate 10% less food, gained 50% less weight, and exhibited reduced glucose and plasma insulin levels compared to the control group. The results show that depletion of MT1-MMP protects mice from obesity induced by a high-fat diet.
Further analysis of the obese mice revealed increased activity of MT1-MMP in the parts of the brain involved in appetite and weight regulation. This finding suggests that increased MT1-MMP activity in the brain of obese mice could be a risk factor that potentially leads to sustained weight gain.
Molecular biology studies
To understand the mechanism by which MT1-MMP suppresses satiety signalling, the research team conducted a series of molecular biology experiments involving animal models and cell culture.
The results show that in cells with active MT1-MMP, a significant reduction in the levels of a neuron receptor in the brain called “GDNF-family receptor α-like” (GFRAL) was observed. As a hormone called growth and differentiation factor 15 (GDF15) normally sends out satiety signals by binding with GFRAL, thus regulating food intake, the researchers believe that MT1-MMP may be removing GFRAL from the surface of the brain neurons, which prevents GDF15 from binding to GFRAL. This, in turn, keeps the neurons from transmitting the satiety signals sent by GDF15, leading to weight gain and potentially obesity.
New drug target for obesity
According to the Population Health Survey conducted in 2014/15 by the Department of Health, about 30% of people in Hong Kong aged 15 to 84 were obese, and another 20% were overweight. This is even higher in places such as the United States.
The research findings have established the role played by MT1-MMP in regulating satiety, and they have provided preliminary indications that the proteolytic enzyme is a promising target for the treatment of obesity.
Dr Xavier Wong Hoi-leong
School of Chinese Medicine
Given the prevalence of obesity around the world and its impact on our health, there is keen demand for an effective drug, and the researchers also explored the therapeutic potential of targeting MT1-MMP for obesity management through pharmacological inhibition of its activity in vivo.
With the application of a specific neutralising antibody that inhibits MT1-MMP, significant improvements in metabolic parameters including food intake, glucose tolerance and body weight were observed in obese mice. The results suggest that MT1-MMP is a potential therapeutic target that could be used in the development of innovative drug treatments for obesity.
Dr Wong said: “The research findings have established the role played by MT1-MMP in regulating satiety, and they have provided preliminary indications that the proteolytic enzyme is a promising target for the treatment of obesity. Pharmacological inhibition of MT1-MMP could be a viable strategy for the development of effective pharmacotherapy for the treatment of obesity.”
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