How do we overcome two global health pandemics?

With the development of COVID-19 vaccines, what looks like a pathway out of the SARS-CoV-2 pandemic has appeared.

Not so for the world’s obesity pandemic. There is still an urgent need for effective interventions to treat the more than 650 million people worldwide facing significant health challenges due to obesity, including 350 million people suffering from type 2 diabetes.

In an effort to understand the causes of obesity better, our team at the Centre of Muscle Research and our research partners have been investigating how a protein called Yap regulates of our metabolism.

Our latest research, published in Nature Communications, has revealed new actions of the Yap protein in skeletal muscles that have important consequences for how muscles make use of the food we eat. The findings may offer us new ways to combat obesity.

Skeletal muscles account for about 40 per cent of most healthy people’s body mass and are vital for our ability to move and to regulate our metabolism. With obesity, the proportion of a person’s body mass that is made up of muscle is reduced.

Critically, the mechanisms that muscles use to regulate metabolism are also affected.

Over the last six years, our team’s investigation of the importance of Yap in metabolism have revealed that the muscles in people who are obese with reduced sensitivity to insulin – a key indicator of impaired metabolism control – contained reduced quantities of Yap protein.

Furthermore, when we reduced the amount of Yap protein in the muscles of healthy mice to model what was observed in humans, we found that these mice developed features of impaired metabolism regulation, similar to those in humans with obesity and diabetes.

Importantly, increasing the amount of Yap protein in the muscles of overweight mice was able to reduce their progression to obesity, by increasing the mice’ energy expenditure.

These discoveries have revealed an exciting new role of the Yap protein in skeletal muscles as a regulator of metabolism.

By exploring approaches that can increase Yap abundance and activity in skeletal muscles, our hope is that new strategies can be identified to help overcome the health complications associated with obesity.

Pandemics interlinked

Since early 2020, the healthcare challenges associated with the COVID-19 pandemic have dominated the global community’s attention. What may be less obvious, is that the challenges we face in overcoming COVID-19 have been complicated by obesity.

Across the world, obesity has emerged as a major risk factor for developing severe COVID-19. Being overweight increases a SARS-CoV-2 patient’s likelihood of needing invasive mechanical ventilation.

Obesity is also an important risk factor for hospitalisation and death, particularly in people under 65. So significant, in fact, that according to a Public Health England report, in people with a Body Mass Index over 40, the risk of death from COVID-19 increases by 90 per cent.

Good exercise and a good diet remain the most effective ways to limit obesity and improve metabolic health. However, for many people, the extended periods of lockdown necessary to counter the spread of COVID-19, and the psychological challenges brought on by the pandemic, have led to reduced physical activity, increased snacking and lower consumption of fresh food.

The result– associated weight gain.

Healthy muscle matters

The challenges encountered in overcoming the COVID-19 pandemic have highlighted that the obesity pandemic remains one of the major healthcare challenges of our time, affecting all ages and costing the world’s healthcare systems billions.

Our findings are significant because they provide new insight into some of the biological processes associated with obesity. Building on these findings may help to reduce the impact of obesity, which continues to be a major risk factor underlying the development of metabolic disease worldwide.

For adults aged between 18 and 64, some form of daily physical activity is advised to reduce the risk of, or help manage, type 2 diabetes and cardiovascular disease. Effective management of body weight can maintain or improve blood pressure, cholesterol, and blood sugar levels, and limit the risk of some cancers.

However, while following the guidelines for physical activity and healthy eating can reduce the risk of obesity-related disease, many people may need additional help to achieve the best results.

It is recognised that reduced skeletal muscle mass and impaired regulation of metabolism in obesity contributes to worse disease outcomes.

Our latest research provides new insight into how muscles become affected in disease, and importantly, how we might be able to address these problems. With a greater understanding of the differences that occur in the skeletal muscles of healthy and obese people, we hope our work can help to identify new ways to treat obesity and type 2 diabetes.

Enhancing our understanding of the complex signalling processes that take place inside our skeletal muscle cells to control metabolism, and their role in the development of metabolic dysfunction, may help to identify new drug, diet and lifestyle interventions to help combat metabolic disease.

The development of drugs to target Yap, which is being explored for other applications, including cancer and regenerative medicine, could be an important avenue of study. Adapting those drugs may offer promise as new tools in the fight against metabolic disease.

But while the world is still focused on COVID-19, it’s important that work continues to tackle the global obesity pandemic.

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