“A gamechanger drug cuts body weight by 20 per cent.” In February, that headline took the world by storm. Obesity has exploded into a global public health crisis, with few drug options available to treat it. More than 1.9 billion adults are overweight and 650 million obese worldwide.

The excitement reveals just how complex obesity is and why it requires as much attention, understanding and support as any other critical medical condition. Better knowledge of the intricate bodily mechanisms, signals and pathways challenged by obesity can help us stay ahead of the curve and combat the condition.

A severe crisis

The crisis is severe, because obesity not only reduces average life expectancy, it is linked to many life-limiting diseases: type-2 diabetes, high blood pressure, heart failure, stroke, non-alcoholic liver disease, obstructive sleep apnea, osteoarthritis,  musculoskeletal diseases, depression to several cancers.

Now COVID-19 has brought obesity into sharp focus. A raft of research in the last year has shown how and why people with obesity are four times more likely to be admitted to hospital with severe infection, often with fatal consequences.

The new drug

The drug under trial is semaglutide, approved for the treatment of type 2 diabetes (T2D) in adults and for reducing the risk of heart events in people with T2D and heart disease. In a large-scale international trial across 16 countries, reported in the New England Journal for Medicine on February 10, it was found to bring a significant weight loss of 15 per cent on average among adults with overweight or obesity.

Weight loss with semaglutide was found to result from its action on the appetite-regulating system in the brain, decreased appetite and energy intake. It was also accompanied by improvements in waist circumference (visceral fat is associated with greater disease risk), blood pressure (causes hardening and thickening of the arteries), amount of haemoglobin with sugar stuck to it (a sign of more sugar in blood than normal), lipid levels in the blood (buildup can clog arteries), C-reactive protein (a marker of inflammation) and health-related quality of life.

A little-understood condition

The concept of obesity has been known since ancient times, when extra weight was considered an indication of good health, wealth and prosperity. In the modern era, bias, misunderstanding and stigma cloud perception, making obesity a comorbidity of other chronic diseases at best and a matter of lazy and greedy lifestyle at worst.

Although enormous research has been done to discover the causes of obesity, a standard definition of obesity and its measurements have been endorsed only about a decade ago. Most drugs developed for its treatment have not been approved or have had to be withdrawn from the market, due to adverse side effects. It is in 2013 that the American Medical Association has recognised obesity as a complex, chronic disease on its own, that requires medical attention.

Obesity is now defined by the World Health Organization (Obesity and overweight fact sheet, 2016) as an excess fat mass—measured as a body mass index of ≥30 kg/m2—that impairs health. The WHO encourages  assessment of waist circumference in clinical and research settings, as visceral fat mass is critical. The cut-offs for waist circumference recommended for men and women are 102 cm and 88 cm respectively.

New science of obesity

Obesity brings on numerous biochemical and metabolic changes. New research focuses on a combination of new factors and processes. The increasing sophistication of scholarship has brought in new concepts and new technical vocabulary. In this section, let us understand the new terms, as we take a peek into the biology of obesity.

Visceral fat

It is the fat that wraps around abdominal organs deep inside your body. Unlike the fat that lies underneath the skin, this fat is more likely to raise your risk for serious medical issues: heart disease, Alzheimer’s, type 2 diabetes, stroke, and high cholesterol and more. Visceral fat damages hormonal signalling (insulin resistance) leading to build-up of sugar in the blood. Visceral fat also produces certain molecules that can inflame the tissues, organs and blood vessels (inflammation). In fact, the more the visceral fat, the higher is the number of these molecules.

Insulin resistance

Once food is digested, glucose (or simple sugar) is released into the bloodstream. In response, the pancreas secretes the hormone insulin, which directs the muscle and fat cells to take in glucose. Cells obtain energy from glucose or convert it to fat for long-term storage. With obesity (and visceral fat) the body finds it difficult to respond to insulin—a process known as insulin resistance—leading to excess sugar in blood. Insulin resistance is harmful as it underpins the development of many different medical conditions.

Oxidative stress

Obesity increases oxidative stress. It is a type of metabolic derangement, in which a biological system is unable to detoxify cells and tissues of a type of molecules, called Reactive Oxygen Species (ROS), that cause cell death and tissue destruction. ROS is a type of molecule that contains oxygen and reacts easily with other molecules in a cell. In normal cells, they are present at low and stationary levels. A build up of ROS increases oxidative stress, making it difficult for oxygen to reach where they should.

Inflammation

Obesity brings on metabolic syndrome–a medical condition in which various metabolic processes (or chemical reactions within cells for energy) are deranged. This increases the risk of inflammation—a process when the immune system goes on an overdrive. Obesity contributes to low-grade inflammation, raising the risk of heart diseases, type II diabetes, degenerative diseases, autoimmunity and cancer.

Cytokines

Cytokines are protein molecules that serve as messengers between cells. They play a broad role to help the immune system respond to diseases. Their roles can be good, bad or ugly. Cytokines may be “good,” for instance, when they stimulate the immune system to fight a foreign pathogens or attack tumours. They may be “bad,” when they cause damaging inflammatory diseases, as in rheumatoid arthritis or asthma. They can be “ugly,” as in COVID-19, when they make the body’s immune system go off-kilter. Cytokines directly impair the sensitivity of cells to insulin.

Leptin

Fat cells produce leptin, a hormone that regulates appetite. High leptin levels make one feel full and stop eating. In people with obesity, however, leptin levels are unusually high, yet they feel hungry. This is because, with a high-fat diet or overeating, the body stops responding to leptin—a process known as leptin resistance. This makes fat cells produce even more leptin, triggering cytokines and setting off inflammation.

Gut microbiome

Our gut microbiome is made up of trillions of microbes that protect our gut, train our immune system, digest our food, process indigestible foodstuffs, manufacture vitamins, break down toxins and medications, kill infections and so on). Unhealthy diets (often consumed by obese people) damage the gut microbiome, making it leak bacteria, viruses, food particles and toxins into the bloodstream. The presence of all this alien particles fire up the immune system, triggering chronic inflammation.

Lipotoxicity

It occurs when there is so much fat in your diet that fat cells cannot store any more. The excess fat spills over into the bloodstream. Free fatty acids are then stored in other tissues such as the liver, heart and kidneys. These fats are toxic and cause organ damage: non-alcoholic liver disease, heart failure, and kidney failure. This process is also associated with insulin and leptin resistance.

The good news

The good news is: losing weight reverses many of the above mechanisms. Just losing five per cent of your body weight will have major health benefits: from reducing insulin resistance to relieving oxidative stress.