Unexpected solutions for the greatest calamities in the human body

Disease and treatment 3. okt 2018 7 min J.S. Simmons Professor of Genetics and Metabolism Gokhan S. Hotamisligil Written by Morten Busch

Chronic metabolic diseases such as diabetes, cardiovascular diseases, cancer and chronic respiratory illness affect billions of people. The recipient of the 2018 EASD–Novo Nordisk Foundation Diabetes Prize for Excellence Professor Gökhan Hotamisligil has devoted his life and career to curbing this global health issue.

Diabetes alone is responsible for more deaths every year than the leading infectious diseases combined. If a condition is so common among humans regardless of where they are on Earth, one has to look back into our evolutionary history to understand the reasons behind this alarming development. 

"For example, one can imagine that neither obesity nor diabetes was a concern for evolution and, as a result, we ended up with weak defences and became vulnerable to disease. Maybe evolution gave us a biological infrastructure that is in mismatch with the current chapter of human history. Our goal is to find the mechanisms underlying these vulnerabilities at the molecular level and help people to overcome them,” says professor of Genetics and Metabolism Gökhan Hotamisligil from Harvard T.H. Chan School of Public Health

An eternal fat cell line

Gökhan Hotamisligil was born in Rize, Turkey and studied medicine at the Ankara University School of Medicine. In the early 1990s, he moved to the United States to complete his training at Harvard Medical School, where his initial interest shifted from neurology and neurobiology to metabolism and metabolic diseases.

“Initially, serendipity brought me into metabolism. In those days, I happened to work with kids with an extremely rare disease called Proteus syndrome. These patients develop large tumours, sometimes the size of a football. They are benign and composed of huge, but healthy, fat cells. My very first idea was to use these tumours to create an eternal human fat cell line and develop ways to study them,” he recollects.

Although this pursuit was ultimately unsuccessful, the idea of understanding the function of fat cells and surrounding metabolic questions has captivated Gökhan Hotamisligil throughout his career. At that time, he came to realize that very little was known in terms of the mechanisms underlying fat cell function and metabolism and, indeed, chronic metabolic diseases overall.

“Given these gaps in knowledge and a paucity of research actively pursuing these questions, we started searching for fat tissue mediators that could contribute to metabolic pathologies, especially these associated with obesity. This resulted in some surprising findings that linked overweight, inflammation and diabetes, fundamental entities of metabolic diseases.”

Different than a sprained ankle

Soon after, in 1995, Gökhan Hotamisligil started his own laboratory to understand how obesity and other challenges of the modern world can induce severe dysfunction in the body and the ways by which it can be reversed. His laboratory has since demonstrated the relevance of an abnormal inflammatory response in impaired metabolic function.

“In the past 25 years, our work has shown that the fat tissue is one of the most sophisticated metabolic and endocrine organs in the body, and it represents a model of unique interactions between immune and metabolic response in obesity and diabetes that can be extrapolated to other tissues. These observations now constitute the pillars of the field called immunometabolism, with extraordinary implications for the most common chronic metabolic diseases.

Gökhan Hotamisligil’s discoveries on the endocrine role of adipose tissue have introduced new models of metabolic control and opened up powerful translational paths for multiple metabolic diseases. Building on genetic evidence establishing the key role of inflammation in metabolic dysregulation, he turned his focus to identifying immune mediators in an attempt to find molecules that could govern known metabolic pathways.

“We first wanted to understand the nature of immune response in an unusual tissue – the fat tissue – and seek answers to fundamental questions about the overall preservation of metabolism. Why and how do metabolic challenges trigger an abnormal immune response? The type of inflammation that occurs in this situation is clearly different from the one that happens if you sprain your ankle.”

Started chasing a mechanistic foundation

Gökhan Hotamisligil coined the term “metaflammation” to describe the metabolically orchestrated and never resolving response. A major breakthrough came in 2002, when his group elucidated critical molecular and immune mechanisms underlying type 2 diabetes.

“We showed that the activity of an inflammatory enzyme called JNK is abnormally elevated in obesity and that its normalization prevents the development of obesity and improves insulin sensitivity.”

Other groups supported this finding by demonstrating a role for JNK in human disease, including a mutation that activates JNK and causes juvenile diabetes.

“We and others have shown that the enzyme also interferes with insulin production and can be activated by free fatty acids and cytokines that play a key role in regulating the immune system.”

This was a major breakthrough not only for elucidating mechanisms of metaflammation in obesity and diabetes but also for opening the path for understanding the underlying causes of other metabolic pathologies. In 2003, Gökhan Hotamisligil became the James S. Simmons Professor at Harvard University in the Department of Genetics and Complex Diseases.

“We were compelled by the idea that metabolic balance could not be explained by a single molecule and started chasing a deep and broad mechanistic foundation for metabolic diseases, resulting in a seminal publication in a few years later.”

A guardian of metabolic integrity

The focus now shifted to an organelle called the endoplasmic reticulum (ER), a vast tubular network in the cell. Its function is to produce proteins for cell membranes and to pass them through a quality control system. However, Gökhan Hotamisligil’s group demonstrated that, in the context of obesity and diabetes, this organelle becomes dysfunctional.

“This powerful organelle succumbs to metabolic challenge. Mouse models showed that obesity causes stress in the ER. This stress then engages many pathological signalling pathways, including JNK, culminating in metabolic dysregulation. We found that stress in the ER is the key driver of obesity and type 2 diabetes, suggesting new opportunities for treating people with these widespread chronic diseases.”

These findings have great relevance to humans as well, since the same systems are altered identically, and rare mutations that compromise the function of the ER cause diabetes in humans.

“The discovery that dysfunction of the ER is central to metabolic pathologies has created a new paradigm to understand obesity and diabetes and to consider a larger cluster of metabolic problems that can be approached from the organelle biology perspective.”

In fact, his group has since produced a series of fascinating discoveries about this new “metabolic biology” of the ER, its alterations during metabolic stress and recovery of normal function by using chemicals, some of which are now in clinical trials.

“Recently we showed that an ER–bound molecule called Nrf1 serves as a guardian of metabolic integrity in cells, defending against metabolic challenges such as excess cholesterol. This was one striking example of the presence of broad and powerful endogenous sense-and-defence systems in the ER that can be leveraged against metabolic stress and disease.”

No signs of metabolic ageing

Beyond the question of how individual cells become dysfunctional in the context of obesity, diabetes and other chronic metabolic diseases, Gökhan Hotamisligil was also interested in the question of how organs that experience the pathologies mentioned above are connected to each other to regulate systemic metabolism.

“It was clear from our work that fat tissue, particularly in the context of obesity and metabolic dysfunction, contributed much more to systemic metabolism through interactions with other organs, especially the liver and the pancreas.”

When Gökhan Hotamisligil started his laboratory, he was fascinated by a fatty acid binding molecule found in the fat tissue called adipocyte protein 2 (aP2). Later, his lab showed the immunological functions of this molecule.

“Surprisingly, when aP2 is not expressed in mice, they become protected against insulin resistance and diabetes even when severely obese due to dietary or genetic interventions. We found that, under these conditions, their general metabolic health was maintained throughout their lives, since they did not develop inflammation, fatty liver disease, atherosclerosis or asthma.”

Although these mice did not live longer than their normal counterparts, they stayed metabolically healthy and did not show signs of metabolic ageing for as long as they lived.

“They even keep their fur, and it shines. But we still do not know exactly how they remain free of inflammation and free of metabolic disease for so long. This is a very interesting and important question.”

Reversing life-threatening alterations

Although aP2 was thought to cause its biological effects in the fat tissue, where it was first found, Hotamisligil’s group noticed dramatic effects of blocking this protein in many other organs. Once again, serendipity opened up an astounding path to explain this phenomenal model of health.

“After decades of work, we realized that aP2, rather than being an intracellular protein, is in fact a novel hormone that creates a communication loop between fat tissue, liver and pancreas, bringing back a tender postulate I had made in my very first years at Harvard.”

In the midst of these discoveries, Gökhan Hotamisligil quickly established collaborations and tested whether circulating aP2 was the actual culprit in metabolic diseases. As suspected, aP2 was indeed elevated in human metabolic diseases, including obesity, diabetes, fatty liver disease and cardiovascular disease.

“In complementary studies from multiple groups around the world, rare people found with mutations in the gene for aP2 were protected against cardiovascular disease and diabetes, just like the mouse model studied in our lab. These findings distil excitement in the field, since they translate into possibilities to therapeutically target aP2 and reverse life-threatening metabolic alterations.”

One of the greatest threats

Recently, Gökhan Hotamisligil’s laboratory has developed antibodies that target aP2, partly blocking its function in the blood. The proof-of-principle results obtained from this simple intervention were exhilarating: the livers of obese mice became as healthy as ones from young and lean mice, and the animals treated with the antibodies were no longer diabetic.

“The next step now will be to investigate whether the same strategy can be applied as a therapy for diabetes and other metabolic diseases in humans. Prospects of therapeutic interventions are stirring while new questions have arisen regarding communication between organs and organelle dysfunction.”

With his high level of commitment to uncovering the core of metabolic regulation, Gökhan Hotamisligil has transformed the field and introduced powerful models that are central for health and disease in general and diabetes in particular. His relentless and inquiring mind pushes him to persevere in the search for deeper understanding of how the body is regulated under metabolic abnormality and dream about contributing to human health.

“In general, defending against deficiencies, not excess, supports survival. Hence, evolution has developed sharp mechanisms in the body to counteract hunger, starvation and hypoglycaemia, whereas defences against excess nutrients were either unnecessary or were limited to short duration, since they used to be very rare.”

Today, with constant access to food, changes in lifestyle and increased lifespan, humans no longer consider these evolutionary traits beneficial.

“In fact, some of these systems have turned into liabilities, and the result is the emergence of one of the greatest threats to human health. Therefore, we must learn how to address these vulnerabilities to circumvent the pandemic, since waiting for evolutionary changes to catch up may take millions of years.”

Professor of Genetics and Metabolism Gökhan Hotamisligil receives the 2018 EASD–Novo Nordisk Foundation Diabetes Prize for Excellence accompanied by DKK 6 million (€806,000) for his outstanding contributions that have increased our knowledge of diabetes.

The major interest of my laboratory is to study the regulatory pathways, which control glucose and lipid metabolism. Our biochemical and genetic studi...

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