Gokhan Hotamisligil on Inflammation and Metabolic Disorders
Emerging Research Front Commentary, October 2010
Article: Inflammation and metabolic disorders
Authors: Hotamisligil, GS
Gokhan Hotamisligil talks with ScienceWatch.com and answers a few questions about this month's Emerging Research Front paper in the field of Clinical Medicine.
Why do you think your paper is highly cited?
This paper represents the culmination of my life’s work on the interactions between metabolic homeostasis and immune response. More specifically, in this paper, I have tried to provide the framework on how metabolic alterations and a unique form of chronic inflammatory response are so intimately related and so important for health.
This idea emerged quite a while ago, but only recently has it gained widespread recognition and been pursued in many labs. I believe the recognition of this paper reflects the excitement in the field about inflammation and our contributions to that field.
Does it describe a new discovery, methodology, or synthesis of knowledge?
"Chronic metabolic diseases are now the leading cause of mortality and morbidity
around the world. The burden they place on human health and cost of health care is enormous."
This paper represents the synthesis of knowledge regarding the inflammatory basis of metabolic disease, particularly obesity, insulin resistance, and diabetes.
Would you summarize the significance of your paper in layman's terms?
Metabolic homeostasis and immune response are the most essential processes for the survival and health of organisms. Sometimes I use the analogy of "energy and defense" and how critical they are in every aspect of life to describe this paradigm. When we made the initial observations in this area, there was not a comprehensive enough picture to appreciate its central position in chronic metabolic disease.
The importance of this paper is that it provides a comprehensive view, including the logic, of this interface, some evolutionary considerations, and the related mechanisms in play in health and disease. Also, in this synthesis, I presented, for the first time, this form of inflammation as a unique response and suggested the use of "metaflammation" to describe this phenomenon. Finally, this manuscript took me the longest time to put together, something I wish I could have the opportunity to do more often.
How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?
I was involved with the area of metabolism when I was a graduate student in the Spiegelman Lab 20 years ago. At the time, there was a huge gap in mechanistic understanding of obesity and diabetes and there existed a very different view of adipose tissue. The prevailing view depicted adipose tissue as a site for energy storage in abundance and disposal at times of scarcity.
During my dissertation work, I discovered that adipose tissue can secrete biologically significant molecules that can impact metabolism, and the first molecule I identified turned out to be an inflammatory cytokine. This observation stimulated me to devote the rest of my academic life to explore the functional and mechanistic interactions between the metabolism and inflammation.
There were several challenges along the way in this path that I have chosen. First, many people did not think much of this idea at the time. Second, it was extraordinarily difficult to publish papers, especially as a young Assistant Professor. For example, in 1997, we published a paper, which I view as one of the cornerstones in this field, providing clear genetic proof of the impact of inflammatory pathways on insulin action.
We needed to have multiple genetic models of both obesity and inflammatory pathways in question to demonstrate the biology and convince the field. Early on, it always took a little more than usual to get the ideas out. However, I was also very fortunate that we were able to raise funds and pursue the underlying mechanisms, for which I am extremely grateful.
We also enjoyed some breakthroughs along the line and gained important insights into the pathways involved. The general field was also rapidly expanding, thanks to the fabulous discoveries made in other labs, including the discovery of leptin, great advances in genetics, better understanding of adipocyte biology and differentiation, and the insights into insulin action, just to name a few. I guess the past two decades were really exciting times to be involved in the field of metabolism.
"This paper represents the synthesis of knowledge regarding the inflammatory
basis of metabolic disease, particularly obesity, insulin resistance, and diabetes."
Our advance was also stimulated by few key discoveries in my lab, including the discovery of JNK as a critical link between stress, inflammation, and insulin action, linking the biology of lipids to the inflammatory pathways in adipocytes and macrophages through chaperone proteins, discovery of the endoplasmic reticulum stress as an important contributor to metabolic regulation, and discovery of molecules that control the physiological stresses associated with nutrient exposure in metabolic tissues such as adipose tissue.
Where do you see your research leading in the future?
In my view, the most exciting possibilities are now in the emergence of translational avenues. As the knowledge base has now sufficiently expanded and the concepts have found general acceptance, I have no doubt that in the coming decade we will see human applications, whether preventive or therapeutic, emerging from our research and related areas.
I also believe, in the next decade, we will understand how metabolic cues regulate immune response in a much better way and provide a much better resolution of the biology of nutrients in mechanistic way. I am very excited about these possibilities.
Do you foresee any social or political implications for your research?
Chronic metabolic diseases are now the leading cause of mortality and morbidity around the world. The burden they place on human health and cost of health care is enormous. Perhaps the most dramatic impact is now seen in the developing world and in children. These problems also are a sad reflection of disparities among populations and the least privileged are most affected and are equipped with the poorest tools to deal with this plague.
As such, I see the resolution of this problem as having a magnificent positive impact on global health and failing to do so as an equally spectacular but negative outcome.
Gokhan S. Hotamisligil M.D., Ph.D.
James S. Simmons Professor Genetics and Metabolism
Chair, Department of Genetics and Complex Diseases
Harvard School of Public Health
Boston, MA, USA
KEYWORDS: TUMOR-NECROSIS-FACTOR; INDUCED INSULIN-RESISTANCE; ENDOPLASMIC-RETICULUM STRESS; ACID-BINDING PROTEIN; NF-KAPPA-B; PROLIFERATOR-ACTIVATED RECEPTORS; DROSOPHILA FAT-BODY; FACTOR-ALPHA; TNF-ALPHA; ADIPOSE-TISSUE.