Inflammation, Stress and Metabolic Diseases
G. Hotamışlıgil

Studies in our lab and others have clearly demonstrated that chronic inflammation is a central feature of obesity and the associated metabolic disease cluster. This inflammatory response is distinct, appears to respond to intrinsic cues, and does not resemble the classical inflammatory paradigm. New names have been suggested to describe this phenomenon including “metaflammation” or “paraflammation”.

We examine the molecular mechanisms leading to the emergence of these inflammatory responses and how they are linked to metabolic homeostasis as well as disease. Our effort is targeted to major cell types and organs where inflammatory and metabolic pathways interface, such as adipose and liver tissue as well as macrophages. In these systems and various genetic models, we explore the hormonal and metabolic signals that generate profound effects on systemic endocrine equilibrium.

Obesity-related activation of the serine/threonine kinases, such as JNK, and the consequent inhibition of insulin receptor signaling via phosphorylation of a substrate of insulin receptor, IRS-1 is a central mechanism of insulin resistance. In mice lacking JNK genes, there is dramatic protection from obesity and diabetes. There is also genetic evidence that JNK activation is linked to type 2 diabetes in humans. Currently, we are investigating the detailed molecular mechanisms, target cell types and organs and different JNK isoforms underlying this crosstalk. We also investigate the metabolic signals and stresses that give rise to JNK activation and explore therapeutic and preventive possibilities for diabetes, obesity, and atherosclerosis by blocking JNK function. The ability of nutrients to trigger inflammation raises an important question regarding the control of overt inflammation during physiological fluctuations in nutrient and energy exposure. In search for molecules that prevent such aberrant responses, we recently identified a new class of molecules called STAMP that control nutrient-induced inflammatory responses, particularly in adipocytes. These molecules are nutritionally regulated, particularly in visceral adipose tissue, and their absence results in visceral adipose tissue inflammation, stress responses, and insulin resistance under regular dietary conditions. We are currently investigating the molecular mechanisms of actions of these molecules and studying their target cells and organs.

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