Sara Vallerie

Hotamisligil Laboratory
Harvard School of Public Health


The focus of our laboratory is to understand the regulation of metabolic pathways. More specifically, my project involves examining the relation and interaction between the metabolic pathways and the related diseases. It is known that obese patients exhibit chronic inflammation and have higher levels of a family of small proteins, called cytokines, that activate the immune system in the vascular system and adipose tissues. Previous work by Dr. Gokhan Hotamisligil has shown that tumor necrosis factor (TNF-alpha), a cytokine, is expressed in adipose tissue in obesity and induces insulin resistance, a precursor to type II diabetes, in cell culture and in whole mice. Subsequently, the molecular mechanisms linking inflammation to abnormal insulin action were uncovered, which involves a JNK-mediated modification of insulin receptor signaling.

My project focuses on further examination of the JNK-deficient mouse. In obesity or cell culture models, TNF-alpha, and other cytokines, activated JNK. Genetic interference with JNK1 leads to a blockade of the metabolic syndrome. Specifically, JNK1-deficient mice fed a high fat/caloric diet are resistant to weight gain, fatty liver disease, and insulin resistance that occurs when a wild type mice consumes a high fat/caloric diet. Furthermore, in JNK1 deficient cells, there is a reduction in the amount of Ser307 phosphorylation on insulin receptor substrate 1 (IRS-1) upon treatment with TNF-alpha compared with wild type cells, an indicator of improved insulin sensitivity. My goals are to examine what tissues play an important role in mediating this phenotype in JNK-deficient mice and also to examine the mechanism of JNK action in the cells. I hope these studies will lead to yet better understanding of the mechanisms of obesity and type 2 diabetes and drug development that will alleviate the metabolic syndrome and its associated disease

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