Gökhan S. Hotamisligil, M.D., Ph.D.

Molecular Mechanisms of Metabolic Syndrome

Metabolic syndrome is a complex cluster of diseases including obesity, insulin resistance, type 2 diabetes mellitus, dyslipidemias, hypertension and cardiovascular disease. Yet the molecular mechanisms underlying these pathological states are not well understood. Our research aims to understand adipocyte formation, their contribution to systemic energy homeostasis and elucidate the molecular mechanisms underlying metabolic disease clusters, particularly, obesity, diabetes and atherosclerosis.

  1. Inflammatory Pathways in Obesity and Diabetes. Recent years have witnessed a significant revision of the traditional view of fat cells as simple stores of excess energy. Studies have clearly demonstrated that adipocytes produce and regulate many metabolic and hormonal signals generating profound effects on systemic endocrine equilibrium. Our work has established inflammation as a key mechanism in obesity, insulin resistance and diabetes. Interestingly in obesity adipose tissue exhibits an inflammatory capacity, which is key to the pathogenesis of insulin resistance and diabetes. The lab is interested in identification of a key molecular mechanism underlying the link between inflammatory responses and metabolic pathways in general and insulin action in particular. One such pathway involves obesity-related activation of the serine/threonine kinase, JNK, and the consequent inhibition of insulin receptor signaling via phosphorylation of a substrate of insulin receptor, IRS-1. In mice lacking JNK genes, or upon inhibition of JNK, there is dramatic protection from obesity and diabetes. Genetic evidence also links type 2 diabetes in humans to JNK activation. Currently, we are investigating the detailed molecular mechanisms underlying this crosstalk, mechanisms leading to JNK activation, and exploring therapeutic and preventive possibilities for diabetes and obesity by blocking JNK function.

  2. Endoplasmic Reticulum Stress. We are also broadly pursuing the molecular mechanisms of the crosstalk between inflammatory and metabolic pathways or integration of nutrient and pathogen sensing pathways. These studies have recently led us to the discovery of endoplasmic reticulum (ER) stress as a central mechanism linking metabolic stress with insulin resistance and type 2 diabetes. ER is a critical organelle responsible for the synthesis, maturation, folding and transport of all secreted and transmembrane proteins.  It is also the site for lipid synthesis and packaging.  Obesity also leads to ER stress in metabolically sensitive tissues such as adipose and liver tissues and pancreatic islets.  Through activation of JNK and other stress signaling pathways, ER is linked with regulation of insulin action and glucose and lipid metabolism.  Currently, we are exploring the molecular mechanisms leading to ER stress in obesity and investigating the role of different UPR branches in metabolic homeostasis.  We are also developing strategies for chemically and genetically targeting these pathways for novel therapeutic opportunities against metabolic diseases.

  3. Lipid Trafficking, Signaling and Biology of Fatty Acid Binding Proteins. The nutrient content of diet has a profound influence on a number of vital physiological pathways. Furthermore, a strong link exists between the dietary trends and a number of common diseases such as cancer, diabetes and atherosclerosis. We approach the molecular basis of these interactions by focusing on fatty acid-mediated transcriptional regulation in cells and the biological role of fatty acid binding proteins (FABP) as molecules involved in intracellular lipid trafficking in immune and metabolic cells. We have demonstrated that these lipid chaperones are essential mediators of lipid-induced responses and their inhibition or lead to dramatic resistance against some of the most detrimental effects of dietary intake of high levels of fatty acids.  We have also demonstrated that FABPs are central to many components of the metabolic syndrome, including obesity, insulin resistance, type 2 diabetes, fatty liver disease and cardiovascular disease. These proteins are proximal to generation of the stress and inflammatory responses upon exposure to lipids. Most recently using systemic approaches and lipomics, we identified a fatty acid hormone or a lipokine, regulated by adipose tissue lipid chaperones.  We are investigating the biology of this lipid hormone in several metabolic diseases in experimental models and humans and explore the mechanisms underlying its specific endocrine actions.

References.
1. Cao H, Gerhold K, Mayers J, Wiest MW, Watkins SM, Hotamisligil GS.  Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 2008,134:933-944. PMCID: PMC2728618

2. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140(6): 900–917. PMCID: PMC2887297

3. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS.Cell Metab. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010; 11(6): 467–478. PMCID: PMC2881480

4. Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.Nature. 2011; 473(7348): 528–531. PMCID: PMC3102791

5. Fu S, Fan J, Blanco J, Gimenez-Cassina A, Danial NN, Watkins SM, Hotamisligil GS. Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting. PLoS Genet. 2012; 8(8): e1002902. doi: 10.1371/journal.pgen.1002902 PMCID: PMC3426552

6. Yalcin A, Hotamisligil GS. Impact of ER protein homeostasis on metabolism. Diabetes. 2013; 62(3): 691–693. PMCID: PMC3581203

7. Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, Inouye K, Rickey LM, Ercal BC, Furuhashi M, Tuncman G, Hotamisligil GS. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 2013 May 7; 17(5): 768–778. PMCID: PMC3755450

8. Nakamura T, Arduini A, Baccaro B, Furuhashi M, Hotamisligil GS. Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice. Diabetes. 2014 Feb;63(2):526-34. PMCID: PMC3900541 [Available on 2015/2/1]

9. Engin F, Nguyen T, Yermalovich A, Hotamisligil GS. Aberrant islet unfolded protein response in type 2 diabetes. Sci Rep. 2014 Feb 11;4:4054. doi: 10.1038/srep04054. PMCID:PMC3920274

 

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