BADERC- Gökhan S. Hotamisligil

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.

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.

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. ER meets the fluctuations in its functional capacity by mounting an adaptive response called “unfolded protein response” or UPR. This system helps adapt ER folding capacity and manages ER stress by regulation of protein synthesis and breakdown and also by activating a transcriptional program to assist ER with the necessary components to establish equilibrium. In addition to proteins, ER is also exquisitely sensitive to energy status, nutrients, and pathogens, hence it can integrate these pathways that are central to metabolic pathways.

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.

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. Using cellular, physiological and systems approaches, we are trying to establish the components of the signaling pathway that is controlled by lipid chaperones and the mechanisms by which these pathways are linked to inflammatory and metabolic responses. We hope to generate insights into the mechanisms leading to obesity, diabetes and atherosclerosis and create novel preventive and therapeutic opportunities. 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.

Reference

Uysal KT, Wiesbrock SM, Marino M and Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF alpha function. Nature, 1997, 389:610-614.
Makowski L, Boord JR, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001;7:699-705.
Hotamisligil GS, Linton, MF. Lack of fatty acid binding protein aP2 in the macrophage protects ApoE-deficient mice from atherosclerosis. Nature Medicine, 2001, 7:699-705.
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature, 2002, 420:333-6
Maeda K, Uysal KT, Makowski L, Gorgun CZ, Atsumi G, Parker RA, Bruning J, Hertzel AV, Bernlohr DA, Hotamisligil GS. Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes.2003;52:300-7.
Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, Cao Q, Atsumi G, Malone H, Krishnan B, Minokoshi Y, Kahn BB, Parker RA, Hotamisligil GS. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Met 2005, 1:107-119.
Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB, Hotamisligil GS. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci USA 2006, 103:6970-6975.
Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006, 313:1137-40.
Wellen K, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 2007, 129:537-548.
Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS. Treatment of diabetes and atherosclerosis by inhibiting fatty acid binding protein aP2. Nature 2007, 447:959-65.
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.






			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. 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. 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. ER meets the fluctuations in its functional capacity by mounting an adaptive response called “unfolded protein response” or UPR. This system helps adapt ER folding capacity and manages ER stress by regulation of protein synthesis and breakdown and also by activating a transcriptional program to assist ER with the necessary components to establish equilibrium. In addition to proteins, ER is also exquisitely sensitive to energy status, nutrients, and pathogens, hence it can integrate these pathways that are central to metabolic pathways. 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. 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. Using cellular, physiological and systems approaches, we are trying to establish the components of the signaling pathway that is controlled by lipid chaperones and the mechanisms by which these pathways are linked to inflammatory and metabolic responses. We hope to generate insights into the mechanisms leading to obesity, diabetes and atherosclerosis and create novel preventive and therapeutic opportunities. 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. Reference Uysal KT, Wiesbrock SM, Marino M and Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF alpha function. Nature, 1997, 389:610-614. Makowski L, Boord JR, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001;7:699-705. Hotamisligil GS, Linton, MF. Lack of fatty acid binding protein aP2 in the macrophage protects ApoE-deficient mice from atherosclerosis. Nature Medicine, 2001, 7:699-705. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature, 2002, 420:333-6 Maeda K, Uysal KT, Makowski L, Gorgun CZ, Atsumi G, Parker RA, Bruning J, Hertzel AV, Bernlohr DA, Hotamisligil GS. Role of the fatty acid binding protein mal1 in obesity and insulin resistance. Diabetes.2003;52:300-7. Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, Cao Q, Atsumi G, Malone H, Krishnan B, Minokoshi Y, Kahn BB, Parker RA, Hotamisligil GS. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Met 2005, 1:107-119. Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB, Hotamisligil GS. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci USA 2006, 103:6970-6975. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006, 313:1137-40. Wellen K, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 2007, 129:537-548. Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS. Treatment of diabetes and atherosclerosis by inhibiting fatty acid binding protein aP2. Nature 2007, 447:959-65. 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.