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. Dr. Gökhan Hotamisligil’s 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. His laboratory’s work primarily embraces the following three major areas of research.

Lineage Commitment and Differentiation of Adipocytes and Control of Energy Metabolism One of the most fundamental questions in biology is how different cell types commit to the specific lineages and regulate their terminal differentiation program. Through the use of adipogenesis as a model system, we study the molecules, which control early stages of differentiation in these cells. While terminal differentiation program of adipocytes is a well-developed area, the earlier developmental stages and the events that control these steps are in complete darkness. We have recently identified a family of transcription factors, which control the very early stages of the transition from the preadipocyte stage to initiation of adipocyte differentiation. Currently we are studying the molecular mechanisms underlying their biology using molecular and cellular approaches as well as mouse genetics. Through this line of research, we hope to generate insights into the process of adipocyte differentiation and the integration of positive and negative hormonal and metabolic signals that regulate the program of differentiation, which could assist the development of new tools for prevention and treatment of obesity.

Inflammatory Pathways and Molecular Basis of Obesity and the Associated Disorders 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. In our earlier studies, we demonstrated that these cells exhibit an inflammatory capacity, which is abnormal in obesity and key to the pathogenesis of insulin resistance and diabetes. Recently, we also identified a key molecular mechanism underlying the link between inflammatory responses and insulin action. This 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, 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 and exploring therapeutic and preventive possibilities for diabetes and obesity by blocking JNK function.

Lipid Trafficking, Signalling 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. We have developed several mice models that are deficient in adipocyte/macrophage FABPs and demonstrated that these animals were protected from some of the most detrimental effects of dietary intake of high levels of fatty acids through alterations in the gene expression pattern of adipocytes and systemic metabolic responses. We have so far demonstrated that FABPs are central to many components of the metabolic syndrome, including obesity, insulin resistance, type 2 diabetes and cardiovascular disease. These proteins are also proximal to generation of the inflammatory responses, especially upon exposure to lipids. Using FABP-deficient animals and cells as model systems, we are trying to establish the components of the signaling pathway that is controlled by FABPs 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.

References:

1. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte FABP. Science, 1996, 274:1377-1379.

2. 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.

3. Tong, Q, Dalgin, G, Xu, H, Ting, CN, Leiden JM and Hotamisligil, GS. GATA transcription factors function as molecular gatekeepers in the preadipocyte-adipocyte transition. Science, 2000, 290:134-138.

4. Nisoli E, Wiesbrock SM, Uysal KT, Briscini L, Giordano A, Cinti S, Carruba MO, and Hotamisligil GS. Tumor necrosis factor-alpha mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity. Proc Natl Acad Sci USA, 2000, 97:8033-8038.

5. 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.

6. 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.

7. 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

8. 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.

9. Tong Q, Sankale JL, Hadigan CM, Tan G, Rosenberg ES, Kanki PJ, Grinspoon SK, Hotamisligil GS. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab. 2003;88:1559-64.

10. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785-8.

11. Wellen KE, Uysal KT, Wiesbrock S, Yang Q, Chen H, Hotamisligil GS. Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity. Endocrinology. 2004;145:2214-20.






			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. Dr. Gökhan Hotamisligil’s 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. His laboratory’s work primarily embraces the following three major areas of research. Lineage Commitment and Differentiation of Adipocytes and Control of Energy Metabolism One of the most fundamental questions in biology is how different cell types commit to the specific lineages and regulate their terminal differentiation program. Through the use of adipogenesis as a model system, we study the molecules, which control early stages of differentiation in these cells. While terminal differentiation program of adipocytes is a well-developed area, the earlier developmental stages and the events that control these steps are in complete darkness. We have recently identified a family of transcription factors, which control the very early stages of the transition from the preadipocyte stage to initiation of adipocyte differentiation. Currently we are studying the molecular mechanisms underlying their biology using molecular and cellular approaches as well as mouse genetics. Through this line of research, we hope to generate insights into the process of adipocyte differentiation and the integration of positive and negative hormonal and metabolic signals that regulate the program of differentiation, which could assist the development of new tools for prevention and treatment of obesity. Inflammatory Pathways and Molecular Basis of Obesity and the Associated Disorders 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. In our earlier studies, we demonstrated that these cells exhibit an inflammatory capacity, which is abnormal in obesity and key to the pathogenesis of insulin resistance and diabetes. Recently, we also identified a key molecular mechanism underlying the link between inflammatory responses and insulin action. This 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, 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 and exploring therapeutic and preventive possibilities for diabetes and obesity by blocking JNK function. Lipid Trafficking, Signalling 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. We have developed several mice models that are deficient in adipocyte/macrophage FABPs and demonstrated that these animals were protected from some of the most detrimental effects of dietary intake of high levels of fatty acids through alterations in the gene expression pattern of adipocytes and systemic metabolic responses. We have so far demonstrated that FABPs are central to many components of the metabolic syndrome, including obesity, insulin resistance, type 2 diabetes and cardiovascular disease. These proteins are also proximal to generation of the inflammatory responses, especially upon exposure to lipids. Using FABP-deficient animals and cells as model systems, we are trying to establish the components of the signaling pathway that is controlled by FABPs 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. References: 1. Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte FABP. Science, 1996, 274:1377-1379. 2. 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. 3. Tong, Q, Dalgin, G, Xu, H, Ting, CN, Leiden JM and Hotamisligil, GS. GATA transcription factors function as molecular gatekeepers in the preadipocyte-adipocyte transition. Science, 2000, 290:134-138. 4. Nisoli E, Wiesbrock SM, Uysal KT, Briscini L, Giordano A, Cinti S, Carruba MO, and Hotamisligil GS. Tumor necrosis factor-alpha mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity. Proc Natl Acad Sci USA, 2000, 97:8033-8038. 5. 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. 6. 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. 7. 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 8. 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. 9. Tong Q, Sankale JL, Hadigan CM, Tan G, Rosenberg ES, Kanki PJ, Grinspoon SK, Hotamisligil GS. Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. J Clin Endocrinol Metab. 2003;88:1559-64. 10. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest. 2003;112:1785-8. 11. Wellen KE, Uysal KT, Wiesbrock S, Yang Q, Chen H, Hotamisligil GS. Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity. Endocrinology. 2004;145:2214-20.