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Research ArticleMetabolism Free access | 10.1172/JCI31743

The central melanocortin system directly controls peripheral lipid metabolism

Ruben Nogueiras,1,2 Petra Wiedmer,2 Diego Perez-Tilve,1 Christelle Veyrat-Durebex,3 Julia M. Keogh,4 Gregory M. Sutton,5 Paul T. Pfluger,1 Tamara R. Castaneda,1 Susanne Neschen,2 Susanna M. Hofmann,6 Philip N. Howles,6 Donald A. Morgan,7 Stephen C. Benoit,1 Ildiko Szanto,8 Brigitte Schrott,1 Annette Schürmann,2 Hans-Georg Joost,2 Craig Hammond,9 David Y. Hui,6 Stephen C. Woods,1 Kamal Rahmouni,7 Andrew A. Butler,5 I. Sadaf Farooqi,4 Stephen O’Rahilly,4 Françoise Rohner-Jeanrenaud,3 and Matthias H. Tschöp1,2

1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

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1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

Find articles by Rohner-Jeanrenaud, F. in: JCI | PubMed | Google Scholar

1Obesity Research Center, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 3Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 4University Departments of Medicine and Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, United Kingdom. 5Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA. 6Center of Arteriosclerosis Studies, Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA. 7Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 8Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 9Eli Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA.

Address correspondence to: Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati Genome Research Institute, 2170 East Galbraith Road, Cincinnati, Ohio 45237, USA. Phone: (513) 558-8648; Fax: (513) 558-8656; E-mail: tschoemh@ucmail.uc.edu.

Find articles by Tschöp, M. in: JCI | PubMed | Google Scholar

Published September 20, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI31743.
© 2007 The American Society for Clinical Investigation
Published September 20, 2007 - Version history
Received: February 7, 2007; Accepted: July 30, 2007
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Abstract

Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.

Version history
  • Version 1 (September 20, 2007): No description
  • Version 2 (November 1, 2007): No description
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