Leptin in Human Energy and Neuroendocrine Homeostasis

Summary

Principal Investigator: RUDOLPH L contact LEIBEL
Affiliation: Columbia University
Country: USA
Abstract: Over 50% of U.S. adults are overweight (BMI > 25 kg/m 2) and "at-risk" for adiposity-related morbidities. The failure of obesity treatments to sustain weight reduction is widely recognized. The central hypotheses of these studies are that: 1.) Energy and neuroendocrine homeostastic systems are altered during the maintenance of a reduced body weight in a manner that favors the regain of lost weight; 2.) These changes occur because weight-reduced individuals are in a state of relative leptin deficiency due to loss of body fat; and 3.) Therefore these changes energy and neuroendocrine homeostatic systems accompanying the maintenance of a reduced body weight will be reversed if circulating leptin concentrations are restored to those that were present prior to weight reduction. Maintenance of a reduced body weight is associated with integrated autonomic and neuroendocrine changes that reduce energy expenditure and increase food intake in a manner that is similar to that seen in rodents and humans who are deficient in, or resistant to, the adipocyte-derived hormone leptin. Systemic leptin administration to leptin-deficient rodents and humans reverses the metabolic (hypometabolism, hyperphagia), autonomic (increased parasympathetic and decreased sympathetic nervous system tone), and neuroendocrine (increased hypothalamic-pituitary-adrenal axis activity, decreased hypothalamic-pituitary -thyroidal and -gonadal axis activity) changes that characterize the leptin-deficient state. The proposed studies focus on the neuroendocrine, behavioral, autonomic, and metabolic changes that characterize the reduced-obese individual, and the effects on these phenotypes of restoration of circulating concentrations of leptin to levels present prior to weight loss. Obese subjects will be admitted to the Columbia University CRC and studied at 1.) usual body weight (Wtinitial), 2.) during maintenance of a 10% reduced body weight (Wt-10%), and 3.) during maintenance of a 10% reduced body weight receiving exogenous leptin at doses sufficient to restore circulating leptin to concentrations present prior to weight loss. During each of these study periods, subjects will undergo detailed evaluation of 1.) energy expenditure (10 day differential excretion of heavy isotopes of water, indirect calorimetry for resting energy expenditure, non-resting energy expenditure, and thermic effect of feeding, time spent in physical activity) and appetitive behavior (assessment of hunger and satiety); 2.) autonomic nervous system tone (serial blockade of sympathetic and parasympathetic inputs, heart rate variability analyses, and urinary catecholamine excretion); 3.) hypothalamic-pituitary -thyroid, -adrenal and -gonadal, axis function; 4.) adipose tissue gene expression; 5.) other molecules (e.g., adiponectin, ghrelin, PYY, IL-6, IL-1Ra) that may influence neuroendocrine and metabolic function. We predict that leptin administration will reverse the metabolic, autonomic, and neuroendocrine phenotypes characterizing the weight-reduced state. The results of these studies will further delineate the physiology of body weight regulation and of leptin.
Funding Period: 2003-07-01 - 2008-04-30
more information: NIH RePORT

Top Publications

  1. pmc Effects of a novel MC4R agonist on maintenance of reduced body weight in diet-induced obese mice
    Alicja A Skowronski
    Department of Pediatrics, Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, NY, USA
    Obesity (Silver Spring) 22:1287-95. 2014
  2. pmc Challenges and opportunities of defining clinical leptin resistance
    Martin G Myers
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA
    Cell Metab 15:150-6. 2012
  3. pmc Estimating energy expenditure in mice using an energy balance technique
    Y Ravussin
    Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
    Int J Obes (Lond) 37:399-403. 2013
  4. pmc Effects of ambient temperature on adaptive thermogenesis during maintenance of reduced body weight in mice
    Yann Ravussin
    Department of Pediatrics, Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, New York, USA
    Am J Physiol Regul Integr Comp Physiol 303:R438-48. 2012
  5. pmc Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ
    Li Qiang
    Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell 150:620-32. 2012
  6. pmc Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro
    Norman Simpson
    Division of Endocrinology, Department of Medicine, Columbia University Medical College, 650 West 168th Street, BB 2006, New York, New York 10032, USA
    Mol Endocrinol 26:1757-72. 2012
  7. pmc Neurofunctional imaging of β-cell dynamics
    P E Harris
    Division of Endocrinology, Department of Medicine, The Naomi Berrie Diabetes Center and Columbia University College of Physicians and Surgeons, New York, NY, USA
    Diabetes Obes Metab 14:91-100. 2012
  8. pmc TNF-α up-regulates protein level and cell surface expression of the leptin receptor by stimulating its export via a PKC-dependent mechanism
    Lixia Gan
    Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA
    Endocrinology 153:5821-33. 2012
  9. doi Brain reorganization following weight loss
    Michael Rosenbaum
    Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
    Nestle Nutr Inst Workshop Ser 73:1-20. 2012
  10. pmc Adaptive thermogenesis in humans
    M Rosenbaum
    Division of Molecular Genetics, Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, NY, USA
    Int J Obes (Lond) 34:S47-55. 2010

Scientific Experts

  • M Rosenbaum
  • WENDY K contact CHUNG
  • Rudolph L Leibel
  • Yann Ravussin
  • R L Leibel
  • Charles A LeDuc
  • Norman Simpson
  • Alicja A Skowronski
  • Kazuhisa Watanabe
  • Y Ravussin
  • Yiying Zhang
  • P E Harris
  • Lixia Gan
  • Li Qiang
  • Martin G Myers
  • Kenneth M Baldwin
  • Lori M Zeltser
  • Rushika Conroy
  • Katherine H Pavlovich
  • Matthew Freeby
  • Dympna Gallagher
  • Antonella Maffei
  • Paul E Harris
  • Denis R Joanisse
  • Rochelle Goldsmith
  • Neeraj Badjatia
  • Boyd A Swinburn
  • Robin Goland
  • George Stratigopoulos
  • M Freeby
  • Ruth B S Harris
  • Stephan Hjorth
  • Michael V Morabito
  • Anders Lehmann
  • Bridget R Mueller
  • Samuel Lee
  • R Gutman
  • C A LeDuc
  • Zachary Freyberg
  • Maria Laura Cremona
  • Wenhui Zhao
  • Rob Knight
  • JONATHAN JAVITCH
  • Stephen R Farmer
  • Kaiying Guo
  • Jack A Yanovski
  • Steven Burroughs
  • Ning Kon
  • Maren Laughlin
  • Liheng Wang
  • Jesse Stombaugh
  • Sangkyu Lee
  • Omry Koren
  • Matthias H Tschop
  • Roee Gutman
  • Aymé Spor
  • Steven B Heymsfield
  • Ruth E Ley
  • Domenico Accili
  • Charles Leduc
  • Carol Haft
  • Wei Gu
  • Yingming Zhao
  • Timothy E McGraw
  • Barbara B Kahn
  • Fadia Haddad
  • Donald J McMahon
  • Monica Girotra
  • Judith Korner
  • Elizabeth Shane
  • Elisabeth L Shamoon
  • Rochelle L Goldsmith
  • Luis Fernandez
  • Katherine Pavlovich
  • Kiwon Lee
  • J Michael Schmidt
  • E Sander Connolly
  • Marin J Schlossberg
  • Stephan A Mayer
  • Jan Claassen
  • Elisabeth Shamoon
  • Yoshifumi Saisho
  • Peter C Butler
  • Masanori Ichise
  • Dileep Kumar
  • Elaine C Rush
  • Klaas R Westerterp
  • Gary Sacks
  • Joy Hirsch
  • Martin Prince

Detail Information

Publications31

  1. pmc Effects of a novel MC4R agonist on maintenance of reduced body weight in diet-induced obese mice
    Alicja A Skowronski
    Department of Pediatrics, Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, NY, USA
    Obesity (Silver Spring) 22:1287-95. 2014
    ..Our aim was to establish a protocol that allows for evaluation of efficacy of weight maintenance agents and to assess the effectiveness of AZD2820, a novel melanocortin 4 receptor (MC4R) agonist in such a paradigm...
  2. pmc Challenges and opportunities of defining clinical leptin resistance
    Martin G Myers
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA
    Cell Metab 15:150-6. 2012
    ..Further advances require biomarkers that can be used to identify patients who may benefit from leptin therapy and that are useful for understanding the determinants of clinical leptin responsiveness...
  3. pmc Estimating energy expenditure in mice using an energy balance technique
    Y Ravussin
    Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA
    Int J Obes (Lond) 37:399-403. 2013
    ..To compare, in mice, the accuracy of estimates of energy expenditure (EE) using an energy balance technique (TEEbal: food energy intake and body composition change) vs indirect calorimetry (TEEIC)...
  4. pmc Effects of ambient temperature on adaptive thermogenesis during maintenance of reduced body weight in mice
    Yann Ravussin
    Department of Pediatrics, Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, New York, USA
    Am J Physiol Regul Integr Comp Physiol 303:R438-48. 2012
    ....
  5. pmc Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ
    Li Qiang
    Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell 150:620-32. 2012
    ..We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import...
  6. pmc Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro
    Norman Simpson
    Division of Endocrinology, Department of Medicine, Columbia University Medical College, 650 West 168th Street, BB 2006, New York, New York 10032, USA
    Mol Endocrinol 26:1757-72. 2012
    ..These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity...
  7. pmc Neurofunctional imaging of β-cell dynamics
    P E Harris
    Division of Endocrinology, Department of Medicine, The Naomi Berrie Diabetes Center and Columbia University College of Physicians and Surgeons, New York, NY, USA
    Diabetes Obes Metab 14:91-100. 2012
    ..Many of these same circuits operate in the central nervous system and can be visualized by molecular imaging. We discuss how these techniques might be applied to measuring the dynamics of β-cell function in real time...
  8. pmc TNF-α up-regulates protein level and cell surface expression of the leptin receptor by stimulating its export via a PKC-dependent mechanism
    Lixia Gan
    Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA
    Endocrinology 153:5821-33. 2012
    ....
  9. doi Brain reorganization following weight loss
    Michael Rosenbaum
    Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
    Nestle Nutr Inst Workshop Ser 73:1-20. 2012
    ..Brain responses to food and the observed changes in energy expenditure that occur during maintenance of a reduced weight are largely reversed by the administration of the adipocyte-derived hormone, leptin. ...
  10. pmc Adaptive thermogenesis in humans
    M Rosenbaum
    Division of Molecular Genetics, Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, NY, USA
    Int J Obes (Lond) 34:S47-55. 2010
    ..Important inferences can be drawn for therapeutic strategies by recognizing obesity as a disease in which the human body actively opposes the 'cure' over long periods of time beyond the initial resolution of symptomatology...
  11. doi VMAT2 quantitation by PET as a biomarker for beta-cell mass in health and disease
    M Freeby
    Department of Medicine of Columbia University Medical Center, New York, NY, USA
    Diabetes Obes Metab 10:98-108. 2008
    ..Thus measurements of [(11)C] DTBZ in the pancreas provide an indirect measurement of BCM. Here we summarize our ongoing efforts to validate the clinical utility of this non-invasive approach to real-time BCM measurements...
  12. ncbi Location, location, location
    Ruth B S Harris
    Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA
    Cell Metab 7:359-61. 2008
    ..While subcutaneous fat seems to confer metabolic benefits, species differences in adipose biology justify caution in interpreting the results...
  13. pmc Regulation of Fto/Ftm gene expression in mice and humans
    George Stratigopoulos
    Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, New York 10032, USA
    Am J Physiol Regul Integr Comp Physiol 294:R1185-96. 2008
    ..Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed "ciliopathy." FTM has recently been shown to be a ciliary basal body protein...
  14. pmc Molecular physiology of weight regulation in mice and humans
    R L Leibel
    Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Int J Obes (Lond) 32:S98-108. 2008
    ..This paper reviews the history of the rationale and methodology of the cloning of leptin (Lep) and the leptin receptor (Lepr), and describes some of the clinical investigation characterizing this axis...
  15. pmc Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli
    Michael Rosenbaum
    Department of Pediatrics, Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University Medical Center New York Presbyterian Medical Center, New York, New York, USA
    J Clin Invest 118:2583-91. 2008
    ..These data are consistent with a model of the weight-reduced state as one of relative leptin deficiency...
  16. pmc Estimating the changes in energy flux that characterize the rise in obesity prevalence
    Boyd A Swinburn
    WHO Collaborating Centre for Obesity Prevention, Faculty of Health, Medicine, Nursing, and Behavioural Sciences, Deakin University, Melbourne, Victoria, Australia
    Am J Clin Nutr 89:1723-8. 2009
    ....
  17. ncbi Relationship between energy balance and complications after subarachnoid hemorrhage
    Neeraj Badjatia
    Departments of Neurology, Neurosurgery, and Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA
    JPEN J Parenter Enteral Nutr 34:64-9. 2010
    ..Subarachnoid hemorrhage patients are hypermetabolic and at risk for developing medical complications. A relationship was hypothesized between energy balance and complications following subarachnoid hemorrhage...
  18. pmc 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls
    Robin Goland
    Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, New York, USA
    J Nucl Med 50:382-9. 2009
    ..We evaluated the feasibility of (11)C-dihydrotetrabenazine PET quantification of pancreatic VMAT2 binding in healthy subjects and patients with long-standing type 1 diabetes...
  19. pmc Responses of gut microbiota to diet composition and weight loss in lean and obese mice
    Yann Ravussin
    Division of Molecular Genetics and Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA
    Obesity (Silver Spring) 20:738-47. 2012
    ..Together, these results suggest that both host adiposity and diet composition impact microbiota composition, possibly through leptin-mediated regulation of mucus production and/or inflammatory processes that alter the gut habitat...
  20. pmc Leptin administration does not prevent the bone mineral metabolism changes induced by weight loss
    Rushika Conroy
    Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Metabolism 60:1222-6. 2011
    ..These results suggest that both decreased bone formation and increased bone resorption underlie bone loss associated with weight loss. Leptin administration did not prevent the uncoupling of bone remodeling that accompanies weight loss...
  21. pmc Energy intake in weight-reduced humans
    Michael Rosenbaum
    Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
    Brain Res 1350:95-102. 2010
    ..Much of this biological opposition to sustained weight loss is mediated by the adipocyte-derived hormone "leptin."..
  22. pmc Effects of weight loss and leptin on skeletal muscle in human subjects
    Kenneth M Baldwin
    Department of Physiology and Biophysics, School of Medicine, University of California at Irvine, Irvine, California, USA
    Am J Physiol Regul Integr Comp Physiol 301:R1259-66. 2011
    ..These findings are consistent with the leptin-reversible increase in skeletal muscle chemomechanical work efficiency and decrease in the ratio of glycolytic/oxidative enzyme activities observed in subjects following dietary weight loss...
  23. ncbi The links between obesity, leptin, and prostate cancer
    Wendy K Chung
    Division of Molecular Genetics and the Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, Russ Berrie Medical Science Pavilion, New York, New York 10032, USA
    Cancer J 12:178-81. 2006
  24. ncbi Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight
    Michael Rosenbaum
    Columbia University College of Physicians and Surgeons, New York Presbyterian Medical Center, New York, NY 10032, USA
    Am J Clin Nutr 88:906-12. 2008
    ..An important clinical issue is whether this reduction, which predisposes to weight regain, persists over time...
  25. pmc Considerations regarding the genetics of obesity
    Wendy K Chung
    Division of Molecular Genetics, Department of Pediatrics, Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA
    Obesity (Silver Spring) 16:S33-9. 2008
    ..New analytic tools will have to be developed to permit the necessary analysis of the gene x gene interactions that must ultimately convey aggregate genetic effects on adiposity...
  26. pmc Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects
    Rochelle Goldsmith
    Department of Medicine, Division of Exercise Physiology, New York, New York, USA
    Am J Physiol Regul Integr Comp Physiol 298:R79-88. 2010
    ....
  27. pmc Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight
    Michael Rosenbaum
    Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
    J Clin Invest 115:3579-86. 2005
    ..These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state...