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Leptin in Human Energy and Neuroendocrine Homeostasis

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ClinicalTrials.gov Identifier: NCT00265980
Recruitment Status : Terminated (Closed by sponsor. Lack of funding.)
First Posted : December 15, 2005
Results First Posted : September 18, 2019
Last Update Posted : September 18, 2019
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Columbia University

Brief Summary:
Previous work in our laboratory, and many others, has shown that body weight is regulated. When anyone, fat or thin, tries to maintain a reduced body weight, many systems affecting energy balance (skeletal muscle, neuroendocrine, and autonomic systems) conspire to slow metabolic rate thus favoring the regain of lost weight. Individuals with leptin deficiency are remarkably similar to weight-reduced individuals. Their metabolism, thyroid hormones, and sympathetic nervous system activity are all low despite their obesity. While administration of leptin to leptin-deficient humans results in substantial weight loss and increases in energy expenditure. However, leptin administration to leptin-sufficient humans at usual body weight has little or no effect on weight unless given in doses 10-20 times what would be considered to be in the normal physiological range. This study examines the hypothesis that leptin is "read" by various systems regulating energy balance as an indicator of how much energy we have stored and that the body perceives the weight-reduced state as a condition of relative leptin insufficiency. Within this model, restoration of leptin to levels present prior to weight loss should relieve much of the metabolic opposition to keeping weight off. Preliminary studies support this hypothesis.

Condition or disease Intervention/treatment Phase
Obesity Weight Loss Drug: Subcutaneous Placebo Drug: Leptin Not Applicable

Detailed Description:

The failure of obesity treatments to sustain weight reduction is widely recognized. The central hypotheses of these studies are that: 1) Energy and neuroendocrine homeostatic systems are altered during the maintenance of a reduced body weight in a manner that favors weight regain; 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 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 changes that characterize the leptin-deficient state. The proposed studies focus on the neuroendocrine, 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.

Healthy lean and overweight subjects are admitted to the General Clinical Research Center at Columbia University Medical College and placed on a liquid formula diet. Calories are adjusted until weight is stable and then subjects undergo testing of neuroendocrine, autonomic, and metabolic function. All subjects undergo an in-patient 10% weight reduction. Subjects are studied in a single blind placebo control design in which they are studied at usual weight and while maintaining a 10% reduced weight. At either usual weight or reduced state subjects undergo a single blind crossover placebo/control study in which they receive placebo, leptin injections while on an isocaloric diet either at usual weight or following a 10% weight loss.

During each of these study periods, subjects will undergo detailed evaluation of 1) energy expenditure; 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) that may influence neuroendocrine and metabolic function. The results of these studies will further delineate the physiology of body weight regulation and of leptin.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized, single-blind, crossover study: half of the subjects had placebo first and half had leptin first. The order does not affect data analysis.
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Leptin in Human Energy and Neuroendocrine Homeostasis
Actual Study Start Date : July 2002
Actual Primary Completion Date : July 2013
Actual Study Completion Date : July 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
No Intervention: Weight initial
Subjects undergo studies at their usual body weight which is used as a baseline against which to compare subjects following weight loss with or without leptin repletion.
Placebo Comparator: Weight -10% placebo
Subjects are studied while at a 10% reduced body weight and receiving placebo injections for 5 weeks.
Drug: Subcutaneous Placebo
Twice daily injections of saline in the same volume as will be used for leptin injections.
Other Name: Saline

Experimental: Weight -10% leptin
Subjects are studied while at a 10% reduced body weight and receiving leptin injections for 5 weeks.
Drug: Leptin
Leptin will be given as twice daily subcutaneous injections in doses titrated to replicate 8 a.m. circulating leptin concentrations measured in the same subjects prior to weight loss.
Other Name: Metreleptin

Primary Outcome Measures :
  1. Total Energy Expenditure (TEE) [ Time Frame: Baseline, 11 weeks, 18 weeks ]
    To measure the metabolic changes associated with maintenance of a reduced body weight (in kcal/day)

Secondary Outcome Measures :
  1. TEE/FFM [ Time Frame: Baseline, 11 weeks, 18 weeks ]
    To measure the total energy expenditure/fat-free mass (FFM) (in kcal/kg).

Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy lean or overweight males and females who have sustained their current weight for at least 6 months.

Exclusion Criteria:

  • Pregnancy
  • Any illness or chronic medication that affect energy expenditure, neuroendocrine function, autonomic function or that would impair ability to tolerate a prolonged hospital stay including rapid weight reduction and vigorous exercise.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00265980

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United States, New York
Columbia University
New York, New York, United States, 10032
Sponsors and Collaborators
Columbia University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Principal Investigator: Michael Rosenbaum, MD Columbia University
Publications of Results:
Other Publications:

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Responsible Party: Columbia University
ClinicalTrials.gov Identifier: NCT00265980    
Other Study ID Numbers: AAAA5988
R01DK064773 ( U.S. NIH Grant/Contract )
First Posted: December 15, 2005    Key Record Dates
Results First Posted: September 18, 2019
Last Update Posted: September 18, 2019
Last Verified: August 2019
Keywords provided by Columbia University:
Additional relevant MeSH terms:
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Weight Loss
Body Weight
Body Weight Changes