ObesityNCT00265980
Leptin in Human Energy and Neuroendocrine Homeostasis
A study testing Leptin in people with Obesity and Weight Loss, run by Columbia University at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 19 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Obesity, Weight Loss
- What is being tested?
- Leptin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2002to Jul 2013
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy lean or overweight males and females who have sustained their current weight for at least 6 months.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Obesity, Weight Loss
- Being tested
- Subcutaneous Placebo, Leptin
- Keywords
- Leptin, Obesity, Energy, Autonomics, Neuroendocrine
- Medical subject headings
- Obesity, Weight Loss
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Subcutaneous PlaceboDrug
Also called Saline
Twice daily injections of saline in the same volume as will be used for leptin injections.
LeptinDrug
Also called Metreleptin
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.
| Study group | Role | What they receive |
|---|---|---|
| Weight initial | No intervention | 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. |
| Weight -10% placebo | Placebo comparator | Subjects are studied while at a 10% reduced body weight and receiving placebo injections for 5 weeks. Receives: Drug: Subcutaneous Placebo |
| Weight -10% leptin | Experimental | Subjects are studied while at a 10% reduced body weight and receiving leptin injections for 5 weeks. Receives: Drug: Leptin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Total Energy Expenditure (TEE)
To measure the metabolic changes associated with maintenance of a reduced body weight (in kcal/day)
Measured: Baseline, 11 weeks, 18 weeks
Secondary outcomes (1)
TEE/FFM
To measure the total energy expenditure/fat-free mass (FFM) (in kcal/kg).
Measured: Baseline, 11 weeks, 18 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2005 (estimated)
- Study startJul 2002
- Primary completionJul 2013
- Study completionJul 2013
Why it stopped: Closed by sponsor. Lack of funding.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for ObesityStudies of the same condition, open and under way.
- More trials run by Columbia UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- 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 blind
- Who is masked
- Participant
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Columbia University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Michael Rosenbaum, MD, Principal investigator, Columbia University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00265980
- Sponsor's protocol ID
- AAAA5988
- Other IDs
- R01DK064773
- Status last verified
- Aug 2019
- First submitted
- 14 Dec 2005
- Last updated
- 18 Sep 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005 Dec;115(12):3579-86. doi: 10.1172/JCI25977.
PubMed 16322796Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. 2002 May;87(5):2391-4. doi: 10.1210/jcem.87.5.8628.
PubMed 11994393Baldwin KM, Joanisse DR, Haddad F, Goldsmith RL, Gallagher D, Pavlovich KH, Shamoon EL, Leibel RL, Rosenbaum M. Effects of weight loss and leptin on skeletal muscle in human subjects. Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1259-66. doi: 10.1152/ajpregu.00397.2011. Epub 2011 Sep 14.
PubMed 21917907Hinkle W, Cordell M, Leibel R, Rosenbaum M, Hirsch J. Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans. PLoS One. 2013;8(3):e59114. doi: 10.1371/journal.pone.0059114. Epub 2013 Mar 21.
PubMed 23555620Rosenbaum M, Leibel RL. 20 years of leptin: role of leptin in energy homeostasis in humans. J Endocrinol. 2014 Oct;223(1):T83-96. doi: 10.1530/JOE-14-0358. Epub 2014 Jul 25.
PubMed 25063755Page-Wilson G, Reitman-Ivashkov E, Meece K, White A, Rosenbaum M, Smiley RM, Wardlaw SL. Cerebrospinal fluid levels of leptin, proopiomelanocortin, and agouti-related protein in human pregnancy: evidence for leptin resistance. J Clin Endocrinol Metab. 2013 Jan;98(1):264-71. doi: 10.1210/jc.2012-2309. Epub 2012 Nov 1.
PubMed 23118421Kissileff HR, Thornton JC, Torres MI, Pavlovich K, Mayer LS, Kalari V, Leibel RL, Rosenbaum M. Leptin reverses declines in satiation in weight-reduced obese humans. Am J Clin Nutr. 2012 Feb;95(2):309-17. doi: 10.3945/ajcn.111.012385. Epub 2012 Jan 11.
PubMed 22237063Rosenbaum M, Goldsmith RL, Haddad F, Baldwin KM, Smiley R, Gallagher D, Leibel RL. Triiodothyronine and leptin repletion in humans similarly reverse weight-loss-induced changes in skeletal muscle. Am J Physiol Endocrinol Metab. 2018 Nov 1;315(5):E771-E779. doi: 10.1152/ajpendo.00116.2018. Epub 2018 Jun 19.
PubMed 29920214
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Leptin in Human Energy and Neuroendocrine Homeostasis
- ClinicalTrials.gov ID
- NCT00265980
- Acronym / sponsor ID
- AAAA5988
- Conditions
- Obesity, Weight Loss
- Keywords
- Leptin, Obesity, Energy, Autonomics, Neuroendocrine
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Closed by sponsor. Lack of funding.
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Columbia UniversityUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Jul 2002 (actual)
- Primary completion
- Jul 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 15 Dec 2005 (estimated)
- Results
- Posted 18 Sep 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| Weight initial | No intervention | –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. |
| Weight -10% placebo | Placebo comparator | Drug: Subcutaneous PlaceboSubjects are studied while at a 10% reduced body weight and receiving placebo injections for 5 weeks. |
| Weight -10% leptin | Experimental | Drug: LeptinSubjects are studied while at a 10% reduced body weight and receiving leptin injections for 5 weeks. |
Who may qualify
- Ages
- 19 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Healthy lean or overweight males and females who have sustained their current weight for at least 6 months.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Subcutaneous PlaceboAlso: SalineTwice daily injections of saline in the same volume as will be used for leptin injections. | Drug | Weight -10% placebo |
| LeptinAlso: MetreleptinLeptin 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. | Drug | Weight -10% leptin |
Primary outcome
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)
1 secondary outcome
TEE/FFM
Time frame: Baseline, 11 weeks, 18 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16322796Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005 Dec;115(12):3579-86. doi: 10.1172/JCI25977.
- Background: PubMed 11994393Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab. 2002 May;87(5):2391-4. doi: 10.1210/jcem.87.5.8628.
- Background: PubMed 21917907Baldwin KM, Joanisse DR, Haddad F, Goldsmith RL, Gallagher D, Pavlovich KH, Shamoon EL, Leibel RL, Rosenbaum M. Effects of weight loss and leptin on skeletal muscle in human subjects. Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1259-66. doi: 10.1152/ajpregu.00397.2011. Epub 2011 Sep 14.
- Background: PubMed 23555620Hinkle W, Cordell M, Leibel R, Rosenbaum M, Hirsch J. Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans. PLoS One. 2013;8(3):e59114. doi: 10.1371/journal.pone.0059114. Epub 2013 Mar 21.
- Background: PubMed 25063755Rosenbaum M, Leibel RL. 20 years of leptin: role of leptin in energy homeostasis in humans. J Endocrinol. 2014 Oct;223(1):T83-96. doi: 10.1530/JOE-14-0358. Epub 2014 Jul 25.
- Background: PubMed 23118421Page-Wilson G, Reitman-Ivashkov E, Meece K, White A, Rosenbaum M, Smiley RM, Wardlaw SL. Cerebrospinal fluid levels of leptin, proopiomelanocortin, and agouti-related protein in human pregnancy: evidence for leptin resistance. J Clin Endocrinol Metab. 2013 Jan;98(1):264-71. doi: 10.1210/jc.2012-2309. Epub 2012 Nov 1.
- Background: PubMed 22237063Kissileff HR, Thornton JC, Torres MI, Pavlovich K, Mayer LS, Kalari V, Leibel RL, Rosenbaum M. Leptin reverses declines in satiation in weight-reduced obese humans. Am J Clin Nutr. 2012 Feb;95(2):309-17. doi: 10.3945/ajcn.111.012385. Epub 2012 Jan 11.
- Results publication: PubMed 29920214Rosenbaum M, Goldsmith RL, Haddad F, Baldwin KM, Smiley R, Gallagher D, Leibel RL. Triiodothyronine and leptin repletion in humans similarly reverse weight-loss-induced changes in skeletal muscle. Am J Physiol Endocrinol Metab. 2018 Nov 1;315(5):E771-E779. doi: 10.1152/ajpendo.00116.2018. Epub 2018 Jun 19.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Rosenbaum, MD principal investigator
Columbia University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Leptin in people with Obesity and Weight Loss, run by Columbia University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Total Energy Expenditure (TEE) (time frame: Baseline, 11 weeks, 18 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00265980, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2019.