Leptin in Human Energy and Neuroendocrine Homeostasis

NCT00265980 | Terminated Results DMC

• 2 other identifiers: AAAA5988R01DK064773
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity; Weight Loss

Keywords

Leptin; Obesity; Energy; Autonomics; Neuroendocrine

Outcome Measures

Primary Outcomes (1)

• Total Energy Expenditure (TEE)

  To measure the metabolic changes associated with maintenance of a reduced body weight (in kcal/day)

  Baseline, 11 weeks, 18 weeks

Secondary Outcomes (1)

• TEE/FFM

  Baseline, 11 weeks, 18 weeks

Study Arms (3)

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.

Drug: Subcutaneous Placebo

Weight -10% leptin

EXPERIMENTAL

Subjects are studied while at a 10% reduced body weight and receiving leptin injections for 5 weeks.

Drug: Leptin

Interventions

Subcutaneous Placebo DRUG

Twice daily injections of saline in the same volume as will be used for leptin injections.

Also known as: Saline

Weight -10% placebo

Leptin DRUG

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.

Also known as: Metreleptin

Weight -10% leptin

Eligibility Criteria

• Age: 19 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Columbia University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Columbia University

New York, New York, 10032, United States

Location

Related Publications (8)

• 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.

  PMID: 16322796 BACKGROUND

• Rosenbaum 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.

  PMID: 11994393 BACKGROUND

• Baldwin 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.

  PMID: 21917907 BACKGROUND

• Hinkle 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.

  PMID: 23555620 BACKGROUND

• Rosenbaum 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.

  PMID: 25063755 BACKGROUND

• Page-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.

  PMID: 23118421 BACKGROUND

• Kissileff 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.

  PMID: 22237063 BACKGROUND

• Rosenbaum 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.

  PMID: 29920214 RESULT

MeSH Terms

Conditions

Obesity; Weight Loss

Interventions

Sodium Chloride; Leptin; metreleptin

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Body Weight Changes

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Adipokines; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Michael Rosenbaum, MD
• Organization: Professor of Pediatrics and Medicine at the Columbia University

mr475@cumc.columbia.edu

212-305-9949

Study Officials

• Michael Rosenbaum, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, single-blind, crossover study: half of the subjects had placebo first and half had leptin first. The order does not affect data analysis.

Study Record Dates

• First Submitted: December 14, 2005
• First Posted: December 15, 2005
• Study Start: July 1, 2002
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: September 18, 2019
• Results First Posted: September 18, 2019

Record last verified: 2019-08

Locations

US (1)