Role of Leptin in the Neuroendocrine and Immune Response to Fasting

Role of Leptin in the Neuroendocrine and Immune Response to Fasting in Humans

The purpose of this study will be to determine whether giving leptin (r-metHuLeptin) to a person when he or she is fasting will reverse changes in metabolism, and hormone levels, and immune function associated with fasting, which decreases leptin levels.

Study Overview

• Status: Completed
• Conditions: Fasting
• Intervention / Treatment: Drug: r-metHuLeptin; Other: placebo

Detailed Description

Leptin is a hormone secreted by fat cells under normal conditions and acts in the brain to decrease appetite and increase energy use. Leptin levels usually go down with fasting. This study will evaluate the secretion of an investigational agent called leptin in lean and overweight individuals while fasting and investigate the potential role of leptin as a regulator of immune function and mediator of the neuroendocrine response to food deprivation in humans. Data derived from these studies will provide insights into the mechanisms underlying altered hormone levels and immune function in malnutrition and obesity and thus may provide the basis for future therapeutic interventions for obesity.

Comparison: fed state vs. fasting state vs. fasting + leptin state

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy lean women (with body mass indices [BMI] < 25 kg/m2)
• Overweight otherwise healthy men (with BMI > 27 kg/m2)
• Overweight otherwise healthy women (with BMI > 27 kg/m2).

Exclusion Criteria:

• A history of any illness that may affect the concentrations of the hormones to be studied, e.g. infectious diseases, renal or hepatic failure, type 1 or type 2 diabetes mellitus, cancer or lymphoma, hypogonadism, malabsorption or malnourishment, hypo- or hyperthyroidism, hypercortisolism, alcoholism or drug abuse, anemia, or eating disorder
• On medications known to affect the hormones to be measured (glucocorticoids, anti-seizure medications, and thyroid hormones)
• A known history of anaphylaxis or anaphylactoid-like reactions, or a known hypersensitivity to E. coli derived proteins

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metreleptin; r-metHuLeptin self-administered subcutaneously	Drug: r-metHuLeptin; recombinant human leptin; Other Names: metreleptin; Other: placebo; placebo (no active drug)
Placebo Comparator: Placebo; Placebo, administered in same method as active arm.	Drug: r-metHuLeptin; recombinant human leptin; Other Names: metreleptin; Other: placebo; placebo (no active drug)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortisol		four days
ACTH Mean Level	Response of ACTH to leptin administration in fed and fasting state from baseline was measured	4 days
Immune Function CD3 Count		4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
%Fat Mass		four days
(RMR)	Resting Metabolic rate using calorimetry	four days
Autonomic Function	aldosterone level were measured on day 4 in response to leptin in fed and fasting states and compared with baseline level on day 1	four days

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Amgen; National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Christos S Mantzoros, MD, DSc, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Chrysafi P, Perakakis N, Farr OM, Stefanakis K, Peradze N, Sala-Vila A, Mantzoros CS. Leptin alters energy intake and fat mass but not energy expenditure in lean subjects. Nat Commun. 2020 Oct 13;11(1):5145. doi: 10.1038/s41467-020-18885-9.
• Bouzoni E, Perakakis N, Connelly MA, Angelidi AM, Pilitsi E, Farr O, Stefanakis K, Mantzoros CS. PCSK9 and ANGPTL3 levels correlate with hyperlipidemia in HIV-lipoatrophy, are regulated by fasting and are not affected by leptin administered in physiologic or pharmacologic doses. Metabolism. 2022 Sep;134:155265. doi: 10.1016/j.metabol.2022.155265. Epub 2022 Jul 9.
• Moragianni VA, Aronis KN, Chamberland JP, Mantzoros CS. Short-term energy deprivation alters activin a and follistatin but not inhibin B levels of lean healthy women in a leptin-independent manner. J Clin Endocrinol Metab. 2011 Dec;96(12):3750-8. doi: 10.1210/jc.2011-1453. Epub 2011 Sep 14.
• Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003 May;111(9):1409-21. doi: 10.1172/JCI17490.
• Foo JP, Aronis KN, Chamberland JP, Mantzoros CS. Lack of Day/Night variation in fibroblast growth factor 21 levels in young healthy men. Int J Obes (Lond). 2015 Jun;39(6):945-8. doi: 10.1038/ijo.2014.215. Epub 2014 Dec 26.
• Foo JP, Aronis KN, Chamberland JP, Paruthi J, Moon HS, Mantzoros CS. Fibroblast growth factor 21 levels in young healthy females display day and night variations and are increased in response to short-term energy deprivation through a leptin-independent pathway. Diabetes Care. 2013 Apr;36(4):935-42. doi: 10.2337/dc12-0497. Epub 2012 Nov 27.

Helpful Links

• Click here for more information about the Mantzoros Research Group.
• Click here for more information about Beth Israel Deaconess Medical Center.

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: August 30, 2005
• First Submitted That Met QC Criteria: August 30, 2005
• First Posted (Estimate): September 1, 2005

Study Record Updates

• Last Update Posted (Actual): June 7, 2017
• Last Update Submitted That Met QC Criteria: May 5, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: leptin; immune function; reproductive; fasting; neuroendocrine; energy deficiency associated with short-term fasting
• Other Study ID Numbers: 2002P000049; 2M01RR001032-30 (U.S. NIH Grant/Contract); 5R01DK058785-07 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED