Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide.

Hühne T, Steidel E, Holland J, Finkelberg I, Kiewert C, Pape L, Dinkelbach L, Cetiner M

The Journal of clinical endocrinology and metabolism1 Aug 2026

PMID42538728DOI10.1210/clinem/dgag293PepBankPUB-42538728

Publisher page PubMedAsk about this study

Summary

BackgroundBardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood.MethodsIn this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.FindingsAfter 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter.InterpretationSetmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects.FundingGerman Federal Ministry of Research and Education and Rhythm Pharmaceuticals.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. 8 results from people.

01HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with significantly lower BMI after 6 months.
In plain wordsIn BBS patients, setmelanotide treatment was linked to lower BMI after 6 months compared with baseline.
Peptide
Setmelanotide
Outcome
DecreaseBMI
Study
n = 58
Comparator
Baseline
Outcome group
Body weight · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
After 6 months, significant reductions in BMI and HbA1c were observed.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872801
02HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with significantly lower HbA1c after 6 months.
In plain wordsIn BBS patients, setmelanotide treatment was linked to lower HbA1c after 6 months compared with baseline.
Peptide
Setmelanotide
Outcome
DecreaseHbA1c
Study
n = 58
Comparator
Baseline
Outcome group
Glycemic control · Metabolic and weight
Studied dose
Dose not stated
Source sentences
Summary
After 6 months, significant reductions in BMI and HbA1c were observed.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872802
03HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with age-dependent increases in gonadotropins.
In plain wordsIn BBS patients, setmelanotide treatment was linked to increased gonadotropins, depending on age.
Peptide
Setmelanotide
Outcome
IncreaseGonadotropins
Study
n = 58
Comparator
Baseline
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
Dose not stated
Source sentences
Summary
Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872803
04HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with age-dependent increases in testosterone.
In plain wordsIn BBS patients, setmelanotide treatment was linked to increased testosterone, depending on age.
Peptide
Setmelanotide
Outcome
IncreaseTestosterone
Study
n = 58
Comparator
Baseline
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
Dose not stated
Source sentences
Summary
Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872804
05HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with age-dependent increases in estradiol.
In plain wordsIn BBS patients, setmelanotide treatment was linked to increased estradiol, depending on age.
Peptide
Setmelanotide
Outcome
IncreaseEstradiol
Study
n = 58
Comparator
Baseline
Outcome group
Sex hormones and fertility · Endocrine and hormones
Studied dose
Dose not stated
Source sentences
Summary
Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872805
06HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with increased IGF-1 independently of weight change.
In plain wordsIn BBS patients, setmelanotide treatment was linked to increased IGF-1 independently of weight change.
Peptide
Setmelanotide
Outcome
IncreaseIGF-1
Study
n = 58
Comparator
Baseline
Outcome group
Growth hormone and IGF-1 · Endocrine and hormones
Studied dose
Dose not stated
Source sentences
Summary
IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872806
07HumanObservational studyEfficacy outcome
In BBS patients, setmelanotide treatment was associated with decreased TSH.
In plain wordsIn BBS patients, setmelanotide treatment was linked to lower TSH.
Peptide
Setmelanotide
Outcome
DecreaseTSH
Study
n = 58
Comparator
Baseline
Outcome group
Thyroid function · Endocrine and hormones
Studied dose
Dose not stated
Source sentences
Summary
IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872807
08HumanObservational studyEfficacy outcome
In BBS patients, peripheral thyroid hormones showed no corresponding changes during setmelanotide treatment despite decreased TSH.
In plain wordsIn BBS patients, peripheral thyroid hormones did not change with the lower TSH during setmelanotide treatment.
Peptide
Setmelanotide
Outcome
No significant changePeripheral thyroid hormones
Study
n = 58
Comparator
Baseline
Outcome group
Thyroid function · Endocrine and hormones
Studied dose
Dose not stated
Source sentences
Summary
IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones.
2 context sentences(design, population, supporting numbers)
Summary · context
In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally.
Summary · context
Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time.
Show in the study text Report a problemFND-4253872808

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
28 Oct 2026, 02:03 UTC
Study results updated
Version 1
27 Oct 2026, 16:36 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

Publication types

Journal Article

Keywords

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