Leptin

Summary

Leptin is a 167-amino acid adipokine produced primarily by adipocytes that regulates energy homeostasis, appetite, and metabolism. Recombinant human leptin (metreleptin) is FDA-approved for treatment of generalized lipodystrophy. It is investigational for partial lipodystrophy and congenital leptin deficiency.

Mechanism of Action

Leptin binds to leptin receptors (LepR/ObR) in the hypothalamus and other tissues, activating JAK2-STAT3 signaling pathways to suppress appetite, increase energy expenditure, regulate neuroendocrine function, and modulate immune responses. It signals adipose tissue mass to the brain, suppressing food intake via inhibition of NPY/AgRP neurons and activation of POMC/CART neurons.

Routes of Administration

Goals & Uses

• Treatment of generalized lipodystrophyMetabolic DiseaseHigh
• Neuroendocrine restoration in hypothalamic amenorrheaReproductive EndocrinologyModerate
• Appetite suppression / weight managementObesityLow
• Partial lipodystrophy managementMetabolic DiseaseModerate
• Congenital leptin deficiency treatmentRare Genetic DiseaseModerate
• Immune modulationImmunologyLow

Contraindications

• Active malignancyOncologyHighUse caution or avoid depending on agent and context
• General obesity without lipodystrophyOff Label Use RiskHigh
• Hypersensitivity to metreleptinAllergyHigh

Adverse Effects

• HypoglycemiaMetabolicCommonAbnormally low blood glucose
• Injection site reactionsLocalCommon
• HeadacheNeurologicCommonPain in the head or upper neck
• Anti-metreleptin antibodiesImmunogenicityCommon
• Weight loss / decreased appetiteMetabolicCommon
• LymphomaOncologyRare

Drug Interactions

• InsulinModerateMay increase risk of low blood sugar
• ThiazolidinedionesLow
• SulfonylureasModerateMay increase risk of low blood sugar

Population Constraints

• PregnancyReproductive SafetyRelative
• Hepatic impairmentOrgan FunctionRelative
• Renal impairmentOrgan ImpairmentRelative
• Pediatric patients (<2 years)AgeRelative

Regulatory Status

• European UnionApprovedApproved: Generalized lipodystrophy (adults and children ≥2 years), Partial lipodystrophy (when standard treatments are inadequate)EMA approved Myalepta in 2018 with broader indication including partial lipodystrophy. Orphan drug designation.
• United StatesApprovedApproved: Generalized lipodystrophy (congenital or acquired)FDA approved metreleptin (Myalept) in February 2014. Subject to REMS program. Boxed warning for lymphoma and anti-metreleptin antibody-associated complications.
• United KingdomApprovedApproved: Generalized lipodystrophy, Partial lipodystrophyApproved by MHRA following EU approval; retains post-Brexit authorization for both indications.

Metreleptin (Myalept) is FDA-approved (2014) for leptin deficiency due to generalized lipodystrophy. EMA approved Myalepta in 2018. Use is restricted via REMS program in the US due to risk of anti-metreleptin antibodies and lymphoma risk in patients without lipodystrophy.

Evidence & Sources

No sources recorded yet.