Leptin

1. Overview

Leptin is a 167-amino acid secreted protein (21-aa signal peptide plus a 146-aa mature hormone, approximately 16 kDa) encoded by the LEP (OB) gene on chromosome 7q31.3 in humans. It is produced predominantly by mature white adipocytes in direct proportion to total body fat mass and secondarily by brown adipose tissue, placenta, gastric chief cells, mammary epithelium, skeletal muscle and selected brain nuclei [1][7]. Leptin is the prototypical adipokine: it was the hormone whose cloning in 1994 transformed adipose tissue from an inert energy depot into a bona fide endocrine organ.

The name derives from the Greek leptos (thin) and was coined by Jeffrey M. Friedman's group at The Rockefeller University following the positional cloning of the mouse ob gene and its human homologue [1]. That eight-year positional-cloning program identified the molecular basis for the spontaneous ob/ob obesity mutation originally described at The Jackson Laboratory in 1950. Within months, recombinant OB protein injection reversed obesity, hyperphagia, hyperinsulinemia and hyperglycemia in ob/ob mice but not in db/db mice, implying the existence of a receptor [2]. The leptin receptor (LEPR, also Ob-R) was cloned in 1995 and shown to be the db gene product [3]. The 2.4 Å crystal structure of human leptin-E100 in 1997 established it as a four-helix-bundle member of the long-chain helical cytokine family (IL-6, granulocyte colony-stimulating factor, leukemia inhibitory factor), stabilized by a single intramolecular disulfide bond between Cys96 and Cys146 [4].

Leptin's principal physiologic role is to signal the magnitude of long-term peripheral energy stores to the central nervous system, where it constrains appetite, permits energy-demanding processes (reproduction, thyroid function, immune competence, growth, linear bone growth), and modulates peripheral glucose and lipid handling. Falling leptin signals starvation and triggers a coordinated set of adaptive responses: hyperphagia, reduced energy expenditure, amenorrhea, hypothyroxinemia, immunosuppression and activation of the HPA axis. This asymmetric physiology explains why leptin replacement is therapeutically effective in states of absolute or relative leptin deficiency (congenital leptin deficiency, lipodystrophy, hypothalamic amenorrhea, post-dieting weight maintenance) but only minimally effective in common obesity, where circulating leptin is chronically elevated and central signaling is blunted — the leptin-resistance state [7][9][25].

The recombinant analog metreleptin (marketed as Myalept in the United States and Myalepta in the European Union) is an N-terminal methionyl human leptin produced in E. coli. It was approved by the FDA on 25 February 2014 as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and is distributed exclusively through a Risk Evaluation and Mitigation Strategy (REMS) program due to risks of anti-drug antibody formation (including neutralizing antibodies), lymphoma, and severe infection [23]. The European Medicines Agency subsequently approved Myalepta for both generalized and partial lipodystrophy in 2018.

Molecular Weight

~16 kDa (16,026 Da mature protein)

Length

167 amino acids (precursor); 146 aa mature peptide after 21-aa signal cleavage

Gene

LEP (OB gene) on chromosome 7q31.3

Structure

Four-helix bundle (long-chain helical cytokine fold) with single intramolecular disulfide bridge (Cys96–Cys146)

Receptor

LEPR (Ob-R), class I cytokine receptor; signals via JAK2/STAT3, PI3K/Akt, MAPK/ERK, SHP2

Half-life

~25 min (endogenous); 3.8–4.7 h (metreleptin SC)

FDA Status

Metreleptin (Myalept) approved 2014 for generalized lipodystrophy; REMS program required

Discovery

OB gene cloned by Zhang, Proenca, Maffei, Barone, Leopold and Friedman (1994); leptin receptor cloned by Tartaglia (1995)

2. Molecular Biology and Structure

LEP Gene and Transcription

The human LEP gene spans ~20 kb on chromosome 7q31.3 and comprises three exons and two introns, with the coding sequence distributed across exons 2 and 3. Transcription is regulated by the adipogenic program (C/EBPalpha, PPARgamma, SREBP-1c), by insulin (which acutely stimulates leptin secretion), by glucocorticoids (stimulatory), by catecholamines via beta-adrenergic signaling (inhibitory), and by inflammatory cytokines including TNF-alpha and IL-6 [7]. Leptin mRNA is restricted largely to mature adipocytes; its abundance scales with adipocyte lipid content, producing the diurnal and fat-mass-dependent plasma leptin pattern. Basal serum leptin is typically 5–15 ng/mL in lean adults and 30–80 ng/mL in obese adults, with mean levels 2- to 3-fold higher in women than men at matched BMI owing to greater subcutaneous adiposity and estrogen-dependent transcription.

Primary Structure

The LEP preproprotein is 167 aa; cleavage of a 21-aa signal peptide during secretion yields the mature 146-aa hormone. The disulfide bridge between Cys96 and Cys146 is essential for biological activity and for the proper four-helix-bundle fold [4]. Metreleptin adds an N-terminal methionine required for E. coli expression, producing a 147-aa analog that is biologically equivalent to native human leptin in receptor binding and downstream signaling.

Tertiary Structure

The 2.4 Å crystal structure (PDB 1AX8) of the E100A mutant (which crystallizes more readily than wild type but retains full biological activity) revealed a four-antiparallel-alpha-helix bundle (helices A, B, C, D) connected by long AB and CD crossovers and a short BC loop, with an up-up-down-down topology characteristic of long-chain helical cytokines [4]. Three receptor-binding epitopes (sites I, II, and III) map to distinct surfaces of this bundle and account for the hexameric 2:4 leptin:LEPR signaling complex.

Leptin Receptor (LEPR/Ob-R)

LEPR is encoded by LEPR on chromosome 1p31.3 and exists as at least six alternatively spliced isoforms in humans (Ob-Ra through Ob-Rf). The long isoform Ob-Rb (LEPR-B) contains the full intracellular signaling domain including a distal conserved box-1 JAK2-docking motif and three phosphorylation-competent tyrosines (Tyr985, Tyr1077, Tyr1138 by mouse numbering). Ob-Rb is enriched in the hypothalamus (arcuate, paraventricular, ventromedial, dorsomedial, lateral nuclei), brainstem (nucleus of the solitary tract) and select peripheral tissues [3][10]. Short isoforms Ob-Ra and Ob-Rc are abundant in choroid plexus and brain microvasculature, where they mediate leptin transport across the blood-brain barrier, and a soluble form Ob-Re circulates as a binding protein that modulates free leptin.

3. Mechanism of Action

LEPR Signaling: JAK2/STAT3 Primary Axis

Leptin binding drives LEPR homodimerization (most likely in a 2:4 leptin-receptor geometry engaging binding sites I, II and III) and activates constitutively receptor-associated Janus kinase 2 (JAK2). Activated JAK2 auto- and trans-phosphorylates, then phosphorylates LEPR intracellular tyrosines. Tyr1138-P recruits and phosphorylates STAT3, which dimerizes, translocates to the nucleus and drives transcription of leptin-responsive genes including SOCS3, POMC, and AgRP (negatively). STAT3 activation in arcuate POMC neurons is the molecularly defined minimum required for leptin's anorexigenic effect, as shown by tissue-specific knockouts [7][10].

Secondary Signaling: PI3K, MAPK, SHP2, mTOR

Tyr985-P recruits SH2-domain-containing tyrosine phosphatase 2 (SHP2), which activates ERK1/2 MAPK signaling relevant to neuronal excitability and gene expression. Tyr1077-P recruits STAT5. Independently, JAK2-mediated IRS-2 phosphorylation activates phosphatidylinositol 3-kinase (PI3K)/Akt, contributing to acute hyperpolarization-versus-depolarization decisions in arcuate POMC and AgRP neurons and to leptin's modulation of glucose homeostasis. Leptin also activates the mTORC1-S6K1 axis within the mediobasal hypothalamus, contributing to food-intake suppression. Negative feedback is dominated by SOCS3, which is STAT3-transcribed and binds both JAK2 and Tyr985-P to terminate signaling, and by protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TCPTP), which dephosphorylate JAK2 and STAT3 respectively [25].

Hypothalamic Circuits: POMC and AgRP/NPY Neurons

The canonical site of central leptin action is the arcuate nucleus (ARC) of the mediobasal hypothalamus, which lies adjacent to the median eminence (a circumventricular organ with attenuated blood-brain barrier). Two reciprocal populations of first-order leptin-sensitive neurons dominate: POMC/CART anorexigenic neurons and AgRP/NPY/GABA orexigenic neurons. Leptin directly depolarizes POMC neurons via a nonselective cation channel and disinhibits them by hyperpolarizing adjacent AgRP/NPY/GABA neurons [10]. Activated POMC neurons release alpha-melanocyte-stimulating hormone (alpha-MSH), which binds MC3R and MC4R on second-order neurons in the paraventricular nucleus and lateral hypothalamic area, suppressing food intake and increasing energy expenditure. AgRP acts as an endogenous MC3R/MC4R inverse agonist and antagonizes alpha-MSH signaling; its hyperpolarization by leptin further unleashes melanocortin tone. Monogenic disruption at any node in this circuit (LEP, LEPR, POMC, PCSK1, MC4R) produces severe early-onset obesity in humans and in mice [17][22].

Peripheral Leptin Actions

Beyond CNS appetite circuits, leptin acts directly on peripheral tissues: pancreatic beta cells (inhibition of insulin secretion via KATP channel modulation); hepatocytes (enhanced insulin sensitivity and reduced steatosis); T lymphocytes (pro-proliferative, Th1-skewing signals; leptin deficiency produces T-cell hyporesponsiveness, as documented in congenitally leptin-deficient patients [12]); endothelium (pro-angiogenic); bone (complex: direct osteoblastic pro-anabolic vs central sympathetic anti-anabolic); and reproductive axis (permissive for pulsatile GnRH secretion, as shown by leptin replacement in hypothalamic amenorrhea [13]).

4. Researched Applications

Generalized Lipodystrophy (FDA-approved)

Generalized lipodystrophies are rare disorders characterized by near-total absence of adipose tissue, extreme hypoleptinemia (serum leptin often <4 ng/mL), severe insulin resistance, diabetes mellitus, hypertriglyceridemia (often >500 mg/dL), and hepatic steatosis. Congenital generalized lipodystrophy (Berardinelli-Seip syndrome) has four subtypes caused by biallelic mutations in AGPAT2 (CGL1), BSCL2/seipin (CGL2), CAV1 (CGL3), or PTRF/CAVIN1 (CGL4). Acquired generalized lipodystrophy (Lawrence syndrome) typically follows autoimmune disease or panniculitis. In the pivotal open-label Oral et al. NEJM trial, 4 months of SC recombinant methionyl human leptin reduced HbA1c by 1.9 percentage points, triglycerides by 60%, and liver volume by 28% in nine leptin-deficient women [11]. Long-term NIH cohort data subsequently demonstrated durable effects over up to 14 years: HbA1c decreased by 2.2 percentage points, triglycerides by 32%, and liver volume by 34% at 12 months, with 41% of insulin-treated patients able to discontinue insulin [20]. Metreleptin received FDA approval on 25 February 2014 as replacement therapy in congenital and acquired generalized lipodystrophy [23]. Early initiation before severe metabolic decompensation produces the best long-term outcomes [24].

Partial Lipodystrophy (EMA-approved; FDA not labeled)

Familial partial lipodystrophies (FPLD 1–6) are characterized by regional fat loss (typically limbs and gluteofemoral depots) with preserved or excess truncal fat; Dunnigan-type FPLD2 (LMNA mutation) and FPLD3 (PPARG mutation) are most common. Leptin is partially reduced but often not in the absolute-deficiency range. Metreleptin is effective particularly in patients with baseline leptin below ~4 ng/mL, producing HbA1c reductions of ~0.6% and triglyceride reductions of ~37% at 12 months [21]. The FDA declined to include partial lipodystrophy in the Myalept label (citing heterogeneity of response) while the EMA included it in the 2018 approval of Myalepta for both generalized and partial forms.

Congenital Leptin Deficiency (Off-label; investigational)

Congenital leptin deficiency (OMIM 614962) is a rare autosomal-recessive disorder of severe, early-onset obesity with intact adiposity producing little or no bioactive leptin. Patients have insatiable hyperphagia from infancy, rapid weight gain, hypogonadotropic hypogonadism, hypothyroidism, T-cell hyporesponsiveness with recurrent infection, and increased risk of T-cell lymphoid malignancies. First identified in a consanguineous Pakistani pedigree with a homozygous single-guanine deletion at codon 133 of LEP [5], additional missense mutations (including biologically inactive variants with normal or elevated immunoreactive leptin but absent bioactivity) have since been described. Daily subcutaneous recombinant methionyl human leptin (0.01–0.04 mg/kg/day, titrated to ~10% of predicted normal serum leptin) normalizes hunger, produces marked fat-specific weight loss, restores pubertal gonadotropin secretion, corrects hypothyroxinemia, and recovers T-cell proliferation [8][12]. Treatment is lifelong.

Functional Hypothalamic Amenorrhea and Relative Energy Deficiency in Sport

Relative energy deficiency, characteristic of low body-weight athletes and restrictive-eating disorders, suppresses leptin below a threshold required for pulsatile GnRH secretion, producing hypothalamic amenorrhea with associated decreased bone mineral density, reduced IGF-1 and hypercortisolism. In a landmark open-label NEJM trial, 0.08 mg/kg/day metreleptin for up to 3 months in 8 women with hypothalamic amenorrhea increased mean LH, LH pulse frequency, follicular diameter, ovarian volume and estradiol; three of eight women achieved ovulatory cycles despite no change in body weight, identifying leptin as a permissive gate on the reproductive axis rather than a simple weight surrogate [13]. Metreleptin is not approved for this indication but remains under active investigation.

Post-Dieting Weight Maintenance

Rosenbaum and Leibel showed in a crossover inpatient metabolic study that maintaining a 10% reduced body weight triggers a coordinated fall in serum leptin, reduced 24-hour and non-resting energy expenditure, reduced thyroid hormones, and increased skeletal muscle work efficiency — together favoring weight regain. Low-dose leptin replacement targeting pre-weight-loss serum concentrations reversed each of these adaptations in 10 weight-reduced subjects, supporting the hypothesis that falling leptin drives post-dieting metabolic compensation [14]. This mechanism underlies ongoing interest in leptin sensitizers and leptin-GLP-1 or leptin-amylin combinations for obesity maintenance after weight loss induced by semaglutide or tirzepatide.

Common Obesity and Leptin Resistance

In contrast to monogenic leptin-deficient states, the overwhelming majority of human obesity is characterized by hyperleptinemia rather than hypoleptinemia — circulating leptin is elevated in proportion to fat mass but is insufficient to restrain appetite or energy intake. This state is termed leptin resistance. In the pivotal Heymsfield 1999 JAMA trial of recombinant methionyl human leptin in obese adults (0.01–0.30 mg/kg/day for 24 weeks), dose-dependent weight loss averaged 7.1 kg at the highest dose but with high interindividual variability, frequent injection-site reactions, and efficacy markedly inferior to current GLP-1 receptor agonists [9]. Mechanisms of leptin resistance include (1) saturation and downregulation of blood-brain-barrier leptin transporters, (2) SOCS3- and PTP1B-mediated termination of LEPR signaling, (3) hypothalamic inflammation and ER stress from chronic high-fat feeding, (4) autophagy defects in arcuate neurons, and (5) altered LEPR trafficking [25]. Leptin monotherapy is therefore not pursued for common obesity, but leptin-sensitizing strategies and leptin-incretin/amylin co-agonism remain active research themes.

Combination Therapy: Pramlintide plus Metreleptin

Amylin Pharmaceuticals demonstrated synergy between the amylin analog pramlintide and metreleptin in a Phase 2 RCT: combination therapy produced 12.7% weight loss at 20 weeks vs 8.2–8.4% with either monotherapy in 177 overweight-obese adults [15]. The mechanism is thought to involve amylin-induced restoration of hypothalamic leptin sensitivity. Phase 3 development was halted in 2011 after a second long-term study identified antibody cross-reactivity concerns, but the combination principle directly informed the design of dual amylin/GLP-1 co-agonists such as cagrilintide/semaglutide (CagriSema).

Setmelanotide and the Downstream Leptin-Melanocortin Axis

When leptin signaling is disabled by LEPR mutations, exogenous metreleptin is ineffective, but the downstream melanocortin pathway remains pharmacologically accessible. The MC4R agonist setmelanotide (Imcivree, Rhythm Pharmaceuticals), approved by the FDA in November 2020, produces ≥10% weight loss at 12 months in 45% of LEPR-deficient and 80% of POMC/PCSK1-deficient patients with reductions in hyperphagia, effectively bypassing the disabled leptin-to-melanocortin transduction step [17][22]. Case reports demonstrate setmelanotide rescue when metreleptin efficacy is lost through neutralizing antibodies in atypical lipodystrophy. The setmelanotide-leptin axis thus represents a node-specific therapeutic strategy: leptin replacement upstream (for LEP deficiency and lipodystrophy) and MC4R agonism downstream (for LEPR, POMC, or PCSK1 deficiency).

5. Clinical Evidence Summary

6. Dosing in Research

7. Pharmacokinetics of Metreleptin

Absorption and Distribution

Metreleptin is administered by subcutaneous injection into the abdomen, thigh, or upper arm. Peak serum concentration (Cmax) is reached approximately 4.0–4.3 hours post-dose after a 0.1 mg/kg subcutaneous dose. Absolute bioavailability has not been formally determined in humans but is estimated at >80% based on population PK models. Apparent volume of distribution is approximately 370 mL/kg, consistent with a water-soluble protein largely restricted to the vascular and interstitial compartments. Metreleptin circulates partly bound to the soluble form of LEPR (Ob-Re), which serves as a binding protein and modulates free-leptin exposure.

Metabolism and Elimination

Metreleptin is cleared principally by renal filtration followed by megalin-mediated tubular uptake and lysosomal degradation, as demonstrated by receptor-associated protein (RAP) studies. Elimination half-life is 3.8–4.7 hours at therapeutic doses, supporting once-daily (twice-daily for some high-dose lipodystrophy regimens) SC dosing. Cytochrome P450 enzymes are not involved in clearance; drug-drug interactions are limited to potential modulation of hepatic CYP expression indirectly by restoration of glucose homeostasis and reduced hepatic steatosis. Dose adjustment is not formally required in mild-to-moderate hepatic or renal impairment but exposure in severe renal impairment has not been systematically studied.

Immunogenicity and Anti-Drug Antibodies

Anti-metreleptin antibodies develop in the majority of treated patients: 86–92% in lipodystrophy and 96–100% in obesity cohorts [18]. Peak titers typically occur at 4–6 months and subsequently decline with continued therapy. In a minority of patients, antibodies with in vitro neutralizing activity develop and may be associated with worsened metabolic control or severe infection [18]. Neutralizing-antibody monitoring is required per the Myalept REMS. Post-marketing cases of severe infection (including sepsis) in the setting of neutralizing antibodies have been reported. Case reports document successful rescue with setmelanotide when neutralizing antibodies abolish metreleptin efficacy in atypical lipodystrophy.

8. Myalept REMS Program

Metreleptin is available in the United States only through the Myalept REMS, which was established at the time of FDA approval in 2014 to mitigate the risks of (1) development of anti-metreleptin antibodies with neutralizing activity, which may inactivate endogenous leptin and worsen the underlying metabolic disease and/or increase susceptibility to severe infection, and (2) a potential increased risk of lymphoma (particularly T-cell lymphoma in acquired generalized lipodystrophy, where underlying immune dysfunction may confound attribution) [23]. REMS elements include:

• Prescriber certification, including attestation of understanding of risks and laboratory-monitoring requirements
• Pharmacy certification (specialty pharmacies only)
• Patient enrollment with documented informed consent
• Required baseline and periodic laboratory monitoring for anti-metreleptin antibodies, neutralizing activity, and signs of lymphoproliferative disease
• A boxed warning in the prescribing information regarding anti-drug antibodies and lymphoma risk

The REMS is reviewed periodically by the FDA; as of 2024 it remains in force with iterative modifications focused on simplifying specialty-pharmacy workflow without relaxing core safety requirements.

9. Safety and Side Effects

Common Adverse Events (Metreleptin)

Pooled data from the NIH open-label cohort (66 patients with generalized lipodystrophy, mean follow-up up to 14 years) and pivotal trials [11][16][20] indicate the following common adverse events:

• Headache (13–33%)
• Hypoglycemia (in patients on concomitant insulin or sulfonylurea; 13–17%)
• Decreased weight (intended but notable at 11%)
• Abdominal pain (8–10%)
• Nausea (5–10%)
• Injection-site reactions (erythema, pruritus, urticaria; 5–10%)
• Fatigue (5–10%)
• Arthralgia, back pain (5%)

Serious Risks (Boxed Warning)

• Anti-drug antibodies with neutralizing activity (see Section 7)
• Lymphoma — post-marketing cases in acquired generalized lipodystrophy, where underlying autoimmune predisposition complicates causal attribution; baseline and on-treatment lymphoma vigilance is mandated
• Severe infection, including sepsis, in a minority of patients with neutralizing antibodies

Hypoglycemia Risk Management

In lipodystrophy patients on insulin, metreleptin's insulin-sensitizing effect may precipitate hypoglycemia within days of initiation; insulin doses commonly require reduction of 50% or more in the first weeks and ongoing downtitration thereafter. Sulfonylurea reduction is similarly required.

Pregnancy and Lactation

Human data are limited. Metreleptin is designated pregnancy category C/undetermined, to be used only if the potential benefit justifies the fetal risk. It is not known whether metreleptin is excreted in human milk.

Pediatric and Geriatric Use

Metreleptin is indicated in pediatric patients with generalized lipodystrophy; weight-based dosing is used in children ≤40 kg. Geriatric experience is limited but no dose adjustment is recommended on the basis of age alone.

10. Leptin Resistance: Mechanisms and Therapeutic Implications

Leptin resistance is the central obstacle to leptin as a therapy for common obesity. Contemporary reviews [25] emphasize that leptin resistance is a multi-level phenomenon rather than a single molecular defect:

1. Transport resistance. Saturable leptin transport across the blood-brain barrier, mediated by short-form LEPR isoforms and megalin in choroid plexus and cerebral microvessels, approaches capacity above ~30 ng/mL plasma leptin. In hyperleptinemic obesity, further peripheral leptin does not proportionally increase brain leptin.

2. SOCS3 and PTP1B upregulation. Chronic leptin signaling induces SOCS3 (direct negative feedback) and PTP1B (a hypothalamic JAK2 phosphatase). Hypothalamic-neuron-specific knockout of either molecule prolongs leptin signaling and restores leptin sensitivity in diet-induced-obese mice, validating the targets. Small-molecule PTP1B inhibitors have entered clinical development.

3. Hypothalamic inflammation and ER stress. High-fat feeding activates IKKbeta/NF-kB in arcuate neurons and induces ER-stress markers (CHOP, XBP1s) that impair LEPR signaling. Chemical chaperones (TUDCA, 4-PBA) restore leptin sensitivity in preclinical models.

4. Defective autophagy. Hypothalamic autophagy declines with age and obesity, impairing POMC neuron function.

5. Altered LEPR trafficking. Obesity is associated with reduced cell-surface LEPR via increased endocytosis and lysosomal degradation.

6. Downstream STAT3 uncoupling. Persistent hyperleptinemia uncouples LEPR from STAT3 in arcuate neurons even when JAK2 phosphorylation is preserved.

Translationally, these mechanisms motivate combinations that restore leptin sensitivity — pramlintide/metreleptin [15], MetAP2 inhibitors (beloranib, abandoned), anti-inflammatory approaches (minocycline, celastrol analogs), and GLP-1-plus-leptin co-administration — and node-specific bypass (setmelanotide at MC4R).

11. Comparative Context: Leptin vs GLP-1 Agonists in Obesity

Leptin (exogenous recombinant methionyl human leptin) and semaglutide (a GLP-1 receptor agonist) occupy fundamentally different therapeutic niches in metabolic medicine despite overlapping anorexigenic effects.

• Mechanism. Leptin signals adipose-tissue sufficiency via LEPR/JAK2/STAT3 in hypothalamic POMC and AgRP neurons. Semaglutide signals acute meal-related satiety via GLP-1 receptors in arcuate, paraventricular, and hindbrain NTS neurons, additionally delaying gastric emptying and stimulating glucose-dependent insulin secretion.
• Common obesity. Semaglutide 2.4 mg weekly produces ~15% mean weight loss over 68 weeks; recombinant leptin produces ~7 kg weight loss at 24 weeks at the highest dose studied (0.30 mg/kg/day) with high inter-individual variability and frequent injection-site reactions [9]. Leptin is not clinically useful for common obesity.
• Leptin-deficient states. Metreleptin is uniquely effective (and necessary) in congenital leptin deficiency and generalized lipodystrophy, whereas GLP-1 agonists have no role in these disorders.
• Weight maintenance after dieting. Low-dose leptin reverses the metabolic adaptation to weight loss [14], whereas continued GLP-1 therapy is required to prevent weight regain (as shown in STEP 4). A plausible future strategy is semaglutide induction followed by leptin-based maintenance, but this remains investigational.

12. Related Peptides

See also: Semaglutide, Setmelanotide, Amylin, Cagrilintide, Oxytocin

13. References

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