Leptin
Leptin (with metreleptin, Myalept, the approved recombinant analogue)
Written by Aaron CuhaReviewed Sep 2026
Also known as: Metreleptin, Myalept, Myalepta, Recombinant methionyl human leptin
The fat-derived hormone that tells the brain how much energy is stored. Replacing it transforms the rare people who lack it; in common obesity a 127-person randomised trial in 1999 found small dose-dependent weight loss and no drug came of it. Metreleptin is approved for generalised lipodystrophy with a boxed warning.
Overview
Leptin is secreted by white fat cells roughly in proportion to fat mass and acts on the hypothalamus through the leptin receptor. It is better understood as a starvation signal than a satiety signal: falling leptin triggers a strong defence of body weight, while raising leptin in someone who already has plenty does very little. The gene was cloned in mice in 1994 and the first humans with congenital leptin deficiency, two severely obese children from one consanguineous family, were described in 1997.
In people who lack it, replacement is dramatic. Three children with congenital leptin deficiency treated with daily recombinant leptin for up to 4 years showed sustained falls in appetite, fat mass, insulin and lipids, normalisation of thyroid hormones, appropriately timed puberty and restoration of T cell function. In lipodystrophy, where fat and therefore leptin are largely absent, an NIH open-label study gave recombinant leptin to 9 women for 4 months: HbA1c fell by 1.9 percentage points in the 8 with diabetes, triglycerides fell 60 percent and liver volume 28 percent. That evidence, extended through a 103-patient NIDDK phase 2 and a 25-patient Texas study, is the basis on which the FDA approved metreleptin (Myalept) on 24 February 2014 as an adjunct to diet for complications of leptin deficiency in congenital or acquired generalised lipodystrophy. The label carries a boxed warning for anti-metreleptin antibodies with neutralising activity and for T-cell lymphoma, and the drug is available only through a REMS programme. It is explicitly not indicated for obesity, partial lipodystrophy, HIV lipodystrophy or liver disease.
In common obesity, the answer came early. A randomised, double-blind, placebo-controlled dose-escalation trial in 1997 to 1998 gave daily recombinant methionyl human leptin at 0 to 0.3 mg/kg to 54 lean and 73 obese adults. There was a dose response: mean weight change at 4 weeks ranged from -0.4 kg on placebo to -1.9 kg at 0.1 mg/kg, and at 24 weeks in obese participants on a 500 kcal deficit from -0.7 kg (n 6) at the lowest dose to -7.1 kg with a standard deviation of 8.5 kg (n 8) at the highest, with injection site reactions the main adverse effect. Baseline leptin did not predict response. The small, variable effect at pharmacological doses in people who already had high leptin is what the term leptin resistance describes, and it is why leptin is not an obesity drug. Antibodies developed in 96 to 100 percent of 579 metreleptin-treated people with obesity in later trials.
Metreleptin is authorised in the EU as Myalepta (30 July 2018) and marketed in Canada under the same name since 2024. Native leptin is not a product anywhere.
Mechanism of action
Established in humans through deficiency and replacement: leptin binds the long form of the leptin receptor on hypothalamic neurons, signalling through JAK2 and STAT3, inhibiting the orexigenic NPY and AgRP neurons and activating POMC neurons upstream of the melanocortin-4 receptor. Absence of leptin in humans causes hyperphagia, severe early obesity, hypogonadotropic hypogonadism, altered thyroid function and impaired T cell immunity, all of which reverse with replacement. In lipodystrophy, replacement lowers glucose, triglycerides and liver fat and reduces food intake and resting metabolic rate. In common obesity, circulating leptin is already high and additional leptin produces small, dose-dependent effects, a state described as leptin resistance whose mechanism (transport across the blood-brain barrier, receptor signalling, SOCS3 feedback) is characterised mostly in rodents. Metreleptin is recombinant methionyl human leptin produced in E. coli: 147 amino acids, one disulfide bond between Cys-97 and Cys-147, about 16.15 kDa, differing from native mature leptin (146 residues) by an added N-terminal methionine. Renal clearance is the major route of elimination and clearance is expected to be delayed in the presence of leptin antibodies.
Human evidence
Extensive but split by population. In congenital leptin deficiency (a handful of children worldwide) and generalised lipodystrophy (open-label studies of 9 to 103 patients) replacement reverses the metabolic disease and is approved. In common obesity a 127-person randomised trial found small, variable, dose-dependent weight loss and antibodies develop in nearly everyone treated.
- Congenital deficiency (JCI 2002, and NEJM 1999 for the first child): 3 children treated up to 4 years, appetite, fat mass, insulin, lipids, thyroid function, puberty and T cell function all corrected. A fourth child in Canada treated 4 years (JCEM 2004) showed the same.
- Lipodystrophy (NEJM 2002): 9 women, 4 months, HbA1c -1.9 points in the 8 with diabetes, triglycerides -60 percent, liver volume -28 percent. Open-label, NIH.
- Lipodystrophy registries: NIDDK phase 2, 103 patients, 2001 to 2015, results posted; UT Southwestern phase 2/3, 25 patients, results posted. Basis of the 2014 approval.
- Partial lipodystrophy (expanded access, 2016): 23 patients, HbA1c -0.88 points and triglycerides -120 mg/dL at 1 year, not statistically significant; outside the approved indication.
- Common obesity (JAMA 1999): 127 adults, randomised, placebo-controlled. Weight change at 24 weeks in obese participants ranged from -0.7 kg to -7.1 kg (SD 8.5) by dose, n 6 to 8 per dose cohort. No leptin obesity drug followed.
- Immunogenicity (Clin Endocrinol 2016): anti-metreleptin antibodies in 96 to 100 percent of 579 people with obesity and 86 to 92 percent of 134 with lipodystrophy; neutralising activity in 3 and 4 people respectively, with worsened metabolic control and two cases of sepsis in the lipodystrophy group.
What this does not tell you: The approved indication rests on open-label data in a rare disease, because placebo-controlled trials in generalised lipodystrophy were judged unethical and impractical; the effect sizes are large but uncontrolled. The obesity trial is small per dose group (6 to 8 obese participants at 24 weeks), the highest-dose result has a standard deviation larger than its mean, and it was accompanied by a 500 kcal deficit diet. Nothing shows leptin helps ordinary weight loss, prevents regain after dieting in the general population, or is safe off-label; the immunogenicity data show that nearly everyone treated makes antibodies and a few develop neutralising ones with serious consequences. Metreleptin's trials say nothing about the native hormone at physiological doses in healthy people, because that has not been studied.
Reading the research record
Leptin is the case study in why a hormone that cures a deficiency does not treat the common disease. The 1994 cloning paper produced immediate commercial interest: Amgen licensed the gene and ran the 1999 JAMA dose-escalation trial in common obesity, which is the trial that settled the question. Weight loss was real and dose-dependent but small and highly variable at doses up to 30 times the lowest, in people whose own leptin was already high. Baseline leptin did not predict who responded. That result, leptin resistance in a sentence, ended leptin as an obesity drug, and the immunogenicity data explain the rest: antibodies in nearly every treated person, with neutralising activity in a few.
The same molecule then followed the deficiency states. Congenital leptin deficiency, described in 1997 in two children, responds to replacement so completely that the case series were enough. Generalised lipodystrophy, in which the near-absence of fat produces near-absence of leptin plus severe insulin resistance, hypertriglyceridaemia and fatty liver, responded in the 2002 NIH study and in the 103-patient NIDDK programme that ran from 2001 to 2015. Amylin Pharmaceuticals, then Bristol-Myers Squibb and AstraZeneca, then Aegerion, then Chiesi carried metreleptin to the 2014 FDA approval, the 2018 EU authorisation and the 2024 Canadian launch. The boxed warning reflects what the trials found: neutralising antibodies that can inhibit the patient's own leptin, and T-cell lymphoma in acquired generalised lipodystrophy, which occurs in that disease with or without treatment but which the label tells prescribers to weigh. The label also states, in its limitations of use, that safety and effectiveness have not been established for partial lipodystrophy or for liver disease including NASH, both of which have been studied and neither of which cleared the bar. Metreleptin is a real success in a rare disease and a documented failure in the common one, and pages that present leptin as a weight-loss hormone are describing the biology of the ob/ob mouse, not the trial in 127 adults.
The evidence, charted
Fig. 1 · evidence composition
7of 10 citations (70%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 8 distinct years, 1994 to 2018, counted from the citation list on this page. The newest citation on file is from 2018, more than five years ago; the published record may have gone quiet.
Fig. 3 · legal status at a glance
US
Approved
UK
Prescription
AU
Prescription
CA
Approved
Approved in 2 of 4, prescription route in 2, not approved in 0. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Animal1994
Positional cloning of the mouse obese gene and its human homologue
Identification of the gene mutated in the ob/ob mouse and of its human homologue, the discovery of leptin. US government funded.
Nature - Human1997
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Two severely obese children from one highly consanguineous family had very low serum leptin despite high fat mass and a homozygous frameshift deletion in codon 133 of the leptin gene, the first genetic evidence that leptin regulates energy balance in humans.
Nature - Human2002
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency
Three children with congenital leptin deficiency treated with daily subcutaneous recombinant human leptin for up to 4 years: sustained reductions in appetite, fat mass, hyperinsulinaemia and hyperlipidaemia, rapid rise in thyroid hormones, appropriately timed puberty, and reversal of reduced CD4 T cell numbers and impaired T cell function. Non-US government funded.
Journal of Clinical Investigation - Human1999
Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial
127 adults (54 lean, 73 obese), randomised double-blind placebo-controlled, daily recombinant methionyl human leptin at 0, 0.01, 0.03, 0.1 or 0.3 mg/kg, 4 weeks for all and 24 weeks for obese participants on a 500 kcal/day deficit. Dose-dependent weight loss (p 0.02 at 4 weeks, p 0.01 at 24 weeks): 4-week change -0.4 kg on placebo to -1.9 kg at 0.1 mg/kg; 24-week change -0.7 kg (n 6) to -7.1 kg, SD 8.5 (n 8). Injection site reactions most common. Baseline leptin did not predict response. Industry and US government funded.
JAMA - Human2002
Leptin-replacement therapy for lipodystrophy
Open-label, 9 women aged 15 to 42 with lipodystrophy and leptin below 4 ng/mL, 8 with diabetes, recombinant methionyl human leptin twice daily for 4 months. HbA1c fell 1.9 percentage points (95 percent CI 1.1 to 2.7) in those with diabetes; triglycerides fell 60 percent and liver volume 28 percent in all nine; antidiabetic drugs were stopped or greatly reduced. NIH and non-US government funded.
New England Journal of Medicine - Human2016
Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy
579 metreleptin-treated people with obesity (two randomised trials, 20 to 52 weeks) and 134 with lipodystrophy (open-label, up to 12.3 years). Anti-metreleptin antibodies developed in 96 to 100 percent with obesity and 86 to 92 percent with lipodystrophy. Three people with obesity and four with generalised lipodystrophy developed in vitro neutralising activity, the latter with worsened metabolic control and two with sepsis. NIH funded.
Clinical Endocrinology - Human2016
Efficacy and Safety of Metreleptin in Patients with Partial Lipodystrophy: Lessons from an Expanded Access Program
Open-label expanded access, 23 patients with partial lipodystrophy and diabetes or hypertriglyceridaemia, 1 year: mean HbA1c change -0.88 percentage points (SE 0.62), triglycerides -119.8 mg/dL (SE 84.1), numerically but not significantly lower. Nausea 39 percent, hypoglycaemia 26 percent. Partial lipodystrophy remains outside the approved indication.
Journal of Diabetes and Metabolism - Human2001
Leptin to Treat Lipodystrophy (NIDDK phase 2)
National Institute of Diabetes and Digestive and Kidney Diseases, phase 2, 103 enrolled, 2001 to 2015, completed, results posted August 2016. The long-running open-label study that underpinned the approval. A separate 25-patient phase 2/3 at UT Southwestern (NCT00896298) completed in 2014 with results posted 2019.
ClinicalTrials.gov - Review2014
MYALEPT (metreleptin) BLA 125390: approval and label
Original approval 24 February 2014, Type 1 new molecular entity, marketing status Prescription (openFDA, 11 September 2026). Label effective March 2024: boxed warning for anti-metreleptin antibodies with neutralising activity (consequences may include inhibition of endogenous leptin and loss of efficacy; severe infection and worsening metabolic control reported) and for T-cell lymphoma in acquired generalised lipodystrophy; REMS restricted; half-life 3.8 to 4.7 hours after single subcutaneous doses in healthy volunteers.
U.S. Food and Drug Administration, Drugs@FDA - Review2018
Myalepta (metreleptin): European public assessment report
EU marketing authorisation issued 30 July 2018 to Chiesi Farmaceutici, orphan designation, status Authorised on 11 September 2026.
European Medicines Agency
Frequently asked questions
Does leptin help with weight loss?
In people who lack it, dramatically. In common obesity, a 127-person randomised trial in 1999 found dose-dependent but small and highly variable weight loss at pharmacological doses (24-week change from -0.7 kg to -7.1 kg, SD 8.5, in cohorts of 6 to 8 on a 500 kcal deficit diet). People with obesity already have high leptin and respond poorly, which is what leptin resistance means. No leptin product is approved for obesity.
What is metreleptin approved for?
Myalept (metreleptin) was approved by the FDA on 24 February 2014 as an adjunct to diet for complications of leptin deficiency in congenital or acquired generalised lipodystrophy, a rare disease. The label states it is not indicated for obesity, partial lipodystrophy, HIV-related lipodystrophy or liver disease including NASH. It is authorised in the EU (2018) and Canada (2024) as Myalepta.
What is the boxed warning on metreleptin?
Two risks, verified against the current FDA label. First, anti-metreleptin antibodies with neutralising activity, whose consequences may include inhibition of the patient's own leptin and loss of drug effect; severe infection and worsening metabolic control have been reported. Second, T-cell lymphoma, reported in patients with acquired generalised lipodystrophy both treated and untreated. Because of both, the drug is dispensed only through a REMS programme.
How different is metreleptin from natural leptin?
By one amino acid. Metreleptin is 147 residues; mature human leptin is 146. The extra residue is an N-terminal methionine left from production in E. coli, which is why the two lengths look inconsistent when quoted side by side.
Does leptin resistance mean my leptin is broken?
It describes the observation that people with obesity have high circulating leptin and respond weakly to more of it. The proposed mechanisms, reduced transport into the brain, receptor signalling changes and SOCS3 feedback, are characterised mainly in rodents. In humans it is defined by the failure of added leptin to produce much weight loss, not by a measurable defect.