Leptin

Metabolic / Appetite

Also known as: OB Protein, Obese Gene Product, LEP, Metreleptin Endogenous

AdipokinesResearch phase: Endogenous hormone (well characterized)Regulatory: Endogenous peptide. Metreleptin (Myalept) is FDA-approved for generalized lipodystrophy. Not effective for common obesity due to leptin resistance.

Mechanism

Leptin is the "satiety hormone" — produced by fat cells in proportion to body fat mass, it signals the brain that energy stores are sufficient. When leptin drops (during dieting or low body fat), the brain triggers intense hunger, reduced metabolism, and fat-storage mode. Most obese individuals have high leptin levels but are leptin-resistant, similar to insulin resistance in diabetes. Recombinant leptin (metreleptin) is approved for rare lipodystrophy.

Technical detail

Leptin is a 167-amino-acid (16 kDa) cytokine-like hormone encoded by the LEP (ob) gene, secreted primarily by white adipose tissue in proportion to fat mass. It signals through the leptin receptor (LEPR/Ob-R, particularly the long isoform Ob-Rb) in the arcuate nucleus, activating JAK2-STAT3, PI3K-Akt, and MAPK/ERK pathways. STAT3 activation upregulates POMC/CART (anorexigenic) and suppresses NPY/AgRP (orexigenic) neurons. Leptin resistance in obesity involves impaired BBB transport, SOCS3-mediated JAK2 inhibition, PTP1B-mediated receptor dephosphorylation, and ER stress in hypothalamic neurons. Leptin deficiency (ob/ob mutations) causes severe obesity reversed by exogenous leptin.

Evidence

Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial
Moon et al. (2005) — International Journal of Obesity — PMID: 16219020
In 284 overweight and obese adults on a mildly energy-restricted diet, 12 weeks of subcutaneous recombinant leptin at three schedules did not significantly improve weight loss versus placebo, while injection-site reactions were more common with active treatment. This is useful negative efficacy evidence for common obesity.
moderate
Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency
Farooqi et al. (2002) — Journal of Clinical Investigation — PMID: 12393845
Case series of three children with congenital leptin deficiency treated with recombinant human leptin for up to 4 years found sustained improvements in appetite, fat mass, hyperinsulinemia, hyperlipidemia, thyroid hormones, pubertal development, and T-cell function, supporting leptin replacement when true deficiency is present.
moderate
Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial
Heymsfield et al. (1999) — JAMA — PMID: 10546697
Randomized dose-escalation trial in lean and obese adults found a dose-response relationship for body-weight and fat loss with daily subcutaneous recombinant leptin over 4 to 24 weeks, with more than 95% of weight loss as fat loss in the highest-dose cohorts and mainly mild injection-site reactions.
moderate

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