rs1137101 — LEPR Q223R (Gln223Arg)

The Leptin Receptor Paradox — When Satiety Signals Misfire

Your leptin receptor (LEPR) gene codes for the protein that receives signals from leptin¹¹ leptin
The "satiety hormone" produced by fat cells to signal energy sufficiency, the hormone your fat cells release to tell your brain you've had enough to eat. The Q223R variant (rs1137101) is one of the most common and widely studied LEPR polymorphisms, present in the extracellular domain where leptin binds to its receptor. This non-conservative amino acid change²² non-conservative amino acid change
Glutamine (neutral) to Arginine (positively charged) alters the charge and structure of the leptin-binding region, potentially affecting how efficiently your body responds to satiety signals.

The G allele (encoding Arginine at position 223) has been associated with obesity susceptibility³³ associated with obesity susceptibility
Meta-analysis of 39 studies shows OR=1.23 for GG vs AA across multiple populations, though the functional significance remains debated. Carriers of the G allele tend to have higher circulating leptin levels, which paradoxically may reflect leptin resistance⁴⁴ leptin resistance
Elevated leptin fails to suppress appetite effectively rather than enhanced signaling—a phenomenon central to the biology of obesity.

The Mechanism

The LEPR Q223R polymorphism results from an A-to-G transition (CAG → CGG) at codon 223, located in exon 6 of the leptin receptor gene on chromosome 1p31. This missense variant changes glutamine to arginine in the cytokine receptor homology 1 (CRH1) domain—specifically in the loop connecting the cytokine receptor and fibronectin type III domains where leptin physically binds⁵⁵ leptin physically binds.

The functional consequences of this variant have been controversial. Early association studies⁶⁶ Early association studies
2001 study found R223 homozygotes had 4.5-5% higher body fat percentage linked the G allele to increased BMI and body fat percentage. However, rigorous functional testing in 2009⁷⁷ rigorous functional testing in 2009
Stratigopoulos et al. found no effects on weight, body composition, or STAT3 signaling using mice with the humanized LEPR allele found no effects on body weight, composition, energy expenditure, or leptin-induced STAT3 signaling—casting doubt on direct biological causation.

More recent studies suggest subtle effects on receptor function⁸⁸ subtle effects on receptor function
21% reduction in STAT3 activation in some cell culture studies that may manifest only under specific conditions. The mutant receptor shows normal leptin binding kinetics but may affect receptor trafficking, surface expression, or downstream signaling efficiency. GG genotype carriers consistently show higher circulating leptin levels, which could indicate compensatory upregulation due to impaired leptin sensitivity⁹⁹ impaired leptin sensitivity
Your body produces more leptin trying to overcome reduced receptor responsiveness.

The Evidence

A comprehensive 2024 meta-analysis¹⁰¹⁰ comprehensive 2024 meta-analysis
39 studies with 6,099 obesity cases and 6,711 controls analyzed rs1137101 across Asian and Caucasian populations. The findings showed significant associations across all genetic models: homozygous model (GG vs AA: OR=1.39, 95% CI=1.12-1.73, p=0.003), dominant model (AG/GG vs AA: OR=1.28, p=0.001), and allelic model (G vs A: OR=1.19, p=0.002). The association remained significant in both Asian and Caucasian subgroups, with no evidence of publication bias.

The allele frequency varies dramatically by ancestry¹¹¹¹ allele frequency varies dramatically by ancestry
East Asians: 87% G allele; Europeans: 45% G allele; Africans: 55% G allele. This makes the G allele the major allele in East Asian populations but a balanced polymorphism in other ancestries—one reason why genetic associations may be stronger in Asian studies.

Beyond obesity, the variant has been linked to type 2 diabetes and metabolic syndrome¹²¹² type 2 diabetes and metabolic syndrome
Associated with insulin resistance, dyslipidemia, and elevated fasting glucose. A meta-analysis of PCOS studies¹³¹³ meta-analysis of PCOS studies
33 studies showing rs1137101 significantly associated with PCOS susceptibility found the G allele increased risk of polycystic ovary syndrome, particularly in Asian populations, with the GG genotype correlating with higher leptin levels and worse metabolic profiles in PCOS patients.

Practical Actions

While the variant's direct functional impact remains uncertain, population-level associations suggest GG carriers may benefit from strategies that enhance leptin sensitivity¹⁴¹⁴ enhance leptin sensitivity
Interventions that restore your body's ability to respond to satiety signals. High-protein diets appear particularly relevant: studies show protein intake enhances leptin's satiating effect¹⁵¹⁵ studies show protein intake enhances leptin's satiating effect
High-protein diets reduced spontaneous energy intake by 441 kcal/day in the central nervous system and reduces spontaneous energy intake independent of leptin levels.

Exercise consistently improves leptin sensitivity¹⁶¹⁶ Exercise consistently improves leptin sensitivity
12+ weeks of moderate-intensity aerobic or resistance training, 3-4x/week, particularly moderate-to-high intensity aerobic exercise and resistance training performed 3-4 times weekly for at least 12 weeks. The mechanism involves downregulating SOCS3 and PTP1B proteins that inhibit leptin signaling, while also increasing hypothalamic leptin receptor expression.

Time-restricted eating aligned with circadian rhythms¹⁷¹⁷ Time-restricted eating aligned with circadian rhythms
Confine eating to an 8-10 hour window during daylight hours may help restore leptin rhythmicity—leptin normally peaks at night and is lowest in the morning, and this rhythm is disrupted in obesity. Eating late into the evening compounds leptin resistance by misaligning feeding with circadian leptin secretion patterns.

The Mediterranean dietary pattern¹⁸¹⁸ Mediterranean dietary pattern
Associated with lower leptin levels and higher adiponectin, rich in fiber, omega-3 fatty acids, and anti-inflammatory compounds, has been associated with lower circulating leptin levels and reduced inflammation—both factors that may improve leptin signaling efficiency in genetically predisposed individuals.

Interactions

The LEPR Q223R variant is one of three common LEPR polymorphisms frequently studied together: K109R (rs1137100), Q223R (rs1137101), and K656N (rs1805094). These variants exist in linkage disequilibrium¹⁹¹⁹ linkage disequilibrium
They're inherited together more often than expected by chance (D'=1 but r²<1), meaning they often occur together but aren't perfectly correlated. Some studies suggest compound effects when multiple variants are present, though Q223R appears to have the strongest independent association with obesity.

The leptin receptor functions within a broader neuroendocrine signaling network. Variants in the LEP gene²⁰²⁰ LEP gene
Encodes leptin itself; rs7799039 affects leptin levels (encoding leptin itself, particularly rs7799039) may interact with LEPR variants to determine overall leptin axis function. Additionally, leptin signaling cross-talks with circadian clock genes²¹²¹ cross-talks with circadian clock genes
CLOCK-BMAL1 regulate PPAR expression which affects leptin production like CLOCK and BMAL1, creating a bidirectional relationship where leptin influences circadian rhythms and circadian disruption worsens leptin resistance.

The variant's effects may be most pronounced in the context of obesogenic environments²²²² obesogenic environments
High-calorie, processed food diets and sedentary behavior amplify genetic susceptibility—high-calorie diets, sedentary behavior, and poor sleep. Environmental factors likely obscure the variant's subtle functional effects in free-living populations, explaining why controlled functional studies show minimal impact while epidemiological studies consistently find associations.