rs10767664 — BDNF

BDNF's Second Role — The Appetite Suppressor in Your Hypothalamus

Most people who know about BDNF (brain-derived neurotrophic factor) know it as the brain's plasticity hormone — the factor that strengthens memories, supports neuroplasticity, and responds to exercise. That well-known story belongs to rs6265 (Val66Met), a coding variant that affects BDNF secretion in neurons and is covered in the Brain & Mental Health section of this encyclopedia.

This variant — rs10767664 — tells a different story entirely. It sits in intron 3 of the BDNF gene, within a conserved enhancer region called BE5.1¹¹ conserved enhancer region called BE5.1
A 494 base pair stretch of DNA that has been preserved across vertebrate evolution for over 360 million years, suggesting a critical biological function. It controls BDNF expression specifically in hypothalamic cells, and it affects BDNF's role not in learning and memory but in hypothalamic satiety signaling²² hypothalamic satiety signaling
The process by which the hypothalamus receives signals from the body that food intake is sufficient and suppresses appetite. BDNF in the ventromedial hypothalamus is a critical relay in this satiety circuit. This variant was identified in one of the largest genome-wide association studies of body mass index ever conducted, affecting approximately 250,000 individuals, and the association is among the strongest ever found for obesity.

The Mechanism

BDNF is highly expressed in the ventromedial hypothalamus (VMH)³³ ventromedial hypothalamus (VMH)
The region of the hypothalamus primarily responsible for satiety. Neurons here receive leptin signals and fire to suppress appetite. When BDNF signaling in the VMH is reduced, animals overeat and gain weight, where it functions as a critical downstream effector of the melanocortin-4 receptor (MC4R) pathway⁴⁴ melanocortin-4 receptor (MC4R) pathway
MC4R is activated by alpha-MSH, a hormone produced when leptin signals "enough food." MC4R activation upregulates BDNF in the VMH, which then sustains the satiety signal. This is why MC4R and BDNF variants both appear as top obesity GWAS hits — they are in the same molecular pathway. When you eat and leptin rises, MC4R activation stimulates BDNF expression in VMH neurons⁵⁵ stimulates BDNF expression in VMH neurons
Xu B et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nature Neuroscience, 2003, and that BDNF signal then propagates satiety through TrkB receptors, suppressing further food intake.

The rs10767664 A allele disrupts this process at the source. Research in primary hypothalamic cells shows that the T allele (the protective minor allele) functions as an active enhancer of BDNF promoter 4 — driving BDNF transcription in response to neuronal signals. The A allele, which is actually the more common version, fails to enhance promoter activity. The result: reduced BDNF expression in the hypothalamus, weaker satiety signaling after meals, and a sustained drive to keep eating.

Recent research further refined this picture by showing that astrocytes in the VMH⁶⁶ astrocytes in the VMH
Non-neuronal support cells that regulate synaptic communication. VMH astrocytes express TrkB.T1 (a truncated BDNF receptor) and use BDNF signaling to modulate neuronal activity in response to energy state also require intact BDNF/TrkB signaling⁷⁷ require intact BDNF/TrkB signaling
Ameroso et al. Astrocytic BDNF signaling within the ventromedial hypothalamus regulates energy homeostasis. Nature Metabolism, 2022 for normal energy homeostasis. Mice lacking TrkB.T1 in VMH astrocytes develop increased body weight, leptin resistance, and impaired glucose tolerance — a metabolic syndrome profile strikingly similar to what rs10767664 A homozygotes are at risk for.

The Evidence

The GIANT consortium meta-analysis⁸⁸ GIANT consortium meta-analysis
Speliotes EK et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genetics, 2010 of 249,796 individuals identified the BDNF locus as one of 18 new BMI- associated signals, with rs10767664 reaching p = 5 × 10⁻²⁶ — far beyond the genome-wide significance threshold. Each copy of the A allele increases BMI by an estimated 0.19 kg/m² (95% CI 0.13–0.25), placing the BDNF locus among the strongest obesity GWAS hits identified. The effect was confirmed in a diverse-ancestry replication cohort.

Human feeding data confirms the mechanistic prediction. In the Look AHEAD Trial⁹⁹ Look AHEAD Trial
A large NIH-funded trial studying lifestyle intervention for overweight adults with type 2 diabetes, n=5,145, carriers of the AA genotype consumed over 100 kcal per day more¹⁰¹⁰ carriers of the AA genotype consumed over 100 kcal per day more
McCaffery et al. Obesity susceptibility loci and dietary intake in the Look AHEAD Trial. Am J Clin Nutr, 2012 than carriers of the T allele (p = 0.006), and this effect persisted after adjusting for body weight — confirming it reflects an appetite difference, not just a consequence of greater body mass.

The metabolic consequences extend beyond weight. In a prospective study of 507 obese Caucasian women, T allele carriers faced 1.33-fold higher odds of type 2 diabetes¹¹¹¹ T allele carriers faced 1.33-fold higher odds of type 2 diabetes
de Luis DA et al. rs10767664 gene variant in BDNF is associated with diabetes mellitus type 2 in Caucasian females with obesity. Ann Nutr Metab, 2017 (95% CI 1.17–2.08) compared to non-carriers, with higher BMI, waist circumference, fasting glucose, HOMA-IR, insulin, and CRP in the T-carrier diabetic subgroup. A separate intervention study in 80 obese patients on a calorie-restricted diet found AA homozygotes lost significantly more weight¹²¹² AA homozygotes lost significantly more weight
de Luis DA et al. RS 10767664 gene variant in brain derived neurotrophic factor (BDNF) affect metabolic changes and insulin resistance after a standard hypocaloric diet. J Diabetes Complications, 2018 (3.4 vs 1.7 kg, p=0.01) with better fat mass reduction, triglyceride improvement, and insulin sensitivity gains than T carriers, suggesting T allele carriers may have a complex metabolic phenotype with worse insulin resistance independent of current weight.

Practical Implications

The A risk allele is very common — roughly 63% of people of European descent are AA homozygotes and another 32% are AT heterozygotes. Carrying the risk allele does not mean inevitable obesity; it means your hypothalamic satiety brake at this locus is less powerful than in the uncommon TT genotype. The 100 kcal/day difference in intake observed in the Look AHEAD trial is modest in isolation, but accumulated over months and years — and compounded with other obesity-risk loci — it represents a genuine appetite disadvantage worth counteracting proactively.

The most genotype-specific intervention follows directly from the mechanism: strategies that enhance post-meal satiety signaling (protein-first eating, high-fiber meal starters, time-structured eating) can compensate for reduced hypothalamic BDNF tone. For AA and AT carriers with metabolic concerns, monitoring fasting insulin and HOMA-IR provides an early warning signal for insulin resistance that this genotype predisposes to.

Interactions

rs10767664 and MC4R (rs17782313) are in the same satiety signaling cascade. BDNF is a downstream effector of MC4R in the VMH, meaning both proteins must function for full satiety signal propagation. A carrier of both the MC4R risk allele (rs17782313 C) and the BDNF obesity allele (rs10767664 A) has impairment at two consecutive steps in the same hypothalamic circuit, creating a compounded appetite dysregulation greater than either variant alone. Specific interaction studies at the genotype level have not been published, but the shared mechanistic pathway provides a strong biological rationale.

FTO (rs9939609) and rs10767664 operate through independent mechanisms — FTO primarily affects thermogenesis and adipogenesis through IRX3/IRX5 in brown fat and hypothalamus, while rs10767664 acts on VMH satiety signaling via the BDNF-TrkB pathway. Their BMI effects are additive rather than synergistic. Large-scale polygenic risk score analyses confirm that carrying risk alleles at both loci produces meaningfully higher obesity risk than either alone.

This variant is distinct from rs6265 (BDNF Val66Met), which is catalogued in the Brain & Mental Health section. rs6265 is a missense variant in the BDNF coding sequence that impairs activity-dependent BDNF secretion from neurons, affecting memory and neuroplasticity. rs10767664 is a regulatory variant that reduces BDNF expression in the hypothalamus, affecting satiety signaling and energy balance. The two variants show weak linkage disequilibrium and can be inherited independently — a person may carry one, both, or neither risk allele.