mc3r

MC3R (melanocortin 3 receptor)

A Class A GPCR in the melanocortin-system expressed in hypothalamic circuits, gut enteroendocrine cells, and immune cells. MC3R translates nutritional state into decisions about growth, pubertal timing, lean mass accrual, and circadian food-anticipatory behavior — functions distinct from the appetite-suppression role of mc4r. Its anti-inflammatory activity at immune cells connects it to the chronic-inflammation hallmark, making it the melanocortin-receptor family member most directly relevant to aging biology after MC1R (pigmentation / DNA-repair) and MC4R (adiposity).

Identity

• UniProt: P41968 (MC3R_HUMAN, Swiss-Prot manually curated)
• NCBI Gene: 4159
• HGNC: HGNC:6931
• Ensembl: ENSG00000124089
• Mouse ortholog: Mc3r (one-to-one; used in KO studies below)
• Length: 323 amino acids; 7 transmembrane helices (GPCR class A)

Structure and key PTMs

• N-linked glycosylation at Asn-2, Asn-16, Asn-28 (extracellular N-terminus)
• S-palmitoylation at Cys-315 (C-terminal tail; anchors fourth intracellular loop, important for G-protein coupling efficiency)
• Disulfide bonds: Cys-35–Cys-276 (extracellular loop stabilization); Cys-268–Cys-274
• MRAP interaction: Melanocortin Receptor Accessory Protein modulates trafficking and pharmacology of MC3R (distinct from MRAP2 effects at MC4R) ¹

Pharmacology

Endogenous ligands (ranked by affinity at MC3R):

Ligand	Source	Relative affinity	Notes
γ-MSH	POMC; arcuate nucleus	High	Physiologically MC3R-relevant (expression overlap); Ki at MC3R ~4.4 × 10⁻⁸ M, comparable to α-MSH
α-MSH	POMC; arcuate nucleus	High	Agonist at MC1/3/4/5; Ki at MC3R ~5.2 × 10⁻⁸ M — similar to γ-MSH
β-MSH	POMC processing	Moderate	Primate-relevant
ACTH (1–39)	Anterior pituitary	Moderate	Full agonist
AgRP	Arcuate NPY/AgRP neurons	Inverse agonist	Constitutive activity + AgRP; competitive with MSH

MC3R is Gαs-coupled — agonist binding activates adenylate cyclase → cAMP ↑ → PKA activation. This was established by Roselli-Rehfuss et al. (1993) using cAMP accumulation assays in 293 cells transfected with rat MC3R cDNA. Minor MAPK (ERK1/2) and Ca²⁺ signaling has been reported in heterologous systems in later literature but is not considered the primary transduction pathway ².

Ligand-binding selectivity: The orthosteric binding pocket of MC3R accommodates the core His-Phe-Arg-Trp (HFRW) pharmacophore shared by all melanocortin peptides. γ-MSH is physiologically relevant at MC3R because MC3R is expressed in hypothalamic regions that receive γ-MSH projections from POMC neurons; binding affinities of γ-MSH and α-MSH at MC3R are comparable (Ki ~4–5 × 10⁻⁸ M for both) ². Receptor-subtype selectivity for MC3R vs MC4R/MC1R is achieved via synthetic peptide probes exploiting differences in extracellular loop residues, not via large native-ligand affinity differences. No MC3R-selective agonist has reached clinical approval as of 2026.

Expression

Brain: Expressed in hypothalamic nuclei including the arcuate nucleus (ARC), paraventricular nucleus (PVN), and ventromedial hypothalamus (VMH). Also expressed in mesolimbic regions including the nucleus accumbens and ventral tegmental area — these extrahypothalamic sites mediate food-seeking motivation during caloric deficit ³.

Periphery: Gut enteroendocrine cells (especially L-cells and K-cells — functional significance for gut-brain melanocortin axis is under study); placenta; immune cells (macrophages, monocytes) where anti-inflammatory signaling occurs.

GTEx note: Bulk-tissue GTEx panels do not resolve hypothalamic subregion expression at the granularity needed for MC3R; the API query returned no data for ENSG00000124089. Expression is documented in primary literature but not reflected in GTEx summary statistics here. needs-gtex-subregion-data

Functions

1. Nutrient-state sensing and linear growth

The defining 2021 finding from Lam et al. demonstrates MC3R as a nutritional gate for growth and puberty rather than a simple appetite regulator ⁴:

• Humans carrying bi-allelic loss-of-function (LoF) MC3R variants showed delayed puberty onset, reduced final height, lower lean mass, and reduced IGF1 — all consistent with a failure to transduce nutritional sufficiency into growth signals.
• Mc3r-null males showed a 2-day delay in sexual maturation vs WT littermates; female Mc3r-null mice had a significantly prolonged oestrous cycle. Critically, in WT mice an overnight fast more than doubled oestrous cycle length, but this fasting-induced cycle prolongation was completely abolished in Mc3r-null mice — demonstrating that MC3R is required to transduce nutritional state into reproductive timing ⁴.
• MC3R expression concentrates in hypothalamic neurons that control GnRH pulsatility and growth-hormone release, placing MC3R upstream of both the reproductive and growth axes.

Proposed model: MC3R bifurcates the melanocortin system. MC4R governs calorie acquisition (appetite suppression via PVN circuits); MC3R governs calorie disposition — allocating ingested calories to linear growth, lean mass, and reproductive readiness rather than fat storage.

Dimension	Status	Notes
Pathway conserved in humans?	yes	Human LoF variants replicate mouse Mc3r-KO puberty/growth phenotype
Phenotype conserved in humans?	yes	Delayed puberty + reduced height in human LoF carriers 4
Replicated in humans?	partial	Lam 2021 (large UKBB genetics + family studies; heterozygous LoF carriers do NOT show elevated fat mass, only growth/puberty/lean mass effects); cross-species Duckett 2025 replication 5

2. Energy partitioning and circadian food-anticipatory behavior

MC3R-null mice do not develop the severe obesity of Mc4r-null mice, but show altered nutrient partitioning and impaired food-anticipatory activity (FAA) — the increase in locomotion that precedes scheduled meals ⁶:

• Under time-restricted feeding, Mc3r-null mice fail to upregulate FAA, suggesting MC3R integrates circadian signals with metabolic state.
• Hyperglycemia and glucose intolerance develop in Mc3r-null mice under caloric restriction despite weight loss — an unusual metabolic phenotype indicating defective adaptation to energy deficit.
• Mesolimbic MC3Rs in the limbic system (nucleus accumbens) modulate food-seeking motivation specifically during weight-loss states, without affecting homeostatic feeding ³.

3. Hepatic autophagy and metabolic regulation

A 2025 Nature Communications study adds a visceral-organ dimension to MC3R biology ⁷:

• MC3R activation in hepatocytes upregulates hepatic autophagy via LC3II activation and TFEB cytoplasmic-to-nuclear translocation, with subsequent upregulation of autophagy- and lysosome-related genes. γ-MSH (the MC3R-preferring endogenous agonist) drives this pathway in vitro and in vivo; Mc3r-deficient hepatocytes show impaired autophagosome flux and p62/SQSTM1 accumulation ⁷.
• Liver-specific MC3R restoration in Mc3r-null mice (Mc3rHep/Hep) improved mitochondrial function, partially reduced systemic adiposity and eWAT weight, and normalized serum TG and NEFA — but did not fully restore body weight to WT levels ⁷.
• This connects MC3R to the disabled-macroautophagy hallmark pathway in hepatic tissue — a novel finding not yet replicated. needs-replication

4. Anti-inflammatory signaling

MC3R, like other melanocortin receptors, is expressed on immune cells and mediates anti-inflammatory effects of α-MSH and related peptides ⁸:

• Macrophage MC3R activation suppresses pro-inflammatory responses; in a mouse peritonitis model, γ₂-MSH (acting via MC3R) reduced neutrophil migration and IL-1β in peritoneal lavage fluids ⁸. Broader TNF-α and IL-6 suppression by melanocortins (via PKA → IκBα stabilization → NF-κB inhibition) is primarily attributed to MC1R and the melanocortin system generally, with MC3R as one of several contributing receptors ⁸. MC3R-specific suppression of IL-12 is not directly demonstrated in this review. no-mechanism
• The tripeptide KPV (C-terminal fragment of α-MSH) retains anti-inflammatory activity partly via MC3R and MC1R; see kpv for mechanistic detail.
• In the aging context, declining melanocortin tone as a contributor to chronic-inflammation (inflammaging) is an underexplored hypothesis. no-mechanism — whether age-related decline in POMC neuron activity reduces MC3R-mediated immune modulation has not been directly tested.

MC3R in aging — synthesis

MC3R’s relevance to aging operates across two axes:

Axis 1 — Growth and body composition across the lifespan. The same MC3R circuit that gates pubertal linear growth likely regulates adult lean-mass maintenance. The Lam 2021 data shows that human MC3R LoF carriers have reduced lean mass in adulthood, not just delayed puberty. Loss of lean mass (sarcopenia-adjacent) with age overlaps the MC3R phenotype, though whether aging-associated hypothalamic dysfunction involves MC3R specifically has not been established. needs-human-replication

Axis 2 — Anti-inflammatory immune modulation. Reduced melanocortin tone with aging (driven by loss of hypothalamic POMC neurons or impaired α-MSH processing) could reduce tonic MC3R-mediated immune suppression, contributing to chronic-inflammation. This is mechanistically plausible but not directly evidenced. no-mechanism

Cross-species consistency: Duckett et al. 2025 examined MC3R across humans, dogs, and mice — LoF consistently delayed puberty in all three species but did not consistently cause obesity ⁵. This cross-species reproducibility of the growth/puberty phenotype strengthens the human relevance of the growth axis, while attenuating concern that MC3R-null metabolic phenotypes are species-specific.

Druggability (tier 2)

• No FDA-approved or Phase 3 clinical drug targets MC3R for any aging-relevant indication.
• Research-grade MC3R agonists exist (e.g., cyclic peptide probes) but none has advanced to clinical trials for aging or metabolic disease as of 2026.
• Setmelanotide (Imcivree) is a melanocortin agonist approved for POMC/PCSK1/LEPR-deficiency obesity — it acts primarily at MC4R; MC3R occupancy is secondary and not the therapeutic target.
• Aging-context tier-2 rationale: High-quality pharmacological probes exist for the MC3R binding pocket; receptor selectivity is achievable; no aging-indication clinical drug exists. Contrast with MC4R (tier 1 via setmelanotide).

MR evidence (partial): Mendelian randomization instruments from the Lam 2021 / UKBB analyses provide genetic evidence for MC3R LoF → delayed puberty and reduced lean mass, but MC3R has not been directly tested as an MR instrument for aging-specific outcomes (mortality, inflammaging biomarkers, biological age clocks). The instrument is available; the aging-outcome MR study is pending. needs-human-replication

Pathway membership

• melanocortin-system — family MOC; upstream POMC → α/γ-MSH → MC3R
• camp-signaling — primary effector pathway (planned wave 2 page; implicit stub)
• disabled-macroautophagy — hepatic autophagy connection ⁷

Key interactors

• alpha-msh — primary agonist shared with MC1R and MC4R
• agrp — inverse agonist; suppresses constitutive MC3R activity in ARC neurons stub
• mrap — melanocortin receptor accessory protein; modulates MC3R trafficking and surface expression stub
• mc4r — functionally complementary receptor in same ARC circuits; distinguishing MC3R vs MC4R contributions is an active research area stub

Limitations and gaps

• No aging-specific mouse KO lifespan study exists for Mc3r. needs-human-replication
• GTEx expression data unavailable from API at this resolution. Hypothalamic subregion bulk-tissue data is needed. needs-gtex-subregion-data
• Hepatic autophagy finding (Patel 2025) is a single study; mechanism linking MC3R → LC3/ULK1 autophagy induction is not fully resolved. needs-replication
• Anti-inflammatory MC3R contribution vs MC1R is not cleanly dissected in human immune cell studies; most mechanistic work uses non-selective MSH peptides. no-mechanism
• No selective MC3R agonist in human trials. Druggability is tier 2 (probe-quality) not tier 1.
• MR for aging outcomes not yet published. Genetic instruments exist; study pending. needs-human-replication

Footnotes

Footnotes

1. UniProt P41968 (MC3R_HUMAN, Swiss-Prot), accessed 2026-05-09 · manually curated; curation evidence: experimental at gene + protein level · MRAP interaction and PTM data from UniProt structured annotations. ↩

2. doi:10.1073/pnas.90.19.8856 · Roselli-Rehfuss L et al. · PNAS 1993 · n=N/A · molecular cloning (in-vitro, heterologous expression in 293 cells) · rat MC3R cDNA cloned from hypothalamic library; Gαs coupling established by cAMP accumulation assay; competition binding Ki values: NDP-MSH (1.0 × 10⁻⁸ M) > γ₂-MSH (4.4 × 10⁻⁸ M) ≈ α-MSH (5.2 × 10⁻⁸ M) >> ACTH₄₋₁₀ (>10⁻⁶ M); MC3R mRNA confined to hypothalamus (not melanocytes or adrenal) · local PDF: (local PDF) ↩ ↩²

3. doi:10.1016/j.molmet.2016.05.002 · Mavrikaki M, Butler AA et al. · Molecular Metabolism 2016 · in-vivo (Mc3rTB/TB mice on C57BL/6J;C57BL/6N mixed background + operant conditioning + ICV γ-MSH pharmacology) · mesolimbic MC3Rs in NAc shell mediate enhanced food-seeking motivation during caloric restriction (10–15% weight loss); Mc3rTB/TB mice showed reduced active lever pressing during CR (FR1 and PR1); DAT-Cre rescue of limbic Mc3r partially restored motivational responses during CR but did not rescue fat-mass phenotype · local PDF: (local PDF) ↩ ↩²

4. doi:10.1038/s41586-021-04088-9 · Lam BYH, O’Rahilly S et al. · Nature 2021 · n=~200,643 UKBB WES participants; ~500,000 genotyped; 812 female rare-MC3R-mutation carriers for menarche analysis; 5,993 ALSPAC participants; Mc3r-null mice · human genetics + mouse in-vivo · 812 female MC3R LoF carriers had 4.7-month delay at menarche (beta=0.39 yr, P=6.4×10⁻¹²); associated with shorter stature, lower lean mass, lower IGF1, lower ALM/BMI; Mc3r-null males had 2-day delay in sexual maturation; fasting-induced oestrous cycle prolongation (>2× in WT) was abolished in Mc3r-null females · local PDF: (local PDF) ↩ ↩² ↩³

5. doi:10.1016/j.molmet.2025.102301 · Duckett K, O’Rahilly S et al. · Molecular Metabolism 2025 · cross-species (human, dog, mouse) · MC3R LoF consistently delayed puberty across all three species; obesity not a consistent phenotype · local PDF: pending (archive status: pending; OA gold) ↩ ↩²

6. doi:10.1016/j.physbeh.2011.04.007 · Begriche K, Butler AA et al. · Physiology & Behavior 2011 · review + Mc3r-null mouse data · MC3R coordinates circadian food-anticipatory behavior with nutritional state; Mc3r-null mice show FAA deficits and glucose intolerance under caloric restriction · local PDF: pending (archive status: not_oa) ↩

7. doi:10.1038/s41467-025-56936-1 · Patel TP, Yanovski JA et al. · Nature Communications 2025 · in-vivo (Mc3rTB/TB and MC3RhDM/hDM mice; C57BL/6 background) + in-vitro (primary hepatocytes, GFP-LC3 transgenic) · MC3R activation upregulates hepatic autophagy via LC3II activation and TFEB nuclear translocation → autophagy/lysosome gene upregulation; γ-MSH activates this pathway; Mc3r-deficient hepatocytes show impaired autophagosome flux and p62 accumulation; liver-specific MC3R rescue (Mc3rHep/Hep) partially restored body weight, improved mitochondrial respiration, normalized serum TG/NEFA/cholesterol, and partially reduced eWAT weight · local PDF: (local PDF) ↩ ↩² ↩³ ↩⁴

8. doi:10.3389/fendo.2020.569241 · Lonati C, Catania A et al. · Frontiers in Endocrinology 2020 · mini-review · melanocortin receptors (MC1R, MC3R, MC4R, MC5R) reduce pro-inflammatory responses in immune and endothelial cells via PKA → NF-κB inhibition; MC3R-specific evidence: γ₂-MSH reduces neutrophil migration and IL-1β in mouse peritonitis model; broad TNF-α/IL-6 suppression attributed to melanocortin system (not MC3R alone); focused on COVID-19/respiratory-virus context · local PDF: (local PDF) ↩ ↩² ↩³