Hypothalamic leptin-melanocortin signaling module

The central adipostat: adipocyte-derived leptin acts on the long leptin receptor isoform of hypothalamic arcuate neurons, whose JAK2-STAT3 output raises POMC and lowers AGRP expression; prohormone convertases cleave POMC in dense-core granules to release alpha-MSH, which activates MC4R on second-order neurons to suppress appetite, while AGRP from a reciprocal neuronal population antagonises the same receptor.

MODULE:leptin_melanocortin_signalingDRAFTSignaling Pathwaymodules/leptin_melanocortin_signaling.yaml

negative regulation of appetite by leptin-mediated signaling pathwayGO:0038108 energy homeostasisGO:0097009

GO:0038108

negative regulation of appetite by leptin-mediated signaling pathway

GO already names the composite process this module decomposes - appetite suppression achieved through the leptin-mediated signaling pathway - which is the module boundary adopted here.

GO:0033210

leptin-mediated signaling pathway

The upstream half of the module is grounded in the GO term for leptin-mediated signaling.

PMID:8548812

Identification and expression cloning of a leptin receptor, OB-R.

"OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus" - establishes the hypothalamic receptor that makes the module a central pathway.

PMID:15207242

Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.

"Mice lacking leptin signaling in POMC neurons are mildly obese, hyperleptinemic, and have altered expression of hypothalamic neuropeptides" - direct genetic evidence for the LEPR-to-POMC connection modelled here, and for POMC neurons carrying part but not all of the leptin signal.

PMID:2023902

PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues.

"PC1 cleaves POMC into corticotropin and beta-lipotropin" and "PC2 cleaves POMC at the five pairs of basic residues analyzed, whereas PC1 cleaves two of them preferentially" - the basis for modelling POMC maturation as two convertase roles rather than one.

PMID:17229951

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

"Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism" - human loss-of-function evidence that the receptor step is required for the module's output.

PMID:27187081

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

Human PCSK1 loss of function produces "obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function" - the processing step is required, though its phenotype is broader than this module because PC1/3 serves many precursors.

file:interpro/panther/PTHR23037/PTHR23037-paint.tsv

PTHR23037 PAINT IBD rows

PANTHER:PTN002745476 in PTHR23037 carries F:GO:0004896 and C:GO:0043235 IBD rows whose seed list includes UniProtKB:P48357, so the node is the cytokine-receptor ancestor through which LEPR inherits receptor-complex function.

file:interpro/panther/PTHR22750/PTHR22750-paint.tsv

PTHR22750 PAINT IBD rows

PANTHER:PTN002733667 in PTHR22750 carries an F:GO:0004980 IBD row seeded by UniProtKB:P32245 (MC4R), i.e. the melanocyte-stimulating hormone receptor function is placed at a node that MC4R itself grounds.

Scope: this module is the hypothalamic appetite-suppressing arm only. Leptin's peripheral actions (angiogenesis, T-cell responses, bone mass, beta-cell function) and POMC's non-hypothalamic products (ACTH-driven adrenal steroidogenesis, alpha-MSH acting at MC1R in skin) are deliberately outside the boundary; they are recorded in the member gene reviews instead. JAK2, STAT3, SOCS3 and PTP1B are the intracellular transduction and feedback machinery; the generic motif is already modelled in modules/jak_stat_signaling.yaml, so this module asserts the receptor's STAT output as a function rather than re-modelling the kinase cascade. PANTHER grounding: family ids and subfamily names were read from the committed PANTHER classifications (interpro/panther/*-entries.csv and the release-pinned human classification), never written from memory, and every family declared here contains its own representative member. Note that the two PANTHER sources disagree about LEPR: the committed PTHR23037 entries file places P48357 at PTHR23037:SF44 while the pinned release classification places it at PTHR23036:SF109. PTHR23037 is used here because the PAINT node cited above (PTN002745476, seeded by P48357) lives in that family; the discrepancy is recorded rather than silently resolved. PTN anchors are asserted only where a local PAINT row names the node together with the member accession; the two convertases carry no PTN anchor (the nodes named in the PCSK1 GOA WITH/FROM field are not in the local PAINT index, so they are not asserted here) and are grounded as UniProt gene products at the subfamily level named in the PANTHER classification, because dibasic-site prohormone specificity is not a property of the whole PTHR42884 family.

6Nodes

5Parts

0Variant Sets

0Variants

7Annotons

5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:leptin_melanocortin_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

6 gene-function check(s) reflected in core functions · 0 conflict(s) · 6 evidence or coverage gap(s) (12 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
leptin_hormone	LEP UniProtKB:P41159 Family Representative	hormone activity GO:0005179	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
leptin_receptor	LEPR UniProtKB:P48357 Family Representative	leptin receptor activity GO:0038021	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pomc_precursor	POMC UniProtKB:P01189 Family Representative	type 4 melanocortin receptor binding GO:0031782	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pcsk1_convertase	PCSK1 (prohormone convertase 1/3, PANTHER subfamily PTHR42884:SF14 NEUROENDOCRINE CONVERTASE 1) UniProtKB:P29120 Gene	serine-type endopeptidase activity GO:0004252	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pcsk2_convertase	PCSK2 (prohormone convertase 2, PANTHER subfamily PTHR42884:SF13 NEUROENDOCRINE CONVERTASE 2) UniProtKB:P16519 Gene	serine-type endopeptidase activity GO:0004252	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mc4_receptor	MC4R UniProtKB:P32245 Family Representative	melanocyte-stimulating hormone receptor activity GO:0004980	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
agrp_antagonist	AGRP UniProtKB:O00253 Family Representative	type 4 melanocortin receptor binding GO:0031782	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
leptin_hormone	leptin, the adipocyte adipostatic hormone PANTHER:PTHR11724 Family	hormone activity GO:0005179	Family Review Missing No supported structured family review is available for PANTHER:PTHR11724.
leptin_receptor	leptin receptor within the class I cytokine receptor family PANTHER:PTHR23037 Family	leptin receptor activity GO:0038021	Family Review Missing No supported structured family review is available for PANTHER:PTHR23037.
pomc_precursor	proopiomelanocortin, the melanocortin precursor PANTHER:PTHR11416 Family	type 4 melanocortin receptor binding GO:0031782	Family Review Missing No supported structured family review is available for PANTHER:PTHR11416.
mc4_receptor	melanocortin receptor 4 within the class A G-protein-coupled receptors PANTHER:PTHR22750 Family	melanocyte-stimulating hormone receptor activity GO:0004980	Family Review Missing No supported structured family review is available for PANTHER:PTHR22750.
agrp_antagonist	agouti-related protein, the endogenous melanocortin receptor antagonist PANTHER:PTHR16551 Family	type 4 melanocortin receptor binding GO:0031782	Family Review Missing No supported structured family review is available for PANTHER:PTHR16551.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

agrp_antagonism ⊣ mc4r_agonism [input]
agrp_antagonism is a negative regulator with no upstream edge (not described as feedback)
leptin_receptor_activation ⊣ agrp_antagonism [closed]
leptin_receptor_activation is regulated by leptin_signal_generation: feedback loop closed

Gene-review completeness (6/7 grounded genes reviewed)

4 complete review(s) · 5 with deep research · 1 missing review · 1 reviewed but lacking deep research

Gene	Review	Complete	Deep research
LEP P41159	✓	134/136	✓
LEPR P48357	✓	✓	✓
MC4R P32245	✓	✓	✓
AGRP O00253	✗	—	—
PCSK1 P29120	✓	28/29	✓
PCSK2 P16519	✓	✓	✗
POMC P01189	✓	✓	✓

Tree

Hypothalamic leptin-melanocortin signalingSignaling Pathwayleptin_melanocortin_signaling

Parts
1. 1. adipostatic hormone release
2. Leptin release as an adipostatic signalRegulatory Stepleptin_signal_generation
  
  Annotons
  - Leptin Family: leptin, the adipocyte adipostatic hormone
3. 2. hypothalamic leptin receptor activation
4. Leptin receptor activation and STAT outputRegulatory Stepleptin_receptor_activation
  
  Annotons
  - Leptin receptor (long signalling isoform) Family: leptin receptor within the class I cytokine receptor family
5. 3. POMC expression and prohormone maturation
6. POMC synthesis and convertase processing to alpha-MSHRegulatory Steppomc_processing
  
  Annotons
  - Proopiomelanocortin precursor Family: proopiomelanocortin, the melanocortin precursor
  - Prohormone convertase 1/3 Gene Product: PCSK1 (prohormone convertase 1/3, PANTHER subfamily PTHR42884:SF14 NEUROENDOCRINE CONVERTASE 1)
  - Prohormone convertase 2 Gene Product: PCSK2 (prohormone convertase 2, PANTHER subfamily PTHR42884:SF13 NEUROENDOCRINE CONVERTASE 2)
7. 4. melanocortin receptor agonism
8. alpha-MSH activation of MC4RRegulatory Stepmc4r_agonism
  
  Annotons
  - Melanocortin 4 receptor Family: melanocortin receptor 4 within the class A G-protein-coupled receptors
9. 5. competitive antagonism of the effector receptor
10. AGRP antagonism of MC4RRegulatory Stepagrp_antagonism
  
  Annotons
  - Agouti-related protein Family: agouti-related protein, the endogenous melanocortin receptor antagonist

Details

Context

mammalsNCBITaxon:40674

arcuate nucleus of hypothalamusUBERON:0001932

extracellular regionGO:0005576 plasma membraneGO:0005886 secretory granule lumenGO:0034774

Hypothalamic leptin-melanocortin signalingSignaling Pathwayleptin_melanocortin_signaling

negative regulation of appetite by leptin-mediated signaling pathwayGO:0038108 energy homeostasisGO:0097009

Context

mammalsNCBITaxon:40674

arcuate nucleus of hypothalamusUBERON:0001932

extracellular regionGO:0005576 plasma membraneGO:0005886 secretory granule lumenGO:0034774

Connections

leptin_signal_generation -> leptin_receptor_activation Causes

Circulating leptin binds and activates the hypothalamic leptin receptor.

leptin_receptor_activation -> pomc_processing Positively Regulates

Receptor STAT3 signalling raises POMC transcription in arcuate neurons, increasing the precursor available to the convertases.

pomc_processing -> mc4r_agonism Provides Input For

Convertase processing of POMC supplies the alpha-MSH that activates MC4R; the uncleaved precursor cannot act on the receptor.

agrp_antagonism -> mc4r_agonism Negatively Regulates

AGRP competes with alpha-MSH at MC4R and opposes the anorexigenic signal.

leptin_receptor_activation -> agrp_antagonism Negatively Regulates

Leptin receptor STAT3 signalling represses AGRP expression, so the antagonist arm falls as the agonist arm rises.

Part 1: adipostatic hormone release

Leptin release as an adipostatic signalRegulatory Stepleptin_signal_generation

Adipocytes secrete leptin in proportion to fat mass, so circulating leptin reports stored energy to the brain. Absence of the hormone, like absence of its receptor, produces hyperphagic obesity.

hormone activityGO:0005179

Annotons

Leptin

leptin_hormone

Participant: Family: leptin, the adipocyte adipostatic hormone

Family:

leptin, the adipocyte adipostatic hormonePANTHER:PTHR11724

Representative Members: LEPUniProtKB:P41159

Function

hormone activityGO:0005179

Locations

extracellular regionGO:0005576

Secreted ligand of the module; binds the leptin receptor ectodomain and drives the ligand-induced receptor assembly that initiates signalling.

PMID:36959263

"The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight" - leptin is the activating ligand of the hypothalamic step.

Part 2: hypothalamic leptin receptor activation

Leptin receptor activation and STAT outputRegulatory Stepleptin_receptor_activation

Leptin binding to the long receptor isoform assembles higher-order leptin:receptor complexes at the neuronal plasma membrane. Receptor-associated JAK2 is activated and phosphorylates STAT3, whose transcriptional programme raises POMC and represses AGRP in arcuate neurons. Only the long isoform signals; the short and soluble isoforms do not.

leptin-mediated signaling pathwayGO:0033210

Annotons

Leptin receptor (long signalling isoform)

leptin_receptor

Participant: Family: leptin receptor within the class I cytokine receptor family

Family:

leptin receptor within the class I cytokine receptor familyPANTHER:PTHR23037

Representative Members: LEPRUniProtKB:P48357

Function

leptin receptor activityGO:0038021

Locations

plasma membraneGO:0005886

Transduces the hormone signal across the membrane of arcuate neurons; its STAT arm is what couples nutritional state to melanocortin gene expression.

file:genes/human/LEPR/LEPR-uniprot.txt

"Control of energy homeostasis and melanocortin" production - stimulation of POMC and repression of AgRP transcription - "is mediated by STAT3 signaling".

PMID:17229951

"All missense mutations resulted in impaired receptor signaling" in patients with hyperphagic severe obesity, so this step is required for the module's output.

Part 3: POMC expression and prohormone maturation

POMC synthesis and convertase processing to alpha-MSHRegulatory Steppomc_processing

Leptin-driven STAT3 signalling raises POMC transcription in arcuate neurons. The POMC precursor enters dense-core secretory granules, where prohormone convertase 1/3 makes the first cleavages (releasing ACTH and beta-lipotropin) and convertase 2, with carboxypeptidase E and downstream amidation and acetylation, completes the conversion to alpha-MSH. The precursor is inert until cleaved, which is why convertase loss mimics melanocortin deficiency.

peptide hormone processingGO:0016486

Annotons

Proopiomelanocortin precursor

pomc_precursor

Participant: Family: proopiomelanocortin, the melanocortin precursor

Family:

proopiomelanocortin, the melanocortin precursorPANTHER:PTHR11416

Representative Members: POMCUniProtKB:P01189

Function

type 4 melanocortin receptor bindingGO:0031782

Locations

secretory granule lumenGO:0034774

Substrate of the processing step and, once cleaved, source of the alpha-MSH agonist that acts at MC4R in the next step.

file:genes/human/POMC/POMC-ai-review.yaml

The POMC gene review records type 4 melanocortin receptor binding (GO:0031782) with negative regulation of appetite and energy homeostasis as a core function of the alpha-MSH product, acting in the hypothalamus.

Prohormone convertase 1/3

pcsk1_convertase

Participant: Gene Product: PCSK1 (prohormone convertase 1/3, PANTHER subfamily PTHR42884:SF14 NEUROENDOCRINE CONVERTASE 1)

Gene Product:

PCSK1 (prohormone convertase 1/3, PANTHER subfamily PTHR42884:SF14 NEUROENDOCRINE CONVERTASE 1)UniProtKB:P29120

Function

serine-type endopeptidase activityGO:0004252

Locations

secretory granule lumenGO:0034774

Makes the first, obligatory cleavages of POMC at paired basic residues, releasing ACTH and beta-lipotropin and thereby committing the precursor to the melanocortin route.

PMID:2023902

"PC1 cleaves POMC into corticotropin and beta-lipotropin" - the first processing step of the melanocortin route.

file:genes/human/PCSK1/PCSK1-uniprot.txt

"Substrates include POMC, renin, oxytocin, vasopressin, enkephalin, dynorphin, somatostatin, insulin and AGRP" - PC1/3 matures both the agonist and the antagonist arms of this module.

Prohormone convertase 2

pcsk2_convertase

Participant: Gene Product: PCSK2 (prohormone convertase 2, PANTHER subfamily PTHR42884:SF13 NEUROENDOCRINE CONVERTASE 2)

Gene Product:

PCSK2 (prohormone convertase 2, PANTHER subfamily PTHR42884:SF13 NEUROENDOCRINE CONVERTASE 2)UniProtKB:P16519

Function

serine-type endopeptidase activityGO:0004252

Locations

secretory granule lumenGO:0034774

Completes POMC maturation in neurons by cleaving at the additional basic-residue pairs that PC1/3 leaves intact, which is the step that actually liberates alpha-MSH.

PMID:2023902

"PC2 cleaves POMC at the five pairs of basic residues analyzed, whereas PC1 cleaves two of them preferentially" and PC2 generates "either alpha MSH or desacetyl-alpha MSH".

Part 4: melanocortin receptor agonism

alpha-MSH activation of MC4RRegulatory Stepmc4r_agonism

alpha-MSH released from arcuate POMC neurons activates MC4R on second-order neurons, notably in the paraventricular nucleus. The receptor couples to Gs, raising cAMP, and the resulting signal suppresses food intake and supports energy expenditure. This is the effector node of the module and the commonest monogenic obesity locus in humans.

negative regulation of appetiteGO:0032099

Annotons

Melanocortin 4 receptor

mc4_receptor

Participant: Family: melanocortin receptor 4 within the class A G-protein-coupled receptors

Family:

melanocortin receptor 4 within the class A G-protein-coupled receptorsPANTHER:PTHR22750

Representative Members: MC4RUniProtKB:P32245

Function

melanocyte-stimulating hormone receptor activityGO:0004980

Locations

plasma membraneGO:0005886

Effector receptor of the module: converts the alpha-MSH concentration set by the preceding steps into a cAMP signal that suppresses appetite.

file:genes/human/MC4R/MC4R-ai-review.yaml

The MC4R gene review's core function is melanocyte-stimulating hormone receptor activity (GO:0004980) coupling to adenylate cyclase activation and negative regulation of appetite, at the plasma membrane of paraventricular neurons.

Part 5: competitive antagonism of the effector receptor

AGRP antagonism of MC4RRegulatory Stepagrp_antagonism

AGRP, released from a reciprocally regulated arcuate neuronal population whose expression leptin suppresses, binds MC4R and opposes alpha-MSH, acting as an antagonist and inverse agonist. The appetite set-point is therefore the balance of two POMC- and AGRP-derived signals at one receptor, not the agonist alone.

Annotons

Agouti-related protein

agrp_antagonist

Participant: Family: agouti-related protein, the endogenous melanocortin receptor antagonist

Family:

agouti-related protein, the endogenous melanocortin receptor antagonistPANTHER:PTHR16551

Representative Members: AGRPUniProtKB:O00253

Function

type 4 melanocortin receptor bindingGO:0031782

Locations

extracellular regionGO:0005576

Orexigenic ligand that competes with alpha-MSH at MC4R; its precursor is itself a PC1/3 substrate, so the processing step serves both arms.

file:genes/human/MC4R/MC4R-ai-review.yaml

The MC4R review records AgRP binding as a core function of the receptor, with AgRP antagonising agonist signalling and acting as an inverse agonist that stimulates food intake.

file:genes/human/LEPR/LEPR-uniprot.txt

"Control of energy homeostasis and melanocortin" production by the receptor includes "full repression of AgRP transcription", placing the antagonist arm under leptin control.