Fibromyalgia: H4 — immuno-metabolic chain (candidate)

Adipose-derived leptin → microglial activation → central sensitization · new bridging-tier chain proposed alongside H1 / H2 / H3

established emerging inferred bridging intervention break-point Hover any node for a preview · Click for full definition + paper links (Esc or backdrop to close)
H4 immuno-metabolic chain — vertical flow read top to bottom · arrow style encodes evidence tier · ① – ⑥ are intervention break-points Metabolic stress obesity · visceral adiposity trigger Insulin resistance MetS · T2DM · MDD overlap trigger T1DM / autoimmune endo cross-condition anchor trigger 1 Adipose tissue dysfunction expanded / inflamed depots · adipokine dysregulation · resident MC + macrophage activation established (basic adipose biology) Leptin ↑ (circulating) crosses BBB · binds LepRb on microglia levels track adiposity + inflammation, not only fat mass bridging (FM-direct evidence pending) Adipose mast cells parallel arm → H2 chain B-IM-1 cross-chain bridge emerging · converges on microglia 2 leptin → LepRb on microglia activates three parallel cascades adipose MC → SP / histamine → microglia (H2 convergence) JAK2 / STAT3 cytokine transcription emerging · animal models MAPK / ERK proliferation · priming emerging PI3K / Akt → NF-κB cross-talk survival · pro-inflammatory transcription emerging 3 MICROGLIAL ACTIVATION ★ H4 convergence node M1 polarization · primed phenotype three ligand classes converge: leptin · MC mediators · DAMPs ★ click for the full story 4 Metformin — AMPK arm opposes inflammatory signaling 624k post-COVID cohort signal inferred · Chaichana 26 5 Pro-inflammatory cytokines + reactive species IL-1β · IL-6 · TNF-α · nitric oxide · reactive oxygen species established (microglial mediator biology) Central sensitization + sickness-behavior loop spinal + thalamic gain ↑ · NMDA-LTP · glycinergic inhibition loss microglial cytokines drive sickness behavior (fatigue, cognitive sx, sleep loss) established (machinery) + emerging (FM-specific microglial PET) Widespread pain hyperalgesia · allodynia established Fatigue sickness behavior established Cognitive sx · sleep loss fibro fog · non-restorative sleep established B-IM-1 — cross-chain integration Adipose tissue feeds the CNS through TWO parallel arms — leptin → microglia (H4) and adipose MC → SP/histamine → microglia (H2). Both arms converge on microglial priming. The H4 chain does NOT replace H2 — it runs in parallel and explains the FM-MetS comorbidity. bridging · cross-chain Six intervention break-points — click any numbered red circle above ① GLP-1 / weight-loss · ② leptin neutralization / LepRb antagonist · ③ JAK inhibitor (baricitinib) · ④ ★ minocycline / microglial inhibitor · ⑤ anti-IL-6 (tocilizumab) · ⑥ metformin (AMPK)
Reads top to bottom. Adipose tissue is the peripheral metabolic source. Leptin (H4 main arm) and adipose mast cells (H2 bridge arm) both converge on microglial activation. The three signaling cascades (JAK2/STAT3, MAPK/ERK, PI3K/Akt) downstream of LepRb are the most pharmacologically tractable intervention layer — multiple node-specific drugs are already FDA-approved for other indications. The H4 chain is project-internal at the chain level (bridging); component steps are emerging in animal models. No FM-direct experiment closes this yet — Q-IM-1..4 capture the testable predictions.