Vasodilation signal
Cyclic GMP — The Other Messenger
Also searched as Cyclic GMP — The Other Messenger.
Two messengers, two roads, one destination. Knowing which one an ingredient works through tells you whether it stacks with another ingredient or simply duplicates it.
In depth
The second road's signal molecule — not the one caffeine and adrenaline work through.
What drives it
cGMP-making enzyme increases it.
10.3389/fphar.2024.1359939 — 10.1371/journal.pone.0015686 — from a published diagram titled 'control DE LA LIPÓLISIS EN EL adipocito HUMANO' — a human-specific control map. Its legend enumerates the whole system: 'Receptores β- y α2A-Adrenérgicos (RA); Adenilato Ciclasa (AC); proteínas G heterotriméricas (Gs y Gi); Proteína Cinasa A (PKA); Lipasa Sensible a Hormona (LSH); Receptor de Insulina (IRS-1/2); Proteína Cinasa B (PKB); Cinasa (PI3-K); Fosfodiesterasa tipo 3B (PDE-3B); GUANILATO Ciclasa (GC); Receptor de Péptidos Natriuréticos (NPR-A); Proteína Cinasa G (PKG); Lipasa de Monoglicéridos (LMG); NEUROPÉPTIDO Y (NPY) Y PÉPTIDO YY (PYY); Proteínas que enlazan lípidos en adipocito (ALBP); Ácidos Grasos No Esterificados (AGNE)' (Revista de Educación Bioquímica, UNAM — 'Control de la lipólisis en el adipocito HUMANO' (ESPAÑOL)). The second, entirely separate road. The natriuretic route does not use the epinephrine messenger at all — it has its own receptor, its own enzyme, its own messenger and its own kinase, and they converge on the same lipases. That independence is why it matters: it still works when the epinephrine road is blunted. And it is human-specific — this road is effectively absent in mice, which voids rodent data on it entirely. doi 10.3389/fphar.2024.1359939
Vasodilation brake reduces it.
10.1038/ncomms8235 — a second way onto the same road, and it does not need the hormone at all. The messenger of this road is destroyed by a specific enzyme, so blocking that enzyme raises the messenger directly: 'the cGMP-mediated browning effect of NPs may underlie the ability of sildenafil (A phosphodiesterase-5 inhibitor) to cause browning' (Mayo Clin Proc s0025-6196(15)00644-8 — An Emerging Role of Natriuretic Peptides). And the road does more than release: 'activation of cGMP-dependent protein kinase through npr-A on adipocytes not only stimulates lipolysis but also activates p38 MAPK, leading to increased expression of UCP-1 and PGC-1α' — it releases fat and turns on the machinery that burns it. One non-ingredient lever is worth knowing: 'circulating levels of ANP and BNP ARE both increased after exposure to cold temperature. Cold exposure increases the expression of NPR-A' — cold raises the hormone and the working receptor at once. doi 10.1038/ncomms8235
Nitric oxide receptor enzyme increases it.
Two different enzymes make the same messenger, and in fat they do opposite things. This is the most counter-intuitive finding on this MAP and it overturns the obvious assumption. The messenger made at the heart-peptide receptor releases fat. The same messenger made by the nitric-oxide enzyme does the reverse. Measured in living people, not in cells: 'the NO synthase inhibitor, L-NMMA, but not the biologically inactive enantiomer, increased glycerol levels in the microdialysates without causing a change of local blood flow... Nitric oxide gas as well as the NO donor, NITROGLYCERINE, reduced glycerol release from isolated adipocytes' (PMID 10323597 — a nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo (microdialysis)). ⇒ blocking nitric oxide raises fat release. Supplying it lowers fat release. And the blood-flow explanation is ruled out in the same experiment. It also favors fat cell formation: 'nitric oxide and downstream second messenger cGMP and cAMP enhance adipogenesis in primary human preadipocytes' (Cytotherapy 2010 — Nitric oxide and downstream second messenger cGMP and cAMP enhance adipogenesis in primary human preadipocytes). The practical rule this establishes: a compound that raises nitric oxide is not a fat-release agent, however good it is for blood flow. The two effects are separable and they point in opposite directions. The field itself is cautious: 'the effect of nitric oxide appears complex and is not fully understood'. PMID 10323597
What it drives
It increases Nitric oxide kinase.
12591946 — 10.3389/fphar.2015.00139 — from a published diagram titled 'control DE LA LIPÓLISIS EN EL adipocito HUMANO' — a human-specific control map. Its legend enumerates the whole system: 'Receptores β- y α2A-Adrenérgicos (RA); Adenilato Ciclasa (AC); proteínas G heterotriméricas (Gs y Gi); Proteína Cinasa A (PKA); Lipasa Sensible a Hormona (LSH); Receptor de Insulina (IRS-1/2); Proteína Cinasa B (PKB); Cinasa (PI3-K); Fosfodiesterasa tipo 3B (PDE-3B); GUANILATO Ciclasa (GC); Receptor de Péptidos Natriuréticos (NPR-A); Proteína Cinasa G (PKG); Lipasa de Monoglicéridos (LMG); NEUROPÉPTIDO Y (NPY) Y PÉPTIDO YY (PYY); Proteínas que enlazan lípidos en adipocito (ALBP); Ácidos Grasos No Esterificados (AGNE)' (Revista de Educación Bioquímica, UNAM — 'Control de la lipólisis en el adipocito HUMANO' (ESPAÑOL)). The second, entirely separate road. The natriuretic route does not use the epinephrine messenger at all — it has its own receptor, its own enzyme, its own messenger and its own kinase, and they converge on the same lipases. That independence is why it matters: it still works when the epinephrine road is blunted. And it is human-specific — this road is effectively absent in mice, which voids rodent data on it entirely. doi 10.3389/fphar.2015.00139
It increases Heat instead of storage.
10.1038/ncomms8235 — a second way onto the same road, and it does not need the hormone at all. The messenger of this road is destroyed by a specific enzyme, so blocking that enzyme raises the messenger directly: 'the cGMP-mediated browning effect of NPs may underlie the ability of sildenafil (A phosphodiesterase-5 inhibitor) to cause browning' (Mayo Clin Proc s0025-6196(15)00644-8 — An Emerging Role of Natriuretic Peptides). And the road does more than release: 'activation of cGMP-dependent protein kinase through npr-A on adipocytes not only stimulates lipolysis but also activates p38 MAPK, leading to increased expression of UCP-1 and PGC-1α' — it releases fat and turns on the machinery that burns it. One non-ingredient lever is worth knowing: 'circulating levels of ANP and BNP ARE both increased after exposure to cold temperature. Cold exposure increases the expression of NPR-A' — cold raises the hormone and the working receptor at once. doi 10.1038/ncomms8235
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.