Lipolysis signal
Protein Kinase A
Also searched as Protein Kinase A.
You want it able to act on demand. Under fed conditions the droplet is deliberately locked: a coat protein sits over the stored fat and holds the activator of the main lipase hostage. This kinase is what unlocks both at once — phosphorylating the coat releases the activator, and phosphorylating the lipase docks it onto its own substrate. It is a switch, not a dial: chronically forcing it is not the same as being able to throw it when energy is genuinely needed.
In depth
The kinase that actually opens the fat droplet — it phosphorylates the coat protein guarding the fat and the lipase that cuts it.
What drives it
The cell's go-signal increases it.
10.1017/S0029665109990279 — 'A rise in cAMP activates protein kinase (PK) A, which phosphorylates hormone-sensitive lipase (HSL) and LD-coating protein perilipin (PLIN) to stimulate lipolysis' (Proc Nutr Soc, Regulation of adipose tissue lipolysis revisited). The step is definitional rather than contested. doi 10.1017/S0029665109990279
What it drives
It increases Fat cell clearance.
We conclude that BMSO is effective in attenuating body fat accumulation through mechanisms associated with PKA activation and programmed cell death in the WAT. doi 10.3945/jn.112.159939
It increases Releases stored fat.
PKA is the key that opens the droplet, and the mechanism is resolved to individual serines. 'Under basal (fed) conditions, perilipin 1A provides a protective barrier against lipolysis of stored triacylglycerols and binds CGI-58, a coactivator of ATGL. When CGI-58 is sequestered on the perilipin scaffold, it cannot interact with or activate ATGL.' On stimulation: 'The phosphorylation of three N-terminal serine residues of perilipin 1A facilitates the docking of PKA-phosphorylated hormone-sensitive lipase... The PKA-mediated phosphorylation of two carboxyl-terminal serine residues facilitates the release of CGI-58 from perilipin 1A, enabling interaction of CGI-58 with ATGL, in turn activating the lipase' (PMC4274058). ATGL is 'the rate-limiting lipase in lipolysis'. PMC4274058
It increases Fat droplet coating.
The unlock, resolved to individual serines. 'The phosphorylation of three N-terminal serine residues of perilipin 1A facilitates the docking of PKA-phosphorylated hormone-sensitive lipase through a protein-protein interaction with the perilipin scaffold... The PKA-mediated phosphorylation of two carboxyl-terminal serine residues of perilipin 1A facilitates the release of CGI-58 from perilipin 1A, enabling interaction of CGI-58 with ATGL, in turn, activating the lipase' (PMC4274058). One protein, two jobs, different ends. PMC4274058
It increases Fat-releasing enzyme (HSL).
'PKA, together with phosphorylated PLIN1, promote HSL translocation from the cytosol to the lipid droplet surface, inducing an acute activation of TG hydrolysis in conjunction with ATGL and MGL' (doi 10.3389/fphys.2022.826314). The kinase does two things at once: it switches this lipase on and it moves it to where its substrate is. doi 10.3389/fphys.2022.826314
It increases Lipase activator.
'Upon activation by PKA-mediated phosphorylation of PLIN1 and CGI58, CGI58 is released from PLIN1 and LDs' (doi 10.3389/fphys.2022.826314). Note the detail: the kinase phosphorylates both partners, not only the coat. doi 10.3389/fphys.2022.826314
It increases Master phosphatase.
The accelerator arms the brake. 'Multiple studies have suggested that pp2a can be activated by the cAMP-PKA pathway via phosphorylation of the regulatory subunit. It seems likely that PKA-PP2A-dependent dephosphorylation may contribute to a negative feedback loop that counterbalances PKA-dependent phosphorylation'. doi 10.3389/fphys.2022.826314
It increases Triglyceride assembly.
The accelerator may be turning the handbrake. 'it has been reported that DGAT1 can be phosphorylated by PKA-dependent pathway. Therefore, PKA might phosphorylatE and activate DGAT1 during lipolysis to promote reesterification' (doi 10.3389/fphys.2022.826314). 'might' is the source's word and it is kept. This is the candidate mechanism for why putting-back rises with letting-out. doi 10.3389/fphys.2022.826314
It increases Lipase docking.
The second lipase is switched on in two separate steps, not one — and most evidence only ever shows one of them. 'HSL is phosphorylated by PKA at Ser660, triggering its translocation to lipid droplets; it then forms a stable association with lipid droplets. The subsequent phosphorylation of HSL Ser563 on the surface of the lipid droplets promotes the intrinsic catalytic activity of the lipase' (doi 10.1371/journal.pone.0100559 (PMC4064000) — PRIP Regulates Lipolysis by Modulating the Phosphorylation of Hormone-Sensitive Lipase). ⇒ one mark gets the enzyme to the fat. A different mark turns it on once it is there. This is why 'it raises the active form of the lipase' is an incomplete claim unless the site is named. An ingredient that marks only the switch-on residue is relying on the enzyme having already arrived by other means. And a good deal of it has: 'up to 50% of cellular HSL is LD-associated in the basal state' (PMID 16595669 — Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms) — half the lipase is already parked at the droplet before any signal arrives. doi 10.1371/journal.pone.0100559 · PMID 16595669 · PMC4064000
It increases Lipase switch-on.
The switch-on step, and the species trap underneath it. Almost all published site numbers come from rodent studies, and the numbering does not carry across: 'in vitro phosphorylation of human HSL by PKA occurs primarily on Ser649 and Ser650 (Ser659 and Ser660 in rat HSL)' (doi 10.1371/journal.pone.0003756 (pmc2582450) — Ser649 and Ser650 Are the Major Determinants of PKA-Mediated Activation of human Hormone-Sensitive Lipase). ⇒ a residue number quoted from a mouse experiment is not the same residue in a person, and the major human site is not the one most often quoted. This does not make the animal work wrong — it means the site-level precision it offers does not transfer without translation. doi 10.1371/journal.pone.0003756
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.