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Evidence-based GLP-1 & peptide discussion since 2023
ForumsPharmacology & MechanismsHas anyone dealt with glucagon receptor signaling?

Has anyone dealt with glucagon receptor signaling?

ricardo_MIA Sun, Jan 4, 2026 at 4:13 AM 20 replies 1,073 viewsPage 1 of 4
ricardo_MIA
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Jan 4, 2026 at 4:13 AM#1

Putting this up for argument rather than for agreement. I have read it twice and I am still not certain what it supports.

The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression. The liver signal is where they look strongest, because hepatic fatty-acid oxidation responds to glucagon directly rather than as a consequence of weight loss.

Where I think it is weakest: the comparator does most of the work in how this gets reported, and it is not the comparator most people think they are citing.

The question I want answered is whether the liver signal is independent of weight loss or downstream of it, because that determines whether any of this is interesting for someone whose weight is already where they want it. I would rather have one careful answer than five confident ones.

Note on sourcing:
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
30 0JakeSmashed95, NauseaFreeNow, SteveThurs and 27 others
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LarryQC_SD
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Jan 4, 2026 at 4:32 AM#2
ricardo_MIA said:
The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression.

Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were relying on physical fullness feel the effect fade while the appetite effect is still working.

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PurityPaulOR
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Jan 4, 2026 at 4:51 AM#3
ricardo_MIA said:
The glucagon co-agonists — survodutide, mazdutide, ecnoglutide — are all chasing the same idea: add energy expenditure to appetite suppression.

Glucagon receptor pharmacology in triple agonists (retatrutide), relevant to the glucagon co-agonists: the glucagon component is the most controversial because glucagon traditionally raises blood glucose. So why include it in an anti-obesity drug?

Key insight: glucagon increases energy expenditure (thermogenesis), promotes hepatic lipid oxidation, and reduces appetite through distinct CNS mechanisms. The hyperglycemic effect is counterbalanced by the GLP-1 component's insulin secretagogue action.

Net result: more weight loss through increased expenditure (glucagon) + decreased intake (GLP-1/GIP), with neutral or improved glycemia. An elegant pharmacological balancing act[1].

References:
[1] Day JW, et al. Nat Rev Drug Discov. 2022;21:37-54.
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Dr.PainCLE
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Jan 4, 2026 at 5:10 AM#4

Short answer first, then the reasoning. The mechanism is more central than most summaries suggest. Receptor agonism in the arcuate nucleus activates POMC neurons and inhibits AgRP/NPY signalling, and the downstream MC4R pathway is the same one disrupted in monogenic obesity — convergent genetic evidence that the target is the right one. Peripherally there is glucose-dependent insulin secretion, glucagon suppression and delayed gastric emptying, but the gastric component largely adapts over months while the central effect persists, which is why the durable effect is appetite rather than fullness.

Ask again with the specifics and you will get a better answer than this one.

Last edited: Jan 4, 2026 at 8:10 AM
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claudia_zurich
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Jan 4, 2026 at 6:55 AM#5
LarryQC_SD said:
Agreed, and the adaptation point cuts both ways: tachyphylaxis to gastric emptying is why tolerability improves, and it is also why people who were…

Adding a me-too, because a thread of one person's experience is not much use.

26 21kevin_tulsa, Dr.PainCLE, mike_mealprep and 23 others
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