Activating the glucagon receptor in humans leads to higher energy expenditure at rest and a faster heart rate while at rest.
Mechanism
Synthesis from 1 study
Turning on the glucagon receptor makes fat cells release fatty acids, which tell the liver to produce a signal that wakes up the body’s heat-burning fat. That fat then burns energy just to make heat, raising the resting calorie burn. The heart beats faster because the nervous system gets activated...
Most probable mechanism
When the glucagon receptor is turned on, fat cells break down stored fat into fatty acids, which travel to the liver and then signal the body's heat-producing fat to burn more energy as heat instead of storing it. This extra burning raises the body's resting calorie burn and also makes the heart beat faster because the nervous system gets activated to support this process.
Glucagon receptor activation on white adipose tissue adipocytes triggers intracellular cAMP/PKA signaling, leading to phosphorylation of hormone-sensitive lipase and breakdown of triglycerides into free fatty acids and glycerol.
Released free fatty acids enter circulation and are taken up by the liver, where they activate PPARα and CPT1a to increase fatty acid oxidation and ketogenesis.
Hepatic fatty acid oxidation and ketogenesis stimulate production and secretion of FGF21, which acts on brown adipose tissue to induce UCP1 expression.
UCP1 protein in brown adipose tissue mitochondria uncouples the proton gradient from ATP production, causing energy to be dissipated as heat, increasing resting energy expenditure.
Increased sympathetic nervous system activity, driven by FGF21 and possibly direct glucagon receptor signaling in the CNS, elevates heart rate as a secondary consequence of systemic metabolic activation.
Less supported by current evidence, but not ruled out
Turning on the glucagon receptor may cause the liver to work harder to make glucose from non-sugar sources, and this extra work burns more energy, raising the body's resting calorie burn.
Glucagon receptor activation in hepatocytes increases expression of gluconeogenic enzymes such as PEPCK and G6Pase.
Increased gluconeogenesis creates futile cycles with glycolysis, consuming ATP and generating heat.
Evidence from Studies
Supporting (1)
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The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk
Contradicting (0)
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