In obese mice, the drug G49 reduces weight and activates fat-burning tissue only when both the glucagon and GLP-1 receptors are active. Blocking either one reduces its effect, but blocking both stops...
Mechanism
Synthesis from 1 study
G49 needs to activate two receptors at once to make the body burn fat. One receptor wakes up fat cells to release energy, which tells the liver to send a signal that turns on heat-burning fat. The other receptor helps the pancreas release insulin and boosts the nervous system’s signal to burn more...
Most probable mechanism
G49 turns on two special receptors at the same time — one in fat tissue and one in the pancreas. This makes fat cells release stored energy as fatty acids, which travel to the liver and trigger it to produce a signal molecule that wakes up brown fat to burn energy as heat. At the same time, the other receptor tells the pancreas to release insulin, which helps the body manage energy use. If both receptors are blocked, none of this happens. If only one is blocked, the process slows down but doesn’t stop.
G49 binds to and activates glucagon receptor (GCGR) on white adipose tissue adipocytes, triggering intracellular cAMP/PKA signaling that phosphorylates hormone-sensitive lipase and initiates lipolysis.
Free fatty acids released from white adipose tissue enter circulation and are taken up by hepatocytes, where they activate PPARα and induce expression of CPT1a and HMGCS2, driving fatty acid oxidation and ketogenesis.
Hepatic ketogenesis and GCGR activation induce transcription and secretion of FGF21, which acts as a hepatokine to stimulate thermogenic gene expression in brown adipose tissue and promote beiging of white adipose tissue.
G49 simultaneously binds to and activates GLP-1 receptor on pancreatic β-cells, enhancing glucose-stimulated insulin secretion, which is amplified by circulating free fatty acids.
FGF21 and sympathetic activation increase UCP1 expression in brown adipocytes, uncoupling mitochondrial respiration to dissipate energy as heat, increasing whole-body energy expenditure.
Simultaneous blockade of both GCGR and GLP-1R abolishes lipolysis, FGF21 release, insulin secretion, and UCP1 activation, eliminating weight loss and thermogenesis.
Less supported by current evidence, but not ruled out
The fatty acids released by fat breakdown attract specific immune cells that release signals to turn white fat cells into energy-burning beige fat cells, but this only happens if the fat cells first break down their stored energy.
Free fatty acids released from white adipose tissue act as chemoattractants for eosinophils and type 2 innate lymphoid cells.
Infiltrating eosinophils and iNKT cells secrete IL-4 and IL-13, which polarize macrophages to an M2 phenotype.
M2 macrophages secrete factors that induce UCP1 expression and mitochondrial biogenesis in white adipocytes, promoting beiging.
Blockade of lipolysis or GCGR activation prevents immune cell infiltration and UCP1 induction in white adipose tissue.
Fat tissue releases a hormone called adiponectin in response to G49, which tells the liver to burn more fat and make less new fat, helping the body shift from storing to burning energy.
G49 stimulates secretion of adiponectin from white adipose tissue within 24 hours of administration.
Adiponectin binds to receptors on hepatocytes, activating AMPK and PPARα signaling pathways.
PPARα activation increases expression of fatty acid oxidation genes (e.g., CPT1a) and suppresses lipogenic genes, enhancing hepatic lipid clearance.
Loss of adiponectin reduces hepatic fatty acid oxidation and blunts FGF21 elevation and weight loss in response to G49.
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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