In obese mice, a compound called G49 triggers a 3- to 4-fold rise in FGF21 hormone levels within 12 hours by activating fat breakdown in the liver via the glucagon receptor. This rise in FGF21 is...
Mechanism
Synthesis from 1 study
This drug makes fat cells release fatty acids, which go to the liver and trigger it to produce a hormone called FGF21. That hormone then turns on heat-burning mode in brown fat, making the body burn more calories and lose weight. Other processes help, but this is the main path.
Most probable mechanism
A drug triggers a receptor in fat tissue that causes fat to break down and release fatty acids into the blood. These fatty acids go to the liver, where they are burned for energy in a way that produces ketones. This process tells the liver to make a hormone called FGF21, which travels to brown fat and turns on a protein that burns energy as heat instead of storing it. This heat production causes the body to lose weight.
The drug binds to glucagon receptors on white adipose tissue adipocytes, activating protein kinase A and phosphorylating hormone-sensitive lipase, triggering triglyceride breakdown and release of free fatty acids into circulation.
Free fatty acids are taken up by hepatocytes, inducing transient lipid accumulation and activating peroxisome proliferator-activated receptor alpha (PPARα), which upregulates carnitine palmitoyltransferase 1a (CPT1a) and promotes mitochondrial fatty acid oxidation.
Increased fatty acid oxidation elevates hepatic expression of HMG-CoA synthase 2 (Hmcs2), driving ketone body production and creating a metabolic state that stimulates fibroblast growth factor 21 (FGF21) transcription and secretion.
Secreted FGF21 acts on brown adipose tissue to upregulate uncoupling protein 1 (UCP1) expression and enhance mitochondrial uncoupling, increasing thermogenesis and energy expenditure.
UCP1-mediated uncoupling of mitochondrial respiration dissipates energy as heat, leading to sustained reduction in fat mass and body weight.
Less supported by current evidence, but not ruled out
The drug also causes fat tissue to release a hormone called adiponectin, which travels to the liver and helps boost the production of FGF21 and the burning of fat, further supporting brown fat activity and weight loss.
G49 stimulates secretion of adiponectin from white adipose tissue, increasing circulating levels.
Adiponectin binds to receptors on hepatocytes, activating AMPK and PPARα signaling pathways to enhance fatty acid oxidation and suppress lipogenesis.
Enhanced hepatic fatty acid oxidation and metabolic rewiring increase FGF21 production and secretion.
Elevated FGF21 and adiponectin synergistically promote UCP1 expression and thermogenesis in brown adipose tissue.
Fat breakdown releases fatty acids that attract specific immune cells into white fat, which then release signals that turn some white fat cells into energy-burning beige fat cells, contributing to weight loss.
Free fatty acids released from white adipose tissue act as chemoattractants for eosinophils and type 2 innate lymphoid cells.
Infiltrating immune cells secrete interleukin-4 and interleukin-13, which polarize macrophages to an M2 phenotype.
M2 macrophages and cytokines induce expression of UCP1 and thermogenic genes in white adipocytes, promoting beiging.
Beiging of white adipose tissue contributes to increased energy expenditure and fat loss.
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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