In obese mice, a compound called G49 triggers fat breakdown in white fat tissue through the glucagon receptor, which leads to the release of two signaling molecules—FGF21 and adiponectin—from the...
Mechanism
Synthesis from 1 study
G49 makes fat cells release fatty acids, which tell the liver to send out signals that turn on heat-burning fat in brown fat tissue. This burns more calories and helps the mice lose weight. Another pathway also turns some white fat into heat-burning fat using immune cells, but the main driver is...
Most probable mechanism
A drug called G49 tells fat cells to break down stored fat into fatty acids. These fatty acids travel to the liver, which responds by releasing two signaling molecules—FGF21 and adiponectin. These molecules then go to the brown fat tissue and turn on a protein called UCP1, which makes the brown fat burn energy as heat instead of storing it. This process causes the body to use up more calories and lose weight.
G49 binds to glucagon receptors on white adipose tissue adipocytes, activating protein kinase A and phosphorylating hormone-sensitive lipase, triggering triglyceride breakdown into free fatty acids and glycerol.
Free fatty acids released from white adipose tissue are taken up by hepatocytes, inducing transient lipid accumulation and activating peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1a (CPT1a), which enhance fatty acid oxidation and ketogenesis.
Hepatic fatty acid oxidation and ketogenesis stimulate transcription and secretion of fibroblast growth factor 21 (FGF21) from liver cells.
G49 stimulates secretion of adiponectin from white adipose tissue, which circulates to the liver and enhances fatty acid oxidation via AMPK and PPARα activation.
Circulating FGF21 and adiponectin bind to receptors on brown adipocytes, activating transcription of uncoupling protein 1 (UCP1) and other thermogenic genes.
UCP1 protein inserts into the inner mitochondrial membrane of brown adipocytes, uncoupling the proton gradient from ATP production and dissipating energy as heat.
Increased mitochondrial uncoupling in brown adipose tissue elevates whole-body energy expenditure, leading to net loss of fat mass.
Less supported by current evidence, but not ruled out
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 eosinophils and innate lymphoid cells secrete interleukin-4 and interleukin-13, which polarize macrophages to an M2 phenotype.
M2 macrophages secrete factors that induce uncoupling protein 1 (UCP1) expression in white adipocytes, promoting their conversion to beige adipocytes.
Beige adipocytes contribute to increased energy expenditure through UCP1-mediated thermogenesis.
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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