In obese mice, blocking the breakdown of fat in white fat tissue prevents G49 from triggering increased production of FGF21, ketone bodies, activation of brown fat, and weight loss.
Mechanism
Synthesis from 1 study
G49 makes fat cells release stored fat, which tells the liver to produce a hormone and energy molecules that turn on brown fat to burn calories. If fat cells can't release their fat, none of this happens. Other helpers like immune cells and a second hormone also contribute, but they all depend on...
Most probable mechanism
G49 tells fat cells to break down stored fat into fatty acids. These fatty acids travel to the liver, which uses them to make ketones and a hormone called FGF21. FGF21 and ketones then signal brown fat to burn energy as heat, and also help white fat turn into a more energy-burning type. This whole process burns more calories and leads to weight loss. If fat cells can't break down their stored fat, none of this happens.
G49 binds to glucagon receptors on white adipose tissue adipocytes, activating PKA and phosphorylating hormone-sensitive lipase to trigger triglyceride breakdown and release of free fatty acids into circulation
Free fatty acids are taken up by hepatocytes, inducing transient lipid accumulation and activating PPARα and CPT1a to drive mitochondrial fatty acid oxidation and ketogenesis
Hepatic fatty acid oxidation and ketogenesis stimulate transcription and secretion of FGF21, which enters circulation as a hepatokine
Circulating FGF21 binds to receptors on brown adipose tissue and white adipose tissue, upregulating UCP1 expression and promoting thermogenic gene programs
UCP1 protein inserts into mitochondrial membranes in brown adipocytes, uncoupling electron transport from ATP production to dissipate energy as heat, increasing whole-body energy expenditure
Increased energy expenditure and reduced lipid storage lead to net loss of adipose tissue mass and body weight
Less supported by current evidence, but not ruled out
When fat cells break down stored fat, they release fatty acids that attract specific immune cells. These immune cells release signals that cause white fat cells to take on brown-fat-like properties, helping burn more energy. This can happen even if FGF21 is blocked.
Free fatty acids released from white adipose tissue act as chemoattractants for eosinophils and invariant natural killer T 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
Beiging of white adipose tissue increases local thermogenesis and contributes to whole-body energy expenditure
Fat breakdown also causes fat cells to release a hormone called adiponectin, which travels to the liver and helps it burn more fat. This helps the liver make more FGF21 and ketones, which then activate brown fat and burn energy.
G49 stimulates secretion of adiponectin from white adipose tissue
Adiponectin binds to receptors on hepatocytes, activating AMPK and PPARα signaling pathways
PPARα activation increases expression of CPT1a and other fatty acid oxidation genes, enhancing hepatic lipid clearance
Enhanced hepatic fatty acid oxidation supports sustained FGF21 production and ketogenesis
Evidence from Studies
Supporting (1)
Community contributions welcome
The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk
Contradicting (0)
Community contributions welcome
Gold Standard Evidence Needed
According to GRADE and EBM methodology, here is what ideal scientific evidence would look like to definitively prove or disprove this specific claim, ordered from strongest to weakest evidence.