The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk

Turning on two specific body switches—one for glucagon and one for GLP-1—helps burn more energy without raising blood sugar, because one speeds up metabolism and the other keeps blood sugar in check.

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 required to fully activate brown fat and maintain long-term weight loss.

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.

In obese mice, a compound called G49 reduces weight and improves metabolism only when both glucagon and GLP-1 receptors are active; blocking either receptor significantly reduces weight loss and stops the activation of brown fat and the increase in energy use.

In obese mice, a compound called G49 leads to a temporary buildup of fat in the liver within six hours, accompanied by increased activity of genes involved in fat production, triggered by hormonal signals from glucagon and insulin.

In obese mice, a single injection of a specific drug called G49 causes fat cells to break down stored fat quickly, releasing a large increase of free fatty acids into the blood. This process depends on the glucagon receptor and happens before changes occur in the liver and brown fat.