New research uncovers how the GLP-1R-FGF21 axis regulates body weight in a carbohydrate-dependent manner.

Gut-brain interactions that regulate energy balance being investigated by Julio E. Ayala, Ph.D., a molecular physiologist and biophysicist at Vanderbilt University Medical Center, are helping to untangle the molecular mechanisms involved in glucagon-like peptide-1 receptor (GLP-1R) agonist effects on eating behavior.

GLP-1R agonists comprise a class of drugs that stimulate insulin secretion and promote weight loss, the latter primarily driven by the interactions of these drugs within specific regions of the brain. Ayala is seeking to better elucidate how GLP-1R activation promotes weight loss.

“The effects of long-term administration of these drugs remains largely unknown,” Ayala said. “Since individuals using these medications for weight loss have to take them for the rest of their lives, we need to learn how these agents regulate body weight and promote weight loss.”

His investigation is using transgenic mouse models, targeted pharmacological interventions, and state-of-the-art metabolic phenotyping capabilities.

Uncovering the Role of FGF21

Fibroblast growth factor-21 (FGF21) is a hormone predominantly produced by the liver in response to metabolic challenges, such as high carbohydrate consumption and low caloric intake, particularly low intake of proteins. The effects of FGF21 overlap with many also associated with GLP-1R activation, Ayala said, including suppression of carbohydrate intake, weight reduction and better glycemic control.

“We know that GLP-1R activation induces FGF21 production,” Ayala said.

However, since GLP-1R agonists reduce caloric intake, and reduced caloric intake also stimulates FGF21 production, questions persist regarding whether stimulation of FGF21 production could just be secondary to reduced food intake.

New Insight into Carbohydrates

In a study published in Molecular Metabolism, Ayala and his team used mouse models to test the metabolic relevance of liver FGF21 in response to liraglutide, a widely used GLP-1R agonist. The results showed that liraglutide increases FGF21 levels independently of decreased food intake via neuronal GLP-1R activation.

In addition, they found that liraglutide-induced FGF21 is required for the full weight-lowering effect of GLP-1R activation in mice. The researchers hypothesized that FGF21 specifically reduces the intake of carbohydrates in response to GLP-1R agonists.

“Mice lacking liver FGF21 are resistant to liraglutide-induced weight loss only when fed high-carbohydrate diets and not when fed low-carbohydrate diets,” Ayala said. “Additional results showed that central FGF21 signaling is required for FGF21 to mediate the weight loss action of liraglutide.”

Potential Therapeutic Impact

Ayala’s work unexpectedly identified the liver hormone FGF21 as key mediator of a novel brain-liver-brain crosstalk that results when using GLP-1R agonists in the presence of high carbohydrate diets.

He explains the findings could have important therapeutic implications.

“More in-depth preclinical and clinical studies into the role of the brain GLP-1R-liver FGF21 crosstalk may shed light on the well-documented variability in response to GLP-1R agonists,” he said. “Our results raise the possibility that a low versus high carbohydrate diet consumed by individuals taking these drugs may affect their weight loss potential.

“Long-term, we hope to enable precision medicine tailoring of GLP-1-based therapeutics to different individuals based on their genetics and environment such as diet.”

About the Expert

Julio E. Ayala, Ph.D.

Julio E. Ayala, Ph.D., is an associate professor of molecular physiology and biophysics at Vanderbilt University Medical Center. His research focuses on the gut-brain interactions that regulate energy balance.