GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions

Area of Science:

• Endocrinology
• Molecular Biology
• Metabolic Research

Background:

• Glucagon-like peptide-1 (GLP-1) therapeutics are vital for type 2 diabetes and obesity management.
• The precise mechanisms by which GLP-1 influences body weight remain under investigation.

Purpose of the Study:

• To elucidate the role of fibronectin type III domain containing 5 (FNDC5) in mediating GLP-1's lipolytic and anti-obesity effects.
• To identify and characterize novel isoforms of FNDC5 involved in metabolic regulation.

Main Methods:

• Investigated GLP-1-induced FNDC5 expression and secretion in pancreatic beta cells.
• Utilized FNDC5-knockout beta cells to assess GLP-1's lipolytic activity.
• Administered liraglutide to mouse models to evaluate FNDC5 induction in vivo.
• Characterized membrane-associated and secretable FNDC5 (sFNDC5) isoforms.
• Assessed the effects of recombinant sFNDC5 on adipocytes and in an obese mouse model.

Main Results:

• GLP-1 upregulates FNDC5 expression and secretion in beta cells, crucial for lipolysis.
• GLP-1's lipolytic effect is dependent on FNDC5; it's absent in FNDC5-knockout cells.
• Liraglutide increases FNDC5 expression in mouse pancreas/brain and serum FNDC5 levels.
• A novel secretable FNDC5 (sFNDC5) isoform was identified and shown to stimulate lipolysis and adipocyte browning.
• Recombinant sFNDC5 demonstrated potent anti-obesity activities in vivo.

Conclusions:

• GLP-1 exerts anti-obesity effects partly through inducing FNDC5 secretion from responsive tissues.
• FNDC5 and its secretable isoform (sFNDC5) are key mediators of GLP-1's metabolic actions.
• These findings offer new mechanistic insights into GLP-1-based therapies for obesity and diabetes.