Abstract
Multiple GLP-1-derived therapeutics are clinically used to treat type 2 diabetes and obesity. However, the underlying mechanism of how these drugs regulate the body weight of obese patients remains incompletely understood. Here, we report that the lipolysis effects of GLP-1 on β cells can depend on its induced expression of fibronectin type III domain containing 5 (FNDC5). The transmembrane FNDC5 is a precursor of the recently identified hormone irisin that possesses a range of bioactivities, including anti-obesity and anti-diabetes. We revealed that GLP-1 upregulates the expression and secretion of FNDC5 in β cells, while GLP-1 itself fails to activate the lipolysis genes in FNDC5-knockout β cells. In addition, liraglutide, a clinically used GLP-1 receptor agonist, induced the expression of FNDC5 in mouse pancreas and brain tissues and increased the serum level of secreted FNDC5. Furthermore, we observed the expression of the well-known membrane-associated FNDC5 and a novel, secretable FNDC5 (sFNDC5) isoform in β cells and multiple rat tissues. Recombinant sFNDC5 stimulated lipolysis of wild type and FNDC5-knockout β cells. This new isoform further induced lipolysis and browning of adipocytes, and similar to irisin, executed potent anti-obesity activities in an obese mouse model. Overall, our studies provided new mechanistic insights into GLP-1’s anti-obesity actions in which GLP-1 induces the secretion of FNDC5 derivatives from its responsive organs that then mediate its anti-obesity activities.
Highlights
Obesity is a rising epidemic that puts people at higher risk for serious diseases such as diabetes, heart disease, and cancer (Engin, 2017)
The glucagon-like peptide-1 (GLP-1)-induced expression of the fibronectin type III domain containing 5 (FNDC5) gene and protein was observed in the rat β cell line INS-1 (Supplementary Figures S1A,B), which expressed a higher level of insulin gene upon GLP-1 treatment (Supplementary Figure S1C)
Except for the p38 inhibitor, the protein kinase A (PKA), AKT, and ERK inhibitors all significantly suppressed the GLP-1 induced activation of three key lipolysis genes, adipose triglyceride lipase, HSL, and hepatic lipase C (LIPC) (Supplementary Figure S2), suggesting their mediation of the lipolysis actions of GLP-1 in β cells. These inhibitors suppressed the GLP-1 induced expression of FNDC5 to the basal level (Figure 1D), while SB203589 showed no inhibition. These results indicated that the ERK, PKA, and AKT pathways all are required to mediate the GLP1-induced expression of FNDC5 in β cells
Summary
Obesity is a rising epidemic that puts people at higher risk for serious diseases such as diabetes, heart disease, and cancer (Engin, 2017). The US Food and Drug Administration (FDA) has approved multiple prescription medications to treat adults with body mass index (BMI) > 30 or >27 for those with weight-related comorbidity. These anti-obesity medications mainly reduce nutrient absorption or food intake. The latest approved anti-obesity therapeutic is liraglutide that is a glucagon-like peptide-1 (GLP-1) analog, or named GLP-1 receptor agonist (GLP-1RA). GLP-1 mediates the incretin effect, is essential for postprandial regulation of glucose, and is a major factor in regulating insulin secretion following oral glucose consumption.
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