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

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...

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Autores principales:	Hui Li, William Donelan, Fang Wang, Peilan Zhang, Lijun Yang, Yousong Ding, Dongqi Tang, Shiwu Li
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	GLP-1 FNDC5 lipolysis β-cells obesity Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7bdb554328d646d6b1fcf7fdac2da5a2
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spelling	oai:doaj.org-article:7bdb554328d646d6b1fcf7fdac2da5a22021-11-11T06:30:00ZGLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions2296-634X10.3389/fcell.2021.777026https://doaj.org/article/7bdb554328d646d6b1fcf7fdac2da5a22021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.777026/fullhttps://doaj.org/toc/2296-634XMultiple 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.Hui LiHui LiWilliam DonelanFang WangPeilan ZhangLijun YangYousong DingDongqi TangShiwu LiFrontiers Media S.A.articleGLP-1FNDC5lipolysisβ-cellsobesityBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GLP-1 FNDC5 lipolysis β-cells obesity Biology (General) QH301-705.5
spellingShingle	GLP-1 FNDC5 lipolysis β-cells obesity Biology (General) QH301-705.5 Hui Li Hui Li William Donelan Fang Wang Peilan Zhang Lijun Yang Yousong Ding Dongqi Tang Shiwu Li GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions
description	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.
format	article
author	Hui Li Hui Li William Donelan Fang Wang Peilan Zhang Lijun Yang Yousong Ding Dongqi Tang Shiwu Li
author_facet	Hui Li Hui Li William Donelan Fang Wang Peilan Zhang Lijun Yang Yousong Ding Dongqi Tang Shiwu Li
author_sort	Hui Li
title	GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions
title_short	GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions
title_full	GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions
title_fullStr	GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions
title_full_unstemmed	GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions
title_sort	glp-1 induces the expression of fndc5 derivatives that execute lipolytic actions
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7bdb554328d646d6b1fcf7fdac2da5a2
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GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions

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