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Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Published version
Peer-reviewed

Change log

Authors

Georgiadi, Anastasia  ORCID logo  https://orcid.org/0000-0002-9648-8682
Lopez-Salazar, Valeria 
Karikari, Rhoda Anane 
Ma, Xiaochuan 

Abstract

Abstract: The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

Description

Funder: European Foundation for the Study of Diabetes (EFSD); doi: https://doi.org/10.13039/501100001648

Keywords

Article, /631/80/304, /692/163/2743/2037, /38, /38/1, /42, /42/41, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

12

Publisher

Nature Publishing Group UK
Sponsorship
Deutsche Forschungsgemeinschaft (German Research Foundation) (SFB1118, SFB1052)
Helmholtz Association (Ampro)
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) (Rubicon)