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

Autor: Torsten Schöneberg, Arie Geerlof, Michael Kruse, Juliano Machado, Maximilian Lassi, Michael Sattler, Annette Feuchtinger, Adam Linford, Katharina Kessler, Shigehisa Hirose, Lea Bühler, Arne Dietrich, Rabih El Merahbi, Xiaochuan Ma, Katrin Fischer, Ana Jimena Alfaro, Matthias Blüher, Andreas Pfeiffer, Madeleen Bosma, Rhoda Anane Karikari, Nobuhiro Nakamura, Doreen Thor, Peter P. Nawroth, Olli Ritvos, Timo Dirk Müller, Andreas Blutke, Valeria Lopez-Salazar, Silke Hornemann, Raffaele Teperino, Marcel Scheideler, Stephan Herzig, Isabell Kaczmarek, Olga Pivovarova-Ramich, Olga Shilkova, André Mourão, Anastasia Georgiadi, Katarina Klepac
Přispěvatelé: Georgiadi, Anastasia [0000-0002-9648-8682], Merahbi, Rabih El- [0000-0001-8133-8297], Bosma, Madeleen [0000-0003-0547-0100], Shilkova, Olga [0000-0001-8607-4008], Nakamura, Nobuhiro [0000-0002-0249-2665], Teperino, Raffaele [0000-0001-8815-1409], Scheideler, Marcel [0000-0003-4650-7387], Müller, Timo Dirk [0000-0002-0624-9339], Schöneberg, Torsten [0000-0001-5313-0237], Thor, Doreen [0000-0002-9522-5098], Nawroth, Peter [0000-0002-6134-7804], Sattler, Michael [0000-0002-1594-0527], Herzig, Stephan [0000-0003-3950-3652], Apollo - University of Cambridge Repository, Department of Physiology, Growth factor physiology, Department of Bacteriology and Immunology, Medicum, University of Helsinki
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
medicine.medical_treatment
Glucose uptake
PROTEIN
General Physics and Astronomy
Adipose tissue
White adipose tissue
MOUSE
Receptors
G-Protein-Coupled
Cohort Studies
Mice
38/1
0302 clinical medicine
692/163/2743/2037
Adipocytes
42/41
Glucose homeostasis
Insulin
GLUT4 TRANSLOCATION
Mice
Knockout
Multidisciplinary
biology
article
Hep G2 Cells
Middle Aged
Metabolic syndrome
3. Good health
RECEPTORS
Mechanisms of disease
Liver
OBESITY
Gene Knockdown Techniques
Female
631/80/304
EXPRESSION
Adult
medicine.medical_specialty
Adolescent
Science
Adipose Tissue
White
Recombinant Fusion Proteins
Primary Cell Culture
CHO Cells
Diet
High-Fat
General Biochemistry
Genetics and Molecular Biology
38
Prediabetic State
03 medical and health sciences
Islets of Langerhans
Young Adult
Cricetulus
Internal medicine
3T3-L1 Cells
medicine
Animals
Humans
3T3-L1
Aged
42
business.industry
Membrane Proteins
Proteins
General Chemistry
medicine.disease
Insulin receptor
Disease Models
Animal
030104 developmental biology
Endocrinology
Cross-Sectional Studies
Glucose
HEK293 Cells
Diabetes Mellitus
Type 2
FAT
CELLS
biology.protein
NIH 3T3 Cells
3111 Biomedicine
Insulin Resistance
business
RESISTANCE
030217 neurology & neurosurgery
Zdroj: Nat. Commun. 12:2999 (2021)
Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-21 (2021)
Popis: 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.
The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.
Databáze: OpenAIRE
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