PMID- 34884763
OWN - NLM
STAT- MEDLINE
DCOM- 20211220
LR  - 20211220
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 23
DP  - 2021 Nov 30
TI  - Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes 
      through Inflammation and Autophagic Degradation of GLUT4 Vesicles.
LID - 10.3390/ijms222312960 [doi]
LID - 12960
AB  - The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin 
      resistance. Here, we analyze how the downregulation of Nrg4 influences insulin 
      action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral 
      vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 
      adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a 
      complete impairment of the insulin-induced 2-deoxyglucose uptake, which was 
      likely the result of reduced insulin receptor and Glut4 protein. Downregulation 
      of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory 
      agents recovered the insulin receptor, but not Glut4, content. Proteins enriched 
      in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) 
      and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular 
      retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce 
      autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR 
      phosphorylation, at the time that proteins involved in autophagy such as LC3-II, 
      Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor 
      bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those 
      found in control adipocytes. Our study reveals that Nrg4 preserves the insulin 
      responsiveness by preventing inflammation and, in turn, benefits the insulin 
      regulation of autophagy.
FAU - Diaz-Saez, Francisco
AU  - Diaz-Saez F
AUID- ORCID: 0000-0002-5881-1928
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
FAU - Blanco-Sinfreu, Carla
AU  - Blanco-Sinfreu C
AUID- ORCID: 0000-0002-8645-9722
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
FAU - Archilla-Ortega, Adria
AU  - Archilla-Ortega A
AUID- ORCID: 0000-0001-6951-1501
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
FAU - Sebastian, David
AU  - Sebastian D
AUID- ORCID: 0000-0002-7260-3869
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
AD  - Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of 
      Science and Technology (BIST), 08028 Barcelona, Spain.
FAU - Romero, Montserrat
AU  - Romero M
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
AD  - Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of 
      Science and Technology (BIST), 08028 Barcelona, Spain.
FAU - Hernandez-Alvarez, Maria Isabel
AU  - Hernandez-Alvarez MI
AUID- ORCID: 0000-0003-2483-7000
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
FAU - Mora, Silvia
AU  - Mora S
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
FAU - Testar, Xavier
AU  - Testar X
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
FAU - Ricart, Wifredo
AU  - Ricart W
AD  - Department of Medicine, Universitat de Girona, Carrer Emili Grahit, 77, 17071 
      Girona, Spain.
AD  - Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigacio 
      Biomedica de Girona (IDIBGI), Carrer del Dr. Castany, s/n, 17190 Salt, Spain.
AD  - Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y 
      Nutricion (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain.
FAU - Fernandez-Real, Jose Manuel
AU  - Fernandez-Real JM
AUID- ORCID: 0000-0002-7442-9323
AD  - Department of Medicine, Universitat de Girona, Carrer Emili Grahit, 77, 17071 
      Girona, Spain.
AD  - Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigacio 
      Biomedica de Girona (IDIBGI), Carrer del Dr. Castany, s/n, 17190 Salt, Spain.
AD  - Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y 
      Nutricion (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain.
FAU - Moreno-Navarrete, Jose Maria
AU  - Moreno-Navarrete JM
AD  - Department of Medicine, Universitat de Girona, Carrer Emili Grahit, 77, 17071 
      Girona, Spain.
AD  - Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigacio 
      Biomedica de Girona (IDIBGI), Carrer del Dr. Castany, s/n, 17190 Salt, Spain.
AD  - Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y 
      Nutricion (CIBEROBN), Carlos III Health Institute, 28029 Madrid, Spain.
FAU - Aragones, Julian
AU  - Aragones J
AD  - Research Unit, Hospital of Santa Cristina, Research Institute Princesa, 
      Autonomous University of Madrid, c/Maestro Vives, 2, 28009 Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red Enfermedades Cardiovasculares, Carlos 
      III Health Institute, 28029 Madrid, Spain.
FAU - Camps, Marta
AU  - Camps M
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
FAU - Zorzano, Antonio
AU  - Zorzano A
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
AD  - Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of 
      Science and Technology (BIST), 08028 Barcelona, Spain.
FAU - Guma, Anna
AU  - Guma A
AUID- ORCID: 0000-0001-9390-5252
AD  - Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, 
      University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain.
AD  - Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.
AD  - Centro de Investigacion Biomedica en Red Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Carlos III Health Institute, 28029 Madrid, Spain.
LA  - eng
PT  - Journal Article
DEP - 20211130
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cytokines)
RN  - 0 (GTPase-Activating Proteins)
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (Insulin)
RN  - 0 (Neuregulins)
RN  - 0 (Qa-SNARE Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Slc2a4 protein, mouse)
RN  - 0 (Tbc1d4 protein, mouse)
RN  - 0 (neuregulin-4)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 3.4.11.3 (Cystinyl Aminopeptidase)
RN  - EC 3.4.11.3 (leucyl-cystinyl aminopeptidase)
SB  - IM
MH  - 3T3 Cells
MH  - Adipocytes/metabolism
MH  - Animals
MH  - Autophagy/*physiology
MH  - Cell Line
MH  - Cystinyl Aminopeptidase/biosynthesis
MH  - Cytokines/biosynthesis
MH  - Deoxyglucose/metabolism
MH  - Down-Regulation
MH  - GTPase-Activating Proteins/biosynthesis
MH  - Glucose Transporter Type 4/*metabolism
MH  - Inflammation/pathology
MH  - Insulin/metabolism
MH  - Insulin Resistance/*physiology
MH  - Mice
MH  - Neuregulins/biosynthesis/genetics/*metabolism
MH  - Qa-SNARE Proteins/biosynthesis
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Receptor, Insulin/*biosynthesis
PMC - PMC8657571
OTO - NOTNLM
OT  - Glut4
OT  - adipocytes
OT  - autophagy
OT  - inflammation
OT  - insulin receptor
OT  - insulin resistance
OT  - neuregulin 4
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2021/12/11 06:00
MHDA- 2021/12/21 06:00
PMCR- 2021/11/30
CRDT- 2021/12/10 01:04
PHST- 2021/10/28 00:00 [received]
PHST- 2021/11/25 00:00 [revised]
PHST- 2021/11/25 00:00 [accepted]
PHST- 2021/12/10 01:04 [entrez]
PHST- 2021/12/11 06:00 [pubmed]
PHST- 2021/12/21 06:00 [medline]
PHST- 2021/11/30 00:00 [pmc-release]
AID - ijms222312960 [pii]
AID - ijms-22-12960 [pii]
AID - 10.3390/ijms222312960 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Nov 30;22(23):12960. doi: 10.3390/ijms222312960.