Format

Send to

Choose Destination
J Biol Chem. 2018 Apr 20;293(16):6064-6074. doi: 10.1074/jbc.RA118.002162. Epub 2018 Feb 26.

Alternative splicing variant of the scaffold protein APPL1 suppresses hepatic adiponectin signaling and function.

Author information

1
From the Departments of Cell Systems and Anatomy.
2
the Department of Clinical and Applied Science Education, University of the Incarnate Word School of Osteopathic Medicine, San Antonio, Texas 78253.
3
Medicine and.
4
The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
5
the Geriatric Research Education and Clinical Center (GRECC), South Texas Veterans Health Care System, San Antonio, Texas 78229.
6
the Department of Medicine, University of California, San Diego, La Jolla, California 92093.
7
the Merck Research Laboratory, Diabetes Early Discovery, Boston, Massachusetts 02115-5727.
8
the Center for Biomedical Informatics, Department of Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, and.
9
Pharmacology, and.
10
From the Departments of Cell Systems and Anatomy, DongQ@uthscsa.edu.

Abstract

Adiponectin is an adipocyte-derived hormone with antidiabetic activities that include increasing the sensitivity of cells to insulin. Adaptor protein containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif (APPL1) stimulates adiponectin signaling and promotes adiponectin's insulin-sensitizing effects by binding to two adiponectin receptors, AdipoR1 and AdipoR2, and the insulin receptor. In this study, we report an alternative splicing variant of APPL1 (APPL1sv) that is highly expressed in mouse liver, pancreas, and spleen tissues. The expression levels of APPL1sv in liver tissues were enhanced in a mouse model of obesity and diabetic dyslipidemia (i.e. db/db mice) and reduced in calorie-restricted mice compared with ad libitum-fed mice. APPL1sv overexpression or suppression inhibited or enhanced, respectively, adiponectin-stimulated phosphorylation of AMP protein kinase (AMPK) in mouse hepatocytes. We also found that APPL1sv binds to AdipoR1 and AdipoR2 under basal conditions and that adiponectin treatment reduces this binding. Overexpression of APPL1sv blocked adiponectin-induced interactions of APPL1 with the adiponectin receptors. Moreover, adenovirus-mediated and short hairpin RNA-based suppression of APPL1sv greatly reduced high fat diet-induced insulin resistance and hepatic glucose production in mice. Our study identifies a key suppressor of hepatic adiponectin signaling and insulin sensitivity, a finding that may shed light on identifying effective therapeutic targets for treating insulin resistance and type 2 diabetes.

KEYWORDS:

AMP-activated kinase (AMPK); APPL1; APPL1sv; adiponectin; alternative splicing; diabetes; insulin resistance; liver; metabolic disorder; metabolism

PMID:
29483192
PMCID:
PMC5912452
DOI:
10.1074/jbc.RA118.002162
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center