TY - JOUR
T1 - Alternative splicing variant of the scaffold protein APPL1 suppresses hepatic adiponectin signaling and function
AU - Galan-Davila, Amanda K.
AU - Ryu, Jiyoon
AU - Dong, Kun
AU - Xiao, Yang
AU - Dai, Zhe
AU - Zhang, Deling
AU - Li, Zhi
AU - Dick, Amanda M.
AU - Liu, Kevin D.
AU - Kamat, Amrita
AU - Lu, Min
AU - Dong, Qunfeng
AU - Liu, Feng
AU - Dong, Lily Q.
N1 - Funding Information:
This work was supported in part by NIDDK, National Institutes of Health Pre-Doctoral Fellowship PA-11-112 (to A. K. G.-D.); National Institutes of Health R01 Grant DK76902 (to F. L.), Veterans Affairs Merit Review Award 1I01BX001744-01 (to A. K.); and American Heart Association Research Award 15GRNT23230053, American Diabetes Association Grant 7-13-BS-043, and National Institutes of Health R01 Grant DK102965 (to L. Q. D.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2018/4/20
Y1 - 2018/4/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045835339&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045835339&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA118.002162
DO - 10.1074/jbc.RA118.002162
M3 - Article
C2 - 29483192
AN - SCOPUS:85045835339
VL - 293
SP - 6064
EP - 6074
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 16
ER -