PMID- 32045627
OWN - NLM
STAT- MEDLINE
DCOM- 20210503
LR  - 20210503
IS  - 1872-8057 (Electronic)
IS  - 0303-7207 (Linking)
VI  - 506
DP  - 2020 Apr 15
TI  - APPL1 knockdown blocks adipogenic differentiation and promotes adipocyte 
      lipolysis.
PG  - 110755
LID - S0303-7207(20)30055-1 [pii]
LID - 10.1016/j.mce.2020.110755 [doi]
AB  - Adipocyte dysfunction is closely associated with the development of obesity, 
      insulin resistance, and type 2 diabetes. In addition to having a positive effect 
      on adiponectin pathway and insulin signaling through direct and/or indirect 
      mechanisms, adapter protein APPL1 has also been reported to regulate body weight, 
      brown fat tissues thermogenesis, and body fat distribution in diabetic 
      individuals. However, there is dearth of data on the specific role of APPL1 on 
      adipogenic differentiation and adipocyte lipolysis. In this study, APPL1's 
      function in adipocyte differentiation and adipocyte lipolysis was evaluated, and 
      the possible mechanisms were investigated. We found that APPL1 knockdown (KD) 
      impeded differentiation of 3T3-L1 preadipocytes into mature 3T3-L1 adipocytes and 
      enhanced basal and insulin-suppressed lipolysis in mature 3T3-L1 adipocytes. 
      APPL1 KD cells presented a reduced autophagic activity in 3T3-L1 preadipocytes 
      and mature 3T3-L1 adipocytes. In 3T3-L1 preadipocytes, APPL1 KD reduced PPARgamma 
      protein levels, which was prevented by administration with proteasome inhibitor 
      MG132. Furthermore, APPL1 KD-reduced autophagic activity in mature 3T3-L1 
      adipocytes was markedly restored by inhibition of PKA, accompanied with 
      prevention of APPL1-induced lipolysis. In addition, APPL1 KD caused insulin 
      resistance in mature 3T3-L1 adipocytes. Unexpectedly, we found that APPL1 
      overexpression did not appear to play a role in adipogenic differentiation and 
      adipocyte lipolysis. Our results confirmed that APPL1 KD inhibits adipogenic 
      differentiation by suppressing autophagy and enhances adipocyte lipolysis through 
      activating PKA respectively. These findings may deepen our understanding of APPL1 
      function, especially its regulation on adipocyte biology.
CI  - Copyright (c) 2020 Elsevier B.V. All rights reserved.
FAU - Wen, Zhongyuan
AU  - Wen Z
AD  - Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, 430060, 
      China.
FAU - Tang, Zhao
AU  - Tang Z
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Department of Integrative Medicine, 
      Huashan Hospital, Fudan University, Shanghai, 200040, China.
FAU - Li, Mingxin
AU  - Li M
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Disease, Wuhan, 430071, China.
FAU - Zhang, Yemin
AU  - Zhang Y
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Disease, Wuhan, 430071, China.
FAU - Li, Junfeng
AU  - Li J
AD  - Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, 430060, 
      China.
FAU - Cao, Yingkang
AU  - Cao Y
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Disease, Wuhan, 430071, China.
FAU - Zhang, Deling
AU  - Zhang D
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Disease, Wuhan, 430071, China.
FAU - Fu, Yalin
AU  - Fu Y
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Disease, Wuhan, 430071, China.
FAU - Wang, Changhua
AU  - Wang C
AD  - Department of Pathology and Pathophysiology, Wuhan University School of Basic 
      Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of 
      Developmentally Originated Disease, Wuhan, 430071, China. Electronic address: 
      chwang0525@whu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200208
PL  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Appl1 protein, mouse)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adaptor Proteins, Signal Transducing/antagonists & inhibitors/*genetics
MH  - Adipocytes/drug effects/*metabolism/physiology
MH  - Adipogenesis/drug effects/*genetics
MH  - Animals
MH  - Autophagy/drug effects/genetics
MH  - Cell Differentiation/drug effects/genetics
MH  - Cells, Cultured
MH  - Down-Regulation/drug effects/genetics
MH  - Gene Knockdown Techniques
MH  - Lipolysis/drug effects/*genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - RNA, Small Interfering/pharmacology
OTO - NOTNLM
OT  - APPL1
OT  - Adipocytes
OT  - Autophagy
OT  - Differentiation
OT  - Lipolysis
OT  - PKA
COIS- Declaration of competing interest None.
EDAT- 2020/02/12 06:00
MHDA- 2021/05/04 06:00
CRDT- 2020/02/12 06:00
PHST- 2019/10/29 00:00 [received]
PHST- 2020/01/19 00:00 [revised]
PHST- 2020/02/06 00:00 [accepted]
PHST- 2020/02/12 06:00 [pubmed]
PHST- 2021/05/04 06:00 [medline]
PHST- 2020/02/12 06:00 [entrez]
AID - S0303-7207(20)30055-1 [pii]
AID - 10.1016/j.mce.2020.110755 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 2020 Apr 15;506:110755. doi: 10.1016/j.mce.2020.110755. Epub 
      2020 Feb 8.