PMID- 37998385
OWN - NLM
STAT- MEDLINE
DCOM- 20231130
LR  - 20240201
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 12
IP  - 22
DP  - 2023 Nov 18
TI  - Sustained Nrf2 Overexpression-Induced Metabolic Deregulation Can Be Attenuated by 
      Modulating Insulin/Insulin-like Growth Factor Signaling.
LID - 10.3390/cells12222650 [doi]
LID - 2650
AB  - The modulation of insulin/insulin-like growth factor signaling (IIS) is 
      associated with altered nutritional and metabolic states. The Drosophila genome 
      encodes eight insulin-like peptides, whose activity is regulated by a group of 
      secreted factors, including Ecdysone-inducible gene L2 (ImpL2), which acts as a 
      potent IIS inhibitor. We recently reported that cncC (cncC/Nrf2), the fly 
      ortholog of Nrf2, is a positive transcriptional regulator of ImpL2, as part of a 
      negative feedback loop aiming to suppress cncC/Nrf2 activity. This finding 
      correlated with our observation that sustained cncC/Nrf2 
      overexpression/activation (cncC(OE); a condition that signals organismal stress) 
      deregulates IIS, causing hyperglycemia, the exhaustion of energy stores in flies' 
      tissues, and accelerated aging. Here, we extend these studies in Drosophila by 
      assaying the functional implication of ImpL2 in cncC(OE)-mediated metabolic 
      deregulation. We found that ImpL2 knockdown (KD) in cncC(OE) flies partially 
      reactivated IIS, attenuated hyperglycemia and restored tissue energetics. 
      Moreover, ImpL2 KD largely suppressed cncC(OE)-mediated premature aging. In 
      support, pharmacological treatment of cncC(OE) flies with Metformin, a first-line 
      medication for type 2 diabetes, restored (dose-dependently) IIS functionality and 
      extended cncC(OE) flies' longevity. These findings exemplify the effect of 
      chronic stress in predisposition to diabetic phenotypes, indicating the potential 
      prophylactic role of maintaining normal IIS functionality.
FAU - Gumeni, Sentiljana
AU  - Gumeni S
AUID- ORCID: 0000-0003-0033-2008
AD  - Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens, Panepistimiopolis, 15784 Athens, Greece.
FAU - Lamprou, Maria
AU  - Lamprou M
AUID- ORCID: 0000-0002-9808-5350
AD  - Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens, Panepistimiopolis, 15784 Athens, Greece.
FAU - Evangelakou, Zoi
AU  - Evangelakou Z
AD  - Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens, Panepistimiopolis, 15784 Athens, Greece.
FAU - Manola, Maria S
AU  - Manola MS
AUID- ORCID: 0000-0002-6975-2812
AD  - Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens, Panepistimiopolis, 15784 Athens, Greece.
FAU - Trougakos, Ioannis P
AU  - Trougakos IP
AUID- ORCID: 0000-0002-6179-2772
AD  - Department of Cell Biology and Biophysics, Faculty of Biology, National and 
      Kapodistrian University of Athens, Panepistimiopolis, 15784 Athens, Greece.
LA  - eng
GR  - Tau2EpsilonDKappa-01410/MIS 5095061/European Regional Development Fund of the European Union 
      and Greek national funds through the Operational Program Competitiveness, 
      Entrepreneurship and Innovation, under the call RE-SEARCH - CREATE - INNOVATE/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231118
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Drosophila Proteins)
RN  - 0 (ImpL2 protein, Drosophila)
RN  - 0 (Insulin)
RN  - 0 (Insulin-Like Growth Factor Binding Proteins)
RN  - 77469-44-4 (N,N'-bis((2-chloroethyl)nitrosocarbamoyl)cystamine)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Somatomedins)
RN  - 0 (cnc protein, Drosophila)
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Type 2
MH  - Drosophila/metabolism
MH  - Drosophila melanogaster/genetics
MH  - *Drosophila Proteins/genetics/metabolism
MH  - *Hyperglycemia
MH  - Insulin/metabolism
MH  - Insulin-Like Growth Factor Binding Proteins
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - *Somatomedins/metabolism
PMC - PMC10670064
OTO - NOTNLM
OT  - ImpL2
OT  - Nrf2
OT  - cncC
OT  - insulin/insulin-like growth factors
OT  - metformin
COIS- The authors declare no conflict of interest.
EDAT- 2023/11/24 12:42
MHDA- 2023/11/27 16:18
PMCR- 2023/11/18
CRDT- 2023/11/24 09:35
PHST- 2023/10/10 00:00 [received]
PHST- 2023/11/13 00:00 [revised]
PHST- 2023/11/15 00:00 [accepted]
PHST- 2023/11/27 16:18 [medline]
PHST- 2023/11/24 12:42 [pubmed]
PHST- 2023/11/24 09:35 [entrez]
PHST- 2023/11/18 00:00 [pmc-release]
AID - cells12222650 [pii]
AID - cells-12-02650 [pii]
AID - 10.3390/cells12222650 [doi]
PST - epublish
SO  - Cells. 2023 Nov 18;12(22):2650. doi: 10.3390/cells12222650.