PMID- 37683300
OWN - NLM
STAT- MEDLINE
DCOM- 20230913
LR  - 20230913
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 66
DP  - 2023 Oct
TI  - Adverse bioenergetic effects of N-acyl amino acids in human adipocytes overshadow 
      beneficial mitochondrial uncoupling.
PG  - 102874
LID - S2213-2317(23)00275-6 [pii]
LID - 10.1016/j.redox.2023.102874 [doi]
LID - 102874
AB  - OBJECTIVE: Enhancing energy turnover via uncoupled mitochondrial respiration in 
      adipose tissue has great potential to improve human obesity and other metabolic 
      complications. However, the amount of human brown adipose tissue and its 
      uncoupling protein 1 (UCP1) is low in obese patients. Recently, a class of 
      endogenous molecules, N-acyl amino acids (NAAs), was identified as mitochondrial 
      uncouplers in murine adipocytes, presumably acting via the adenine nucleotide 
      translocator (ANT). Given the translational potential, we investigated the 
      bioenergetic effects of NAAs in human adipocytes, characterizing beneficial and 
      adverse effects, dose ranges, amino acid derivatives and underlying mechanisms. 
      METHOD: NAAs with neutral (phenylalanine, leucine, isoleucine) and polar (lysine) 
      residues were synthetized and assessed in intact and permeabilized human 
      adipocytes using plate-based respirometry. The Seahorse technology was applied to 
      measure bioenergetic parameters, dose-dependency, interference with UCP1 and 
      adenine nucleotide translocase (ANT) activity, as well as differences to the 
      established chemical uncouplers niclosamide ethanolamine (NEN) and 
      2,4-dinitrophenol (DNP). RESULT: NAAs with neutral amino acid residues potently 
      induce uncoupled respiration in human adipocytes in a dose-dependent manner, even 
      in the presence of the UCP1-inhibitor guanosine diphosphate (GDP) and the 
      ANT-inhibitor carboxyatractylate (CAT). However, neutral NAAs significantly 
      reduce maximal oxidation rates, mitochondrial ATP-production, coupling efficiency 
      and reduce adipocyte viability at concentrations above 25 muM. The in vitro 
      therapeutic index (using induced proton leak and viability as determinants) of 
      NAAs is lower than that of NEN and DNP. CONCLUSION: NAAs are potent mitochondrial 
      uncouplers in human adipocytes, independent of UCP1 and ANT. However, previously 
      unnoticed adverse effects harm adipocyte functionality, reduce the therapeutic 
      index of NAAs in vitro and therefore question their suitability as anti-obesity 
      agents without further chemical modifications.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Herrnhold, Marie
AU  - Herrnhold M
AD  - Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius 
      Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
FAU - Hamp, Isabel
AU  - Hamp I
AD  - Institute of Medicinal Chemistry, Helmholtz Zentrum Munchen, German Research 
      Center for Environmental Health (GmbH), Neuherberg, Germany; Institute of Organic 
      Chemistry, Leibniz Universitat Hannover, Hannover, Germany.
FAU - Plettenburg, Oliver
AU  - Plettenburg O
AD  - Institute of Medicinal Chemistry, Helmholtz Zentrum Munchen, German Research 
      Center for Environmental Health (GmbH), Neuherberg, Germany; Institute of Organic 
      Chemistry, Leibniz Universitat Hannover, Hannover, Germany.
FAU - Jastroch, Martin
AU  - Jastroch M
AD  - Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius 
      Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
FAU - Keuper, Michaela
AU  - Keuper M
AD  - Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius 
      Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden. Electronic 
      address: michaela.keuper@su.se.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230902
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Amino Acids)
RN  - 5KV86114PT (Ethanolamine)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Amino Acids
MH  - *Adipocytes
MH  - Ethanolamine
MH  - Adipose Tissue, Brown
MH  - Energy Metabolism
PMC - PMC10493596
OTO - NOTNLM
OT  - Adipocytes
OT  - Metabolism
OT  - Mitochondria
OT  - Obesity
OT  - UCP1
OT  - Uncoupling
COIS- Declaration of competing interest None.
EDAT- 2023/09/08 18:41
MHDA- 2023/09/13 06:41
PMCR- 2023/09/02
CRDT- 2023/09/08 17:59
PHST- 2023/08/10 00:00 [received]
PHST- 2023/08/31 00:00 [revised]
PHST- 2023/09/01 00:00 [accepted]
PHST- 2023/09/13 06:41 [medline]
PHST- 2023/09/08 18:41 [pubmed]
PHST- 2023/09/08 17:59 [entrez]
PHST- 2023/09/02 00:00 [pmc-release]
AID - S2213-2317(23)00275-6 [pii]
AID - 102874 [pii]
AID - 10.1016/j.redox.2023.102874 [doi]
PST - ppublish
SO  - Redox Biol. 2023 Oct;66:102874. doi: 10.1016/j.redox.2023.102874. Epub 2023 Sep 
      2.