Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice

Tomašić, Nikica LU ; Kotarsky, Heike LU ; de Oliveira Figueiredo, Rejane ; Hansson, Eva LU ; Mörgelin, Matthias LU ; Tomašić, Ivan ; Kallijärvi, Jukka LU ; Elmér, Eskil LU orcid ; Jauhiainen, Matti and Eklund, Erik A. LU , et al. (2020) In Biochimica et Biophysica Acta - Molecular Basis of Disease 1866(1).
Abstract

Mice homozygous for the human GRACILE syndrome mutation (Bcs1lc.A232G) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1lp.S78G), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively.... (More)

Mice homozygous for the human GRACILE syndrome mutation (Bcs1lc.A232G) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1lp.S78G), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FAs, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. Summary statement: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
BCS1L, Fasting, Lipid metabolism, Liver disease, Mitochondrial disorder, OXPHOS
in
Biochimica et Biophysica Acta - Molecular Basis of Disease
volume
1866
issue
1
article number
165573
pages
11 pages
publisher
Elsevier
external identifiers
  • pmid:31672551
  • scopus:85074150516
ISSN
0925-4439
DOI
10.1016/j.bbadis.2019.165573
language
English
LU publication?
yes
id
3295d865-0b24-4ce5-a904-20916fd8b599
date added to LUP
2019-11-06 14:29:29
date last changed
2024-05-29 02:44:17
@article{3295d865-0b24-4ce5-a904-20916fd8b599,
  abstract     = {{<p>Mice homozygous for the human GRACILE syndrome mutation (Bcs1l<sup>c.A232G</sup>) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1l<sup>p.S78G</sup>), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FAs, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. Summary statement: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms.</p>}},
  author       = {{Tomašić, Nikica and Kotarsky, Heike and de Oliveira Figueiredo, Rejane and Hansson, Eva and Mörgelin, Matthias and Tomašić, Ivan and Kallijärvi, Jukka and Elmér, Eskil and Jauhiainen, Matti and Eklund, Erik A. and Fellman, Vineta}},
  issn         = {{0925-4439}},
  keywords     = {{BCS1L; Fasting; Lipid metabolism; Liver disease; Mitochondrial disorder; OXPHOS}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Elsevier}},
  series       = {{Biochimica et Biophysica Acta - Molecular Basis of Disease}},
  title        = {{Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice}},
  url          = {{http://dx.doi.org/10.1016/j.bbadis.2019.165573}},
  doi          = {{10.1016/j.bbadis.2019.165573}},
  volume       = {{1866}},
  year         = {{2020}},
}