Inhibitory effects of halothane on the thermogenic pathway in brown adipocytes: localization to adenylyl cyclase and mitochondrial fatty acid oxidation
(2004) In Biochemical Pharmacology 68(3). p.463-477- Abstract
- Volatile anesthetics such as halothane efficiently inhibit nonshivering thermogenesis as well as the cellular manifestation of that phenomenon: norepinephrine-induced respiration in brown adipocytes. To identify the molecular site(s) of action of such anesthetics, we have examined the effect of halothane on the sequential intracellular steps from the interaction of norepinephrine with isolated brown adipocytes to the stimulation of mitochondrial respiration (=thermogenesis). We did not identify an inhibition at the level of the adrenergic receptors, but a first site of inhibition was identified as the generation of cAMP by adenylyl cyclase; this led to inhibition of norepinephrine-induced expression of the uncoupling protein-1 (UCP 1) gene... (More)
- Volatile anesthetics such as halothane efficiently inhibit nonshivering thermogenesis as well as the cellular manifestation of that phenomenon: norepinephrine-induced respiration in brown adipocytes. To identify the molecular site(s) of action of such anesthetics, we have examined the effect of halothane on the sequential intracellular steps from the interaction of norepinephrine with isolated brown adipocytes to the stimulation of mitochondrial respiration (=thermogenesis). We did not identify an inhibition at the level of the adrenergic receptors, but a first site of inhibition was identified as the generation of cAMP by adenylyl cyclase; this led to inhibition of norepinephrine-induced expression of the uncoupling protein-1 (UCP 1) gene and reduced norepinephrine-induced lipolysis as secondary effects. Although an inhibition of lipolysis in itself would inhibit thermogenesis, circumvention of this inhibition revealed that a second, postlipolytic, site of inhibition existed: halothane also inhibited the stimulatory effect of exogenous fatty acids on cellular respiration. This inhibition was independent of the presence of UCP1 in the mitochondria of the cells and was thus not directly on the thermogenic uncoupling mechanism. Since not only fatty acid oxidation but also pyruvate oxidation were inhibited by halothane in isolated mitochondria, whereas glycerol-3-phosphate oxidation was not, the second site of action of halothane, evident when cyclase/lipolytic inhibition was circumvented, was located to the respiratory chain, complex I. The results thus explain the inhibition of nonshivering thermogenesis by identifying two sites of action of halothane in brown adipocytes. In addition, the results may open for new formulations of the molecular background to anesthesia. (C) 2004 Elsevier Inc. All rights reserved. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/272576
- author
- Ohlson, Kerstin LU ; Shabalina, IG ; Lennstrom, K ; Backlund, EC ; Mohell, N ; Bronnikov, GE ; Lindahl, SGE ; Cannon, B and Nedergaard, J
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- brown adipose tissue, acid oxidation, fatty, adenylyl cyclase, thermogenesis, halothane, volatile anesthetics
- in
- Biochemical Pharmacology
- volume
- 68
- issue
- 3
- pages
- 463 - 477
- publisher
- Elsevier
- external identifiers
-
- pmid:15242813
- wos:000222881600008
- scopus:3042701185
- ISSN
- 0006-2952
- DOI
- 10.1016/j.bcp.2004.03.028
- language
- English
- LU publication?
- yes
- id
- 9119cc1f-4ba7-474f-b345-3a29287b3c88 (old id 272576)
- date added to LUP
- 2016-04-01 12:29:52
- date last changed
- 2022-03-29 01:40:55
@article{9119cc1f-4ba7-474f-b345-3a29287b3c88,
abstract = {{Volatile anesthetics such as halothane efficiently inhibit nonshivering thermogenesis as well as the cellular manifestation of that phenomenon: norepinephrine-induced respiration in brown adipocytes. To identify the molecular site(s) of action of such anesthetics, we have examined the effect of halothane on the sequential intracellular steps from the interaction of norepinephrine with isolated brown adipocytes to the stimulation of mitochondrial respiration (=thermogenesis). We did not identify an inhibition at the level of the adrenergic receptors, but a first site of inhibition was identified as the generation of cAMP by adenylyl cyclase; this led to inhibition of norepinephrine-induced expression of the uncoupling protein-1 (UCP 1) gene and reduced norepinephrine-induced lipolysis as secondary effects. Although an inhibition of lipolysis in itself would inhibit thermogenesis, circumvention of this inhibition revealed that a second, postlipolytic, site of inhibition existed: halothane also inhibited the stimulatory effect of exogenous fatty acids on cellular respiration. This inhibition was independent of the presence of UCP1 in the mitochondria of the cells and was thus not directly on the thermogenic uncoupling mechanism. Since not only fatty acid oxidation but also pyruvate oxidation were inhibited by halothane in isolated mitochondria, whereas glycerol-3-phosphate oxidation was not, the second site of action of halothane, evident when cyclase/lipolytic inhibition was circumvented, was located to the respiratory chain, complex I. The results thus explain the inhibition of nonshivering thermogenesis by identifying two sites of action of halothane in brown adipocytes. In addition, the results may open for new formulations of the molecular background to anesthesia. (C) 2004 Elsevier Inc. All rights reserved.}},
author = {{Ohlson, Kerstin and Shabalina, IG and Lennstrom, K and Backlund, EC and Mohell, N and Bronnikov, GE and Lindahl, SGE and Cannon, B and Nedergaard, J}},
issn = {{0006-2952}},
keywords = {{brown adipose tissue; acid oxidation; fatty; adenylyl cyclase; thermogenesis; halothane; volatile anesthetics}},
language = {{eng}},
number = {{3}},
pages = {{463--477}},
publisher = {{Elsevier}},
series = {{Biochemical Pharmacology}},
title = {{Inhibitory effects of halothane on the thermogenic pathway in brown adipocytes: localization to adenylyl cyclase and mitochondrial fatty acid oxidation}},
url = {{http://dx.doi.org/10.1016/j.bcp.2004.03.028}},
doi = {{10.1016/j.bcp.2004.03.028}},
volume = {{68}},
year = {{2004}},
}