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Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells

Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells
Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells
Decreased uncoupling protein (UCP)3 is associated with insulin resistance in muscle of pre-diabetic and diabetic individuals, but the function of UCP3 remains unclear. Our goal was to elucidate mechanisms underlying the negative correlation between UCP3 and insulin resistance in muscle. We determined effects of physiologic UCP3 overexpression on glucose and fatty acid oxidation and on mitochondrial uncoupling and reactive oxygen species (ROS) production in L6 muscle cells. An adenoviral construct caused a 2.2- to 2.5-fold increase in UCP3 protein. Palmitate oxidation was increased in muscle cells incubated under normoglycemic or hyperglycemic conditions, whereas adenoviral green fluorescent protein infection or chronic low doses of the uncoupler dinitrophenol had no effect. Increased UCP3 did not affect glucose oxidation, whereas dinitrophenol and insulin treatments caused increases. Basal oxygen consumption, assessed in situ using self-referencing microelectrodes, was not significantly affected, whereas dinitrophenol caused increases. Mitochondrial membrane potential was decreased by dinitrophenol but was not affected by increased UCP3 expression. Finally, mitochondrial ROS production decreased significantly with increased UCP3 expression. Results are consistent with UCP3 functioning to facilitate fatty acid oxidation and minimize ROS production. As impaired fatty acid metabolism and ROS handling are important precursors in muscular insulin resistance, UCP3 is an important therapeutic target in type 2 diabetes.

cpt, carnitine palmitoyl transferase, coash, uncombined coa, dcfda, 5-(and 6)-carboxy-2?, 7?-dichlorohydofluorescein diacetate, gfp, green fluorescent protein, mte1, mitochondrial thioesterase-1ros, reactive oxygen species, tmre, tetramethylrhodamine ethyl ester, ucp, uncoupling protein
0012-1797
2343-2350
MacLellan, J. Darcy
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Gerrits, Martin F.
11befd5c-5f1e-4b5c-ae54-30d2e30b4bcb
Gowing, Adrienne
083e034a-663a-4d7a-b953-18ba23c30fd6
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Wheeler, Michael B.
f292029a-61e7-4fef-9cb7-15496d2d470b
Harper, Mary-Ellen
d20b2be7-2625-4736-a792-2ec5771072e2
MacLellan, J. Darcy
60bf0049-0124-4da0-bf23-fcf1107dc27e
Gerrits, Martin F.
11befd5c-5f1e-4b5c-ae54-30d2e30b4bcb
Gowing, Adrienne
083e034a-663a-4d7a-b953-18ba23c30fd6
Smith, Peter J.S.
003de469-9420-4f12-8f0e-8e8d76d28d6c
Wheeler, Michael B.
f292029a-61e7-4fef-9cb7-15496d2d470b
Harper, Mary-Ellen
d20b2be7-2625-4736-a792-2ec5771072e2

MacLellan, J. Darcy, Gerrits, Martin F., Gowing, Adrienne, Smith, Peter J.S., Wheeler, Michael B. and Harper, Mary-Ellen (2005) Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes, 54 (8), 2343-2350. (doi:10.2337/diabetes.54.8.2343). (PMID:16046300)

Record type: Article

Abstract

Decreased uncoupling protein (UCP)3 is associated with insulin resistance in muscle of pre-diabetic and diabetic individuals, but the function of UCP3 remains unclear. Our goal was to elucidate mechanisms underlying the negative correlation between UCP3 and insulin resistance in muscle. We determined effects of physiologic UCP3 overexpression on glucose and fatty acid oxidation and on mitochondrial uncoupling and reactive oxygen species (ROS) production in L6 muscle cells. An adenoviral construct caused a 2.2- to 2.5-fold increase in UCP3 protein. Palmitate oxidation was increased in muscle cells incubated under normoglycemic or hyperglycemic conditions, whereas adenoviral green fluorescent protein infection or chronic low doses of the uncoupler dinitrophenol had no effect. Increased UCP3 did not affect glucose oxidation, whereas dinitrophenol and insulin treatments caused increases. Basal oxygen consumption, assessed in situ using self-referencing microelectrodes, was not significantly affected, whereas dinitrophenol caused increases. Mitochondrial membrane potential was decreased by dinitrophenol but was not affected by increased UCP3 expression. Finally, mitochondrial ROS production decreased significantly with increased UCP3 expression. Results are consistent with UCP3 functioning to facilitate fatty acid oxidation and minimize ROS production. As impaired fatty acid metabolism and ROS handling are important precursors in muscular insulin resistance, UCP3 is an important therapeutic target in type 2 diabetes.

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More information

Published date: August 2005
Keywords: cpt, carnitine palmitoyl transferase, coash, uncombined coa, dcfda, 5-(and 6)-carboxy-2?, 7?-dichlorohydofluorescein diacetate, gfp, green fluorescent protein, mte1, mitochondrial thioesterase-1ros, reactive oxygen species, tmre, tetramethylrhodamine ethyl ester, ucp, uncoupling protein

Identifiers

Local EPrints ID: 188817
URI: http://eprints.soton.ac.uk/id/eprint/188817
ISSN: 0012-1797
PURE UUID: 230add38-d7a8-4835-9677-4118f6671e78
ORCID for Peter J.S. Smith: ORCID iD orcid.org/0000-0003-4400-6853

Catalogue record

Date deposited: 03 Jun 2011 13:06
Last modified: 21 Nov 2021 03:04

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Contributors

Author: J. Darcy MacLellan
Author: Martin F. Gerrits
Author: Adrienne Gowing
Author: Michael B. Wheeler
Author: Mary-Ellen Harper

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