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Article: Enhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake

TitleEnhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake
Authors
Issue Date2009
PublisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00125/index.htm
Citation
Diabetologia, 2009, v. 52 n. 5, p. 912-920 How to Cite?
AbstractAims/hypothesis: Carnitine palmitoyltransferase-1 (CPT1)c is a novel isoform in the CPT1 family and is found specifically in the brain. Cpt1c knockout (KO) mice are more susceptible to high-fat diet (HFD)-induced obesity. However, the underlying mechanism of this phenotype and the question of whether CPT1c is involved in the pathogenesis of diet-induced insulin resistance are unclear. Methods: To assess the potential role of CPT1c in the regulation of whole-body glucose homeostasis, we generated Cpt1c KO mice and challenged them with HFD or standard chow. Glucose homeostasis of each group was assessed weekly. Results: After 8 weeks of HFD feeding, Cpt1c KO mice developed a phenotype of more severe insulin resistance than that in wild-type controls. The increased susceptibility of Cpt1c KO mice to HFD-induced insulin resistance was independent of obesity. Impaired glucose tolerance in Cpt1c KO mice was attributable to elevated hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. These effects correlated with decreased hepatic and intramuscular fatty acid oxidation and expression of oxidative genes as well as with elevated triacylglycerol content in these tissues. Interestingly, Cpt1c deletion caused a specific elevation of hypothalamic CPT1a and CPT1b isoform expression and activity. We demonstrated that elevated plasma NEFA concentration is one mechanism via which this compensatory effect is induced. Conclusions/interpretation: These results further establish the role of CPT1c in controlling whole-body glucose homeostasis and in the regulation of hypothalamic Cpt1 isoform expression. We identify changes in hepatic and skeletal muscle glucose metabolism as important mechanisms determining the phenotype of Cpt1c KO mice. © 2009 Springer-Verlag.
Persistent Identifierhttp://hdl.handle.net/10722/59190
ISSN
2015 Impact Factor: 6.206
2015 SCImago Journal Rankings: 3.528
ISI Accession Number ID
Funding AgencyGrant Number
National Science Foundation of China30670457
90813033
30811120429
Guangzhou Administration of Science and Technology2007Z2-E4021
2005Z3-C7181
Guangzhou Economic and Technological Development District2007Ss-P059
National 973 Programme of China2007CB914301
2006CB910202
2006CB503908
2004CB72010
Canadian Institutes of Health Research
Funding Information:

This work was supported in part by funds from: the National Science Foundation of China (30670457, 90813033 and 30811120429), Guangzhou Administration of Science and Technology (2007Z2-E4021 and 2005Z3-C7181), Guangzhou Economic and Technological Development District matching funds (2007Ss-P059) and the National 973 Programme of China (2007CB914301, 2006CB910202, 2006CB503908 and 2004CB720102). G. Sweeney thanks the Canadian Institutes of Health Research for research support.

References

 

DC FieldValueLanguage
dc.contributor.authorGao, XFen_HK
dc.contributor.authorChen, Wen_HK
dc.contributor.authorKong, XPen_HK
dc.contributor.authorXu, AMen_HK
dc.contributor.authorWang, ZGen_HK
dc.contributor.authorSweeney, Gen_HK
dc.contributor.authorWu, Den_HK
dc.date.accessioned2010-05-31T03:44:43Z-
dc.date.available2010-05-31T03:44:43Z-
dc.date.issued2009en_HK
dc.identifier.citationDiabetologia, 2009, v. 52 n. 5, p. 912-920en_HK
dc.identifier.issn0012-186Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/59190-
dc.description.abstractAims/hypothesis: Carnitine palmitoyltransferase-1 (CPT1)c is a novel isoform in the CPT1 family and is found specifically in the brain. Cpt1c knockout (KO) mice are more susceptible to high-fat diet (HFD)-induced obesity. However, the underlying mechanism of this phenotype and the question of whether CPT1c is involved in the pathogenesis of diet-induced insulin resistance are unclear. Methods: To assess the potential role of CPT1c in the regulation of whole-body glucose homeostasis, we generated Cpt1c KO mice and challenged them with HFD or standard chow. Glucose homeostasis of each group was assessed weekly. Results: After 8 weeks of HFD feeding, Cpt1c KO mice developed a phenotype of more severe insulin resistance than that in wild-type controls. The increased susceptibility of Cpt1c KO mice to HFD-induced insulin resistance was independent of obesity. Impaired glucose tolerance in Cpt1c KO mice was attributable to elevated hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. These effects correlated with decreased hepatic and intramuscular fatty acid oxidation and expression of oxidative genes as well as with elevated triacylglycerol content in these tissues. Interestingly, Cpt1c deletion caused a specific elevation of hypothalamic CPT1a and CPT1b isoform expression and activity. We demonstrated that elevated plasma NEFA concentration is one mechanism via which this compensatory effect is induced. Conclusions/interpretation: These results further establish the role of CPT1c in controlling whole-body glucose homeostasis and in the regulation of hypothalamic Cpt1 isoform expression. We identify changes in hepatic and skeletal muscle glucose metabolism as important mechanisms determining the phenotype of Cpt1c KO mice. © 2009 Springer-Verlag.en_HK
dc.languageengen_HK
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00125/index.htmen_HK
dc.relation.ispartofDiabetologiaen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBase Sequenceen_HK
dc.subject.meshBody Weighten_HK
dc.subject.meshCarnitine O-Palmitoyltransferase - deficiency - geneticsen_HK
dc.subject.meshCholesterol - blooden_HK
dc.subject.meshDietary Fats - adverse effectsen_HK
dc.subject.meshGluconeogenesis - physiologyen_HK
dc.subject.meshGlucose - metabolismen_HK
dc.subject.meshGlucose Intolerance - enzymology - etiology - metabolismen_HK
dc.subject.meshGlucose Tolerance Testen_HK
dc.subject.meshHeterozygoteen_HK
dc.subject.meshInsulin Resistance - geneticsen_HK
dc.subject.meshLiver - metabolismen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Knockouten_HK
dc.subject.meshMolecular Sequence Dataen_HK
dc.subject.meshMuscle, Skeletal - metabolismen_HK
dc.subject.meshObesity - enzymology - etiology - metabolismen_HK
dc.subject.meshRNA Interferenceen_HK
dc.subject.meshRNA, Messenger - geneticsen_HK
dc.subject.meshTriglycerides - blooden_HK
dc.titleEnhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptakeen_HK
dc.typeArticleen_HK
dc.identifier.emailXu, AM:amxu@hkucc.hku.hken_HK
dc.identifier.authorityXu, AM=rp00485en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s00125-009-1284-0en_HK
dc.identifier.pmid19224198-
dc.identifier.scopuseid_2-s2.0-64149110214en_HK
dc.identifier.hkuros157976en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-64149110214&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume52en_HK
dc.identifier.issue5en_HK
dc.identifier.spage912en_HK
dc.identifier.epage920en_HK
dc.identifier.isiWOS:000264884100024-
dc.publisher.placeGermanyen_HK
dc.identifier.scopusauthoridGao, XF=26028577700en_HK
dc.identifier.scopusauthoridChen, W=36012338300en_HK
dc.identifier.scopusauthoridKong, XP=7202794607en_HK
dc.identifier.scopusauthoridXu, AM=7202655409en_HK
dc.identifier.scopusauthoridWang, ZG=7410036390en_HK
dc.identifier.scopusauthoridSweeney, G=7102852659en_HK
dc.identifier.scopusauthoridWu, D=7404297751en_HK
dc.identifier.citeulike4081402-

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