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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.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.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.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.