Overexpression of carnitine palmitoyltransferase I in skeletal muscle in vivo increases fatty acid oxidation and reduces triacylglycerol esterification

Bruce, Clinton R.; Brolin, Camilla; Turner, Nigel; Cleasby, Mark E.; Leij, Feike R. van der; Cooney, Gregory J.; Kraegen, Edward W.

doi:10.1152/ajpendo.00561.2006

Cited by 63 publications

(54 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…62 An increased CPT-1 expression in Y1-deficient mice suggests an increased capacity for fatty acid influx into mitochondria, which in itself is sufficient to increase fat oxidation. 63 This is confirmed by the significantly increased maximal activities of MCAD and/or b-HAD in germline and conditional Y1-receptor-knockout mice, which are key enzymes involved in b-oxidation.…”

Section: Discussionmentioning

confidence: 82%

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

et al. 2009

View full text Add to dashboard Cite

Objective: Neuropeptide Y and its Y receptors are important players in the regulation of energy homeostasis. However, while their functions in feeding regulation are well recognized, functions in other critical aspects of energy homeostasis are largely unknown. To investigate the function of Y1 receptors in the regulation of energy homeostasis, we examined energy expenditure, physical activity, body composition, oxidative fuel selection and mitochondrial oxidative capacity in germline Y1 À/À mice as well as in a conditional Y1-receptor-knockdown model in which Y1 receptors were knocked down in peripheral tissues of adult mice. Results: Germline Y1À/À mice of both genders not only exhibit a decreased respiratory exchange ratio, indicative of increased lipid oxidation, but interestingly also develop late-onset obesity. However, the increased lipid oxidation is a primary effect of Y1 deletion rather than secondary to increased adiposity, as young Y1 À/À mice are lean and show the same effect. The mechanism behind this is likely because of increased liver and muscle protein levels of carnitine palmitoyltransferase-1 (CPT-1) and maximal activity of key enzymes involved in b-oxidation; b-hydroxyacyl CoA dehydrogenase (bHAD) and medium-chain acyl-CoA dehydrogenase (MCAD), leading to increased mitochondrial capacity for fatty acid transport and oxidation. These effects are controlled by peripheral Y1-receptor signalling, as adult-onset conditional Y1 knockdown in peripheral tissues also leads to increased lipid oxidation, liver CPT-1 levels and bHAD activity. Importantly, these mice are resistant to diet-induced obesity. Conclusions: This work shows the primary function of peripheral Y1 receptors in the regulation of oxidative fuel selection and adiposity, opening up new avenues for anti-obesity treatments by targeting energy utilization in peripheral tissues rather than suppressing appetite by central effects.

show abstract

Section: Discussionmentioning

confidence: 82%

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

et al. 2009

View full text Add to dashboard Cite

show abstract

“…In addition, channelling fatty acids to mitochondrial oxidation, as demonstrated in the present study, further reduces the likelihood that FATP1 contributes to the development of insulin resistance in skeletal muscle. A rise in fatty acid oxidation has been shown to protect against diet-induced insulin resistance [46]. It could therefore be speculated from the current data that overabundance of FATP1 and the subsequent targeting of fatty acids towards oxidation would protect against diet-induced insulin resistance.…”

Section: Mitochondrial Fatp1mentioning

confidence: 94%

Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis We examined in skeletal muscle (1) whether fatty acid transport protein (FATP) 1 channels long-chain fatty acid (LCFA) to specific metabolic fates in rats; and (2) whether FATP1-mediated increases in LCFA uptake exacerbate the development of diet-induced insulin resistance in mice. We also examined whether FATP1 is altered in insulin-resistant obese Zucker rats. Methods LCFA uptake, oxidation and triacylglycerol esterification rates were measured in control and Fatp1-transfected soleus muscles to determine FATP1-mediated lipid handling. The effects of FATP1 on insulin sensitivity and triacylglycerol accumulation were determined in high-fat diet-fed wild-type mice and in muscle-specific Fatp1 (also known as Slc27a1) overexpressing transgenic mice driven by the muscle creatine kinase (Mck [also known as Ckm]) promoter. We also examined the relationship between FATP1 and both fatty acid transport and metabolism in insulin-resistant obese Zucker rats. Results Transient Fatp1 overexpression in soleus muscle increased (p<0.05) palmitate transport (24%) and oxidation (35%), without altering triacylglycerol esterification or the intrinsic rate of palmitate oxidation in isolated mitochondria. In Mck/Fatp1 animals, Fatp1 mRNA and 15-(p-G. P. Holloway and C. J. Chou contributed equally to this study. Electronic supplementary material The online version of this article

show abstract

“…To determine the 14 C counts present in the acid-soluble metabolites we performed a 'Folch extraction' of the cells, measured the radioactivity in the aqueous phase and combined these values with the 14 CO 2 values to give the total fatty acid oxidation rate. Fatty acid oxidation in EDL strips was conducted as described in detail elsewhere [22].…”

Section: Methodsmentioning

confidence: 99%

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

et al. 2010

View full text Add to dashboard Cite

Aims/hypothesis A hallmark feature of the metabolic syndrome is abnormal glucose metabolism which can be improved by exercise. Recently the orphan nuclear receptor subfamily 4, group A, member 1 (NUR77) was found to be induced by exercise in muscle and was linked to transcriptional control of genes involved in lipid and glucose metabolism. Here we investigated if overexpression of Nur77 (also known as Nr4a1) in skeletal muscle has functional consequences for lipid and/or glucose metabolism. Methods L6 rat skeletal muscle myotubes were infected with a Nur77-coding adenovirus and lipid and glucose oxidation was measured. Nur77 was also overexpressed in skeletal muscle of chow-and fat-fed rats and the effects on glucose and lipid metabolism evaluated. Results Nur77 overexpression had no effect on lipid oxidation in L6 cells or rat muscle, but did increase glucose oxidation and glycogen synthesis in L6 cells. In chow-and high-fat-fed rats, Nur77 overexpression by electrotransfer significantly increased basal glucose uptake and glycogen synthesis, but no increase in insulin-stimulated glucose metabolism was observed. Nur77 electrotransfer was associated with increased production of GLUT4 and glycogenin and increased hexokinase and phosphofructokinase activity. Interestingly, Nur77 expression in muscle biopsies from obese men was significantly lower than in those from lean men and was closely correlated with bodyfat content and insulin sensitivity. Conclusions/interpretation Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism.

show abstract

Overexpression of carnitine palmitoyltransferase I in skeletal muscle in vivo increases fatty acid oxidation and reduces triacylglycerol esterification

Cited by 63 publications

References 25 publications

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

Peripheral neuropeptide Y Y1 receptors regulate lipid oxidation and fat accretion

Increasing skeletal muscle fatty acid transport protein 1 (FATP1) targets fatty acids to oxidation and does not predispose mice to diet-induced insulin resistance

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

Contact Info

Product

Resources

About