Limits...
Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding.

Kim T, Moore JF, Sharer JD, Yang K, Wood PA, Yang Q - J Diabetes Metab (2014)

Bottom Line: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria.Cpt1b (+/-) mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake.Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Alabama, USA.

ABSTRACT

Background: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isoform CPT1b deficiency demonstrated improved insulin sensitivity when fed a High Fat-Diet (HFD) for up to 5 months. In this follow up study, we further investigated whether the insulin sensitizing effects of partial CPT1b deficiency could be maintained under a prolonged HFD feeding condition.

Methods: We investigated the effects of CPT1b deficiency on HFD-induced insulin resistance using heterozygous CPT1b deficient (Cpt1b (+/-)) mice compared with Wild Type (WT) mice fed a HFD for a prolonged period of time (7 months). We assessed insulin sensitivity using hyperinsulinemic-euglycemic clamps. We also examined body composition, skeletal muscle lipid profile, and changes in the insulin signaling pathways of skeletal muscle, liver, and adipose tissue.

Results: We found that Cpt1b (+/-) mice became severely insulin resistant after 7 months of HFD feeding. Cpt1b (+/-) mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake. While Cpt1b (+/-) mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle of Cpt1b (+/-) but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in the Cpt1b (+/-) as compared to the WT muscles.

Conclusion: Partial CPT1b deficiency, mimicking CPT1b inhibition, may lead to impaired insulin signaling and insulin sensitivity under a prolonged HFD feeding condition. Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy.

No MeSH data available.


Related in: MedlinePlus

Ceramide profile in the gastrocnemius muscle. Ceramide profile in the gastrocnemius muscle from HFD-fed mice at 7 months using high-performance liquid chromatography/mass spectrometry. *p<0.05 WT vs. Cpt1b+/−, n=5 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4286342&req=5

Figure 6: Ceramide profile in the gastrocnemius muscle. Ceramide profile in the gastrocnemius muscle from HFD-fed mice at 7 months using high-performance liquid chromatography/mass spectrometry. *p<0.05 WT vs. Cpt1b+/−, n=5 per group.

Mentions: To gain further insights into the differences in skeletal muscle between Cpt1b+/− and WT mice, we analyzed the lipid contents of skeletal muscle samples obtained at two different time points. The skeletal muscle samples from 5 months of HFD feeding represent insulin sensitive Cpt1b+/− mice and samples from 7 months of HFD feeding represent insulin resistant Cpt1b+/− mice. While non-esterified fatty acids were significantly increased after 7 months of HFD feeding in both WT and Cpt1b+/− mice compared to those at 5 months of HFD feeding, there were no differences in NEFA contents between the two groups after 7 months (Figure 4A). There was no significant difference in the triacylglycerol contents between the two groups of mice (Figure 4B). The acylcarnitine profiles of the two groups were largely similar (Figure 5A), but 3-hydroxybutyryl-carnitine (C4-OH) content was substantially increased only in Cpt1b+/− muscle at 7 months after HFD feeding (p<0.05) (Figure 5B). Hydroxydodecanoyl-carnitine (C12-OH) content was also substantially increased at 7 months of HFD-feeding compared to 5 months of HFD feeding (p<0.05). C12-OH content was also increased in Cpt1b+/− compared to WT mice at both time points of 5 months and 7 months (Figure 5C). In addition, we evaluated 13 different ceramide species. Among these, C18- and C22:1-ceramide contents were substantially increased in Cpt1b+/− mice compared to WT mice (p<0.05) (Figure 6). Therefore, the above results indicate that accumulated C4-OH acylcarnitine and long-chain ceramide in Cpt1b+/− mice muscle after prolonged HFD feeding may account for the impaired insulin signaling.


Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding.

Kim T, Moore JF, Sharer JD, Yang K, Wood PA, Yang Q - J Diabetes Metab (2014)

Ceramide profile in the gastrocnemius muscle. Ceramide profile in the gastrocnemius muscle from HFD-fed mice at 7 months using high-performance liquid chromatography/mass spectrometry. *p<0.05 WT vs. Cpt1b+/−, n=5 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4286342&req=5

Figure 6: Ceramide profile in the gastrocnemius muscle. Ceramide profile in the gastrocnemius muscle from HFD-fed mice at 7 months using high-performance liquid chromatography/mass spectrometry. *p<0.05 WT vs. Cpt1b+/−, n=5 per group.
Mentions: To gain further insights into the differences in skeletal muscle between Cpt1b+/− and WT mice, we analyzed the lipid contents of skeletal muscle samples obtained at two different time points. The skeletal muscle samples from 5 months of HFD feeding represent insulin sensitive Cpt1b+/− mice and samples from 7 months of HFD feeding represent insulin resistant Cpt1b+/− mice. While non-esterified fatty acids were significantly increased after 7 months of HFD feeding in both WT and Cpt1b+/− mice compared to those at 5 months of HFD feeding, there were no differences in NEFA contents between the two groups after 7 months (Figure 4A). There was no significant difference in the triacylglycerol contents between the two groups of mice (Figure 4B). The acylcarnitine profiles of the two groups were largely similar (Figure 5A), but 3-hydroxybutyryl-carnitine (C4-OH) content was substantially increased only in Cpt1b+/− muscle at 7 months after HFD feeding (p<0.05) (Figure 5B). Hydroxydodecanoyl-carnitine (C12-OH) content was also substantially increased at 7 months of HFD-feeding compared to 5 months of HFD feeding (p<0.05). C12-OH content was also increased in Cpt1b+/− compared to WT mice at both time points of 5 months and 7 months (Figure 5C). In addition, we evaluated 13 different ceramide species. Among these, C18- and C22:1-ceramide contents were substantially increased in Cpt1b+/− mice compared to WT mice (p<0.05) (Figure 6). Therefore, the above results indicate that accumulated C4-OH acylcarnitine and long-chain ceramide in Cpt1b+/− mice muscle after prolonged HFD feeding may account for the impaired insulin signaling.

Bottom Line: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria.Cpt1b (+/-) mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake.Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Alabama, USA.

ABSTRACT

Background: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isoform CPT1b deficiency demonstrated improved insulin sensitivity when fed a High Fat-Diet (HFD) for up to 5 months. In this follow up study, we further investigated whether the insulin sensitizing effects of partial CPT1b deficiency could be maintained under a prolonged HFD feeding condition.

Methods: We investigated the effects of CPT1b deficiency on HFD-induced insulin resistance using heterozygous CPT1b deficient (Cpt1b (+/-)) mice compared with Wild Type (WT) mice fed a HFD for a prolonged period of time (7 months). We assessed insulin sensitivity using hyperinsulinemic-euglycemic clamps. We also examined body composition, skeletal muscle lipid profile, and changes in the insulin signaling pathways of skeletal muscle, liver, and adipose tissue.

Results: We found that Cpt1b (+/-) mice became severely insulin resistant after 7 months of HFD feeding. Cpt1b (+/-) mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake. While Cpt1b (+/-) mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle of Cpt1b (+/-) but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in the Cpt1b (+/-) as compared to the WT muscles.

Conclusion: Partial CPT1b deficiency, mimicking CPT1b inhibition, may lead to impaired insulin signaling and insulin sensitivity under a prolonged HFD feeding condition. Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy.

No MeSH data available.


Related in: MedlinePlus