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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

Body composition of mice of HFD feeding. In vivo quantitative magnetic resonance imaging system was used to measure lean and fat mass. (A) 5 months after HFD feeding, (B) 7 months after HFD feeding. *p<0.05, n= 8-7 per group.
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Figure 2: Body composition of mice of HFD feeding. In vivo quantitative magnetic resonance imaging system was used to measure lean and fat mass. (A) 5 months after HFD feeding, (B) 7 months after HFD feeding. *p<0.05, n= 8-7 per group.

Mentions: Body composition analysis using QMR revealed that Cpt1b+/− mice had much lower body weight (30% lower than WT mice, p<0.01), lean mass (10% lower than WT mice, p<0.05), and fat mass (50% lower than WT mice, p<0.05) until 5 month of HFD feeding (Figure 2A). After 7 month of HFD feeding, the body weights of Cpt1b+/− mice remained about 10% lower than that of WT mice (Figure 2B). Lean mass became identical between the Cpt1b+/− and WT mice, whereas fat mass was still lower in Cpt1b+/− mice than in WT mice (p<0.05) (Figure 2B). These data indicate that Cpt1b+/− mice remained at a lower body weight due to less fat mass than that of the WT mice in response to prolonged HFD feeding.


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)

Body composition of mice of HFD feeding. In vivo quantitative magnetic resonance imaging system was used to measure lean and fat mass. (A) 5 months after HFD feeding, (B) 7 months after HFD feeding. *p<0.05, n= 8-7 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Body composition of mice of HFD feeding. In vivo quantitative magnetic resonance imaging system was used to measure lean and fat mass. (A) 5 months after HFD feeding, (B) 7 months after HFD feeding. *p<0.05, n= 8-7 per group.
Mentions: Body composition analysis using QMR revealed that Cpt1b+/− mice had much lower body weight (30% lower than WT mice, p<0.01), lean mass (10% lower than WT mice, p<0.05), and fat mass (50% lower than WT mice, p<0.05) until 5 month of HFD feeding (Figure 2A). After 7 month of HFD feeding, the body weights of Cpt1b+/− mice remained about 10% lower than that of WT mice (Figure 2B). Lean mass became identical between the Cpt1b+/− and WT mice, whereas fat mass was still lower in Cpt1b+/− mice than in WT mice (p<0.05) (Figure 2B). These data indicate that Cpt1b+/− mice remained at a lower body weight due to less fat mass than that of the WT mice in response to prolonged HFD feeding.

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