Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding
- *Corresponding Author:
- Qinglin Yang, MD., Ph.D.
Department of Nutrition Sciences
University of Alabama at Birmingham
1675 University Blvd., Webb 435, Birmingham
E-mail: [email protected]
Received date: June 05, 2014; Accepted date: June 27, 2014; Published date: July 04, 2014
Citation: Kim T, Moore JF, Sharer JD, Yang K, Wood PA, Yang Q (2014) Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance after Prolonged High Fat Diet Feeding. J Diabetes Metab 5:401. doi:10.4172/2155-6156.1000401
Copyright: © 2014 Yang Q, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of longchain 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.