title: Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding.
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 thatCpt1b+/-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. WhileCpt1b+/-mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle ofCpt1b+/-but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in theCpt1b+/-as compared to the WT muscles.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Teayoun
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Alabama, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Moore
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Sharer
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Yang
authors.affiliation: Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wood
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Alabama, USA.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
keywords: CPT1b; Insulin sensitivity; Skeletal muscle