Long term effects of high fat or high carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a (CPT-1a) deficiency: Diet influences on CPT1a deficient mice.
BACKGROUND: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and beta-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) plays a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks.  METHODS: Insulin sensitivity and glucose tolerance were assessed in heterozygous CPT-1a deficient (CPT-1a+/-) male mice after being fed either a HCD or a HFD for durations of 28 weeks and 46 weeks. Both glucose and insulin tolerance tests were used to investigate beta-cell function and insulin sensitivity. Differences in islet insulin content and hepatic steatosis were evaluated by morphological analysis.  RESULTS: CPT-1a+/- mice were more insulin sensitive than CPT-1a+/+ mice when fed either HCD or HFD. The increased insulin sensitivity was associated with an increased expression of Cpt-1b (muscle isoform) in liver, as well as increased microvesicular hepatic steatosis compared to CPT-1a+/+ mice. CPT-1a+/- mice were more glucose tolerant than CPT-1a+/+ mice when fed the HCD, but there was no significant difference when fed HFD. Moreover, CPT-1a+/- mice fed HFD or HCD had fewer and smaller pancreatic islets than CPT-1a+/+ mice.  CONCLUSIONS: CPT-1a deficiency preserved insulin sensitivity when challenged by long term feeding of either diet. Furthermore, CPT-1a deficient mice had distinct phenotypes dependent on the diet fed demonstrating that both diet and genetics collectively play a role in the development of impaired glucose tolerance.
Department of Genetics, University of Alabama Birmingham, Birmingham Alabama.
Lara R
LR
Nyman
Liqun
L
Tian
Doug A
DA
Hamm
Trenton R
TR
Schoeb
Barbara A
BA
Gower
Tim R
TR
Nagy
Philip A
PA
Wood