Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance

Carnitine Palmitoyl Transferase 1 (CPT1) is the rate-limiting enzyme governing long-chain fatty acid entry into mitochondria. CPT1 inhibitors have been developed and exhibited beneficial effects against type II diabetes in short-term preclinical animal studies. However, the long-term effects of treatment remain unclear and potential non-specific effects of these CPT1 inhibitors hamper in-depth understanding of the potential molecular mechanisms involved.

We investigated the effects of restricting the activity of the muscle isoform CPT1b in mice using heterozygous CPT1b deficient (Cpt1b^+/-) and Wild Type (WT) mice fed with a High Fat Diet (HFD) for 22 weeks. Insulin sensitivity was assessed using Glucose Tolerance Test (GTT), insulin tolerance test and hyperinsulinemic euglycemic clamps. We also examined body weight/composition, tissue and systemic metabolism/energetic status, lipid profile, transcript analysis, and changes in insulin signaling pathways.

We found that Cpt1b^+/- mice were protected from HFD-induced insulin resistance compared to WT littermates. Cpt1b^+/- mice exhibited elevated whole body glucose disposal rate and skeletal muscle glucose uptake. Furthermore, Cpt1b^+/- skeletal muscle showed diminished ex vivo palmitate oxidative capacity by ~40% and augmented glucose oxidation capacity by ~50% without overt change in whole body energy metabolism. HFD feeding Cpt1b^+/- but not WT mice exhibited well-maintained insulin signaling in skeletal muscle, heart, and liver.

The present study on a genetic model of CPT1b restriction supports the concept that partial CPT1b inhibition is a potential therapeutic strategy.