Abstract
Inhibiting fatty acid oxidation is one approach to lowering glucose levels in diabetes. Skeletal muscle specific Carnitine Palmitoyltransferase 1b knockout mice (Cpt1bm-/-) comprise a model of impaired fat oxidation; and have decreased fat mass and enhanced glucose disposal and muscle oxidative capacity compared to controls. However, unfavorable effects occur relative to controls when Cpt1bm-/- mice are fed a 25% fat diet, including decreased activity and fat free mass and increased intramuscular lipid and serum myoglobin. In this study we explore if a low fat, high carbohydrate diet can ablate the unfavorable effects while maintaining the favorable phenotype in Cpt1bm-/- mice. Mice were fed either 10% fat (low fat) or 25% fat (chow) diet. Body composition was measured biweekly and indirect calorimetry was performed. Low fat diet abolishes the decreased activity, fat, and fat free mass seen in Cpt1bm-/- mice fed chow diet. Low fat diet also reduces serum myoglobin levels in Cpt1bm-/- mice and diminishes differences in IGF-1 seen between Cpt1bm-/- mice and control mice fed chow diet. Glucose tolerance tests reveal that glucose clearance is improved in Cpt1bm-/- mice relative to controls regardless of diet, and serum analysis shows increased levels of muscle derived FGF21. Electron microscopic analyses and measurements of mRNA transcripts show increased intramuscular lipids, FGF21, mitochondrial and oxidative capacity markers regardless of diet. The favorable metabolic phenotype of Cpt1bm-/- mice therefore remains consistent regardless of diet; and a combination of a low fat diet and pharmacological inhibition of CPT1b may offer remedies to reduce blood glucose.
Highlights
Considerable evidence supports the idea that oversupply of dietary fat exceeds the storage capacity of adipose tissue and leads to ectopic lipid accumulation resulting in “metabolic stress” in skeletal muscle, liver, pancreas and possibly other tissues, contributing to insulin resistance [1,2,3,4]
We have reported that the most substantial weight differences between control and Cpt1bm-/animals are due to differences in fat mass, which begins to deviate several weeks before differences in food intake become significant (Fig 1 and reference [14])
Cpt1bm-/- mice eat less with age when fed chow diet, their fat mass stays essentially the same as it was at 10–12 weeks of age throughout life, and FFM peaks around 16 weeks of age (Fig 1)
Summary
Considerable evidence supports the idea that oversupply of dietary fat exceeds the storage capacity of adipose tissue and leads to ectopic lipid accumulation resulting in “metabolic stress” in skeletal muscle, liver, pancreas and possibly other tissues, contributing to insulin resistance [1,2,3,4]. Dietary effects on Cpt1b skeletal muscle knockout mice. Research Centers (National Institute of Diabetes and Digestive and Kidney Diseases Grant 2P30DK-072476-11A1)
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