4.5 Article

Conventional Knockout of Tbc1d1 in Mice Impairs Insulin- and AICAR-Stimulated Glucose Uptake in Skeletal Muscle

Journal

ENDOCRINOLOGY
Volume 154, Issue 10, Pages 3502-3514

Publisher

ENDOCRINE SOC
DOI: 10.1210/en.2012-2147

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Funding

  1. Deutsche Forschungsgemeinschaft [GRK1208, AL452/4-1]
  2. European Foundation of the Study of Diabetes (EFSD)/Lilly European Diabetes Research Program and Deutsches Zentrum fur Diabetesforschung

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In the obesity-resistant SJL mouse strain, we previously identified a naturally occurring loss-of-function mutation in the gene for Tbc1d1. Characterization of recombinant inbred mice that carried the Tbc1d1(SJL) allele on a C57BL/6J background indicated that loss of TBC1D1 protects from obesity, presumably by increasing the use of fat as energy source. To provide direct functional evidence for an involvement of TBC1D1 in energy substrate metabolism, we generated and characterized conventional Tbc1d1 knockout mice. TBC1D1-deficient mice showed moderately reduced body weight, decreased respiratory quotient, and an elevated resting metabolic rate. Ex vivo analysis of intact isolated skeletal muscle revealed a severe impairment in insulin-and AICAR-stimulated glucose uptake in glycolytic extensor digitorum longus muscle and a substantially increased rate of fatty acid oxidation in oxidative soleus muscle. Our results provide direct evidence that TBC1D1 plays a major role in glucose and lipid utilization, and energy substrate preference in skeletal muscle.

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