Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aminoimidazole Carboxamide / analogs & derivatives*
-
Aminoimidazole Carboxamide / pharmacology
-
Animals
-
Anti-Obesity Agents / pharmacology*
-
Biological Transport / drug effects
-
Carbon Dioxide / metabolism
-
Diabetes Mellitus, Type 2 / blood
-
Diabetes Mellitus, Type 2 / metabolism
-
Disease Susceptibility
-
Energy Metabolism / drug effects
-
GTPase-Activating Proteins
-
Glucose / analysis
-
Glucose / metabolism*
-
Hypertriglyceridemia / blood
-
Hypertriglyceridemia / metabolism
-
Hypoglycemic Agents / pharmacology*
-
Insulin Resistance*
-
Lipid Metabolism / drug effects
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Mutant Strains
-
Muscle, Skeletal / drug effects*
-
Muscle, Skeletal / metabolism
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism*
-
Obesity / blood
-
Obesity / metabolism
-
Oxygen Consumption / drug effects
-
Ribonucleotides / pharmacology*
Substances
-
Anti-Obesity Agents
-
GTPase-Activating Proteins
-
Hypoglycemic Agents
-
Nuclear Proteins
-
Ribonucleotides
-
Tbc1d1 protein, mouse
-
Carbon Dioxide
-
Aminoimidazole Carboxamide
-
AICA ribonucleotide
-
Glucose