Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity

We previously identified Nob1 as a quantitative trait locus for high-fat diet–induced obesity and diabetes in genome-wide scans of outcross populations of obese and lean mouse strains. Additional crossbreeding experiments indicated that Nob1 represents an obesity suppressor from the lean Swiss Jim Lambert (SJL) strain. Here we identify a SJL-specific mutation in the Tbc1d1 gene that results in a truncated protein lacking the TBC Rab–GTPase-activating protein domain. TBC1D1, which has been recently linked to human obesity, is related to the insulin signaling protein AS160 and is predominantly expressed in skeletal muscle. Knockdown of TBC1D1 in skeletal muscle cells increased fatty acid uptake and oxidation, whereas overexpression of TBC1D1 had the opposite effect. Recombinant congenic mice lacking TBC1D1 showed reduced body weight, decreased respiratory quotient, increased fatty acid oxidation and reduced glucose uptake in isolated skeletal muscle. Our data strongly suggest that mutation of Tbc1d1 suppresses high-fat diet–induced obesity by increasing lipid use in skeletal muscle.

[1]  A. Bernards.  GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. , 2003, Biochimica et biophysica acta.

[2]  S. Kane,et al.  A Method to Identify Serine Kinase Substrates , 2002, The Journal of Biological Chemistry.

[3]  A. Schürmann,et al.  Characterisation of the mouse diabetes susceptibility locus Nidd/SJL: islet cell destruction, interaction with the obesity QTL Nob1, and effect of dietary fat , 2002, Diabetologia.

[4]  G. Hjälm,et al.  The 5′-AMP-activated Protein Kinase γ3 Isoform Has a Key Role in Carbohydrate and Lipid Metabolism in Glycolytic Skeletal Muscle* , 2004, Journal of Biological Chemistry.

[5]  Steven C Hunt,et al.  TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. , 2006, Human molecular genetics.

[6]  Sylvia Ortmann,et al.  Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. , 2006, Physiological genomics.

[7]  P. Grimaldi,et al.  CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness. , 2004, Diabetes.

[8]  D. Lambright,et al.  TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism , 2006, Nature.

[9]  H. Joost,et al.  A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice , 2007, International Journal of Obesity.

[10]  J. Raes,et al.  Nonsense-mediated mRNA decay: Target genes and functional diversification of effectors. , 2006, Trends in biochemical sciences.

[11]  G Churchill,et al.  Maternal environment and genotype interact to establish diabesity in mice. , 2000, Genome research.

[12]  H. Lodish,et al.  A family of Acrp30/adiponectin structural and functional paralogs. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  B. Balkau,et al.  R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. , 2008, Human molecular genetics.

[14]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[15]  Ortlepp,et al.  A metabolic syndrome of hypertension, hyperinsulinaemia and hypercholesterolaemia in the New Zealand obese mouse , 2000, European journal of clinical investigation.

[16]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[17]  O. Boss,et al.  GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. , 2004, The Journal of clinical investigation.

[18]  M. Tschöp,et al.  Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction , 2007, Diabetologia.

[19]  E. Leiter,et al.  NIDDM Genes in Mice: Deleterious Synergism by Both Parental Genomes Contributes to Diabetogenic Thresholds , 1998, Diabetes.

[20]  O. Crofford,et al.  GROWTH CHARACTERISTICS, GLUCOSE TOLERANCE AND INSULIN SENSITIVITY OF NEW ZEALAND OBESE MICE. , 1965, Metabolism: clinical and experimental.

[21]  L. Plum,et al.  Quantitative trait loci for obesity and insulin resistance (Nob1, Nob2) and their interaction with the leptin receptor allele (LeprA720T/T1044I) in New Zealand obese mice , 2000, Diabetologia.

[22]  F. Carlotti,et al.  Lentiviral vectors efficiently transduce quiescent mature 3T3-L1 adipocytes. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[23]  Claude Bouchard,et al.  The Human Obesity Gene Map: The 2005 Update , 2006, Obesity.

[24]  R Herwig,et al.  Statistical evaluation of differential expression on cDNA nylon arrays with replicated experiments. , 2001, Nucleic acids research.

[25]  L. Plum,et al.  Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5. , 2003, Biochemical and biophysical research communications.

[26]  Laurence Ettwiller,et al.  A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior. , 2007, Cell metabolism.

[27]  C N Boozer,et al.  Dietary obesity in nine inbred mouse strains. , 1992, The American journal of physiology.

[28]  L. Plum,et al.  Type 2 diabetes-like hyperglycemia in a backcross model of NZO and SJL mice: characterization of a susceptibility locus on chromosome 4 and its relation with obesity. , 2000, Diabetes.