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

Alexandra Chadt; Katja Leicht; Atul Deshmukh; Lake Q Jiang; Stephan Scherneck; Ulrike Bernhardt; Tanja Dreja; Heike Vogel; Katja Schmolz; Reinhart Kluge; Juleen R Zierath; Claus Hultschig; Rob C Hoeben; Annette Schürmann; Hans-Georg Joost; Hadi Al-Hasani

doi:10.1038/ng.244

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

Alexandra Chadt, Katja Leicht, Atul Deshmukh, Lake Q Jiang, Stephan Scherneck, Ulrike Bernhardt, Tanja Dreja, Heike Vogel, Katja Schmolz, Reinhart Kluge, Juleen R Zierath, Claus Hultschig, Rob C Hoeben, Annette Schürmann, Hans-Georg Joost, Hadi Al-Hasani

149 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	40
Udgave nummer	11
Sider (fra-til)	1354-1359
Antal sider	6
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.244
Status	Udgivet - 2008
Udgivet eksternt	Ja

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Chadt, A., Leicht, K., Deshmukh, A., Jiang, L. Q., Scherneck, S., Bernhardt, U., Dreja, T., Vogel, H., Schmolz, K., Kluge, R., Zierath, J. R., Hultschig, C., Hoeben, R. C., Schürmann, A., Joost, H-G., & Al-Hasani, H. (2008). Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nature Genetics, 40(11), 1354-1359. https://doi.org/10.1038/ng.244

Chadt, A, Leicht, K, Deshmukh, A, Jiang, LQ, Scherneck, S, Bernhardt, U, Dreja, T, Vogel, H, Schmolz, K, Kluge, R, Zierath, JR, Hultschig, C, Hoeben, RC, Schürmann, A, Joost, H-G & Al-Hasani, H 2008, 'Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity', Nature Genetics, bind 40, nr. 11, s. 1354-1359. https://doi.org/10.1038/ng.244

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title = "Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity",

abstract = "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.",

keywords = "Adiposity, Amino Acid Sequence, Animals, Base Sequence, Cells, Cultured, Diet, Exons, Fatty Acids, GTPase-Activating Proteins, Gene Expression Profiling, Glucose, Mice, Mice, Mutant Strains, Molecular Sequence Data, Muscle Cells, Muscle, Skeletal, Mutation, Nuclear Proteins, Obesity, Oxidation-Reduction, Protein Structure, Tertiary, Quantitative Trait Loci, Sequence Deletion, Suppression, Genetic, Thinness, Journal Article, Research Support, Non-U.S. Gov't",

author = "Alexandra Chadt and Katja Leicht and Atul Deshmukh and Jiang, {Lake Q} and Stephan Scherneck and Ulrike Bernhardt and Tanja Dreja and Heike Vogel and Katja Schmolz and Reinhart Kluge and Zierath, {Juleen R} and Claus Hultschig and Hoeben, {Rob C} and Annette Sch{\"u}rmann and Hans-Georg Joost and Hadi Al-Hasani",

year = "2008",

doi = "10.1038/ng.244",

language = "English",

volume = "40",

pages = "1354--1359",

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T1 - Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity

AU - Chadt, Alexandra

AU - Leicht, Katja

AU - Deshmukh, Atul

AU - Jiang, Lake Q

AU - Scherneck, Stephan

AU - Bernhardt, Ulrike

AU - Dreja, Tanja

AU - Vogel, Heike

AU - Schmolz, Katja

AU - Kluge, Reinhart

AU - Zierath, Juleen R

AU - Hultschig, Claus

AU - Hoeben, Rob C

AU - Schürmann, Annette

AU - Joost, Hans-Georg

AU - Al-Hasani, Hadi

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - Adiposity

KW - Amino Acid Sequence

KW - Animals

KW - Base Sequence

KW - Cells, Cultured

KW - Diet

KW - Exons

KW - Fatty Acids

KW - GTPase-Activating Proteins

KW - Gene Expression Profiling

KW - Glucose

KW - Mice

KW - Mice, Mutant Strains

KW - Molecular Sequence Data

KW - Muscle Cells

KW - Muscle, Skeletal

KW - Mutation

KW - Nuclear Proteins

KW - Obesity

KW - Oxidation-Reduction

KW - Protein Structure, Tertiary

KW - Quantitative Trait Loci

KW - Sequence Deletion

KW - Suppression, Genetic

KW - Thinness

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ng.244

DO - 10.1038/ng.244

M3 - Letter

C2 - 18931681

SN - 1061-4036

VL - 40

SP - 1354

EP - 1359

JO - Nature: New biology

JF - Nature: New biology

IS - 11

ER -

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

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