R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population

Meyre, David; Farge, M.; Lecoeur, Constant; Proença, Christine; Durand, Emmanuelle; Allegaert, FrÃ©dÃ©ric; Tichet, Jean; Marre, Michel; Balkau, Beverley; Weill, Jacques; Delplanque, J.; Froguel, Philippe

doi:10.1093/hmg/ddn070

Cited by 78 publications

(78 citation statements)

References 28 publications

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“…By positional cloning, we previously identified a naturally occurring loss-of-function mutation in Tbc1d1 as an obesity suppressor in the lean, diabetes-resistant SJL mouse strain (10). In humans, mutations in TBC1D4 (R3633) and TBC1D1 (R125W) have been linked to severe postprandial hyperinsulinemia and obesity, respectively (11)(12)(13). TBC1D4 is found mainly in the heart, adipose tissue, and oxidative muscle fibers, whereas TBC1D1 is predominantly expressed in glycolytic skeletal muscle and is nearly absent from fat tissue (10,14,15).…”

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confidence: 99%

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

et al. 2014

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The Rab-GTPase-activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response to activation of AKT and AMPdependent kinase. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake in fat and muscle tissue. The aim of this study was to determine the impact of the combined inactivation of Tbc1d1 and Tbc1d4 on glucose metabolism in double-deficient (D1/4KO) mice. D1/4KO mice displayed normal fasting glucose concentrations but had reduced tolerance to intraperitoneally administered glucose, insulin, and AICAR. D1/4KO mice showed reduced respiratory quotient, indicating increased use of lipids as fuel. These mice also consistently showed elevated fatty acid oxidation in isolated skeletal muscle, whereas insulin-stimulated glucose uptake in muscle and adipose cells was almost completely abolished. In skeletal muscle and white adipose tissue, the abundance of GLUT4 protein, but not GLUT4 mRNA, was substantially reduced. Cell surface labeling of GLUTs indicated that RabGAP deficiency impairs retention of GLUT4 in intracellular vesicles in the basal state. Our results show that TBC1D1 and TBC1D4 together play essential roles in insulin-stimulated glucose uptake and substrate preference in skeletal muscle and adipose cells.

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confidence: 99%

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

et al. 2014

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“…In summary, our efforts here in using conditional Tardbp KO strategies revealed a physiological role for TDP-43 in regulating body fat and identified one specific target, Tbc1d1, a gene associated with human obesity (19,25), regulated by TDP-43. These unexpected observations indicate that TDP-43 plays a crucial role in controlling energy metabolism.…”

Section: Marked Fat Loss and High Fatty Acid Consumption In Conditionalmentioning

confidence: 93%

“…Tbc1d1, a critical protein associated with human obesity (19,25), was drastically reduced in the Tardbp deleted iTDPKO cells (−7.35 fold, P = 7.02E−228). As it has been reported that a nonfunctional Tbc1d1mutant in the skeletal muscle is responsible for the lean phenotype in mice and thatTbc1d1is essential for Glut4 translocation to the plasma membrane of skeletal muscle cells for glucose uptake (18), a decrease inTbc1d1 in skeletal muscle might offer an explanation for the lean phenotype shown in our conditional Tardp-KO mouse model (Fig.…”

Section: Marked Fat Loss and High Fatty Acid Consumption In Conditionalmentioning

confidence: 99%

“…By using digital high-throughput RNA-sequencing (RNA-seq) analysis of our conditional Tardbp-KO embryonic stem (ES) cells, we report here the identification and verification of a set of downstream genes regulated by TDP-43, including those that impact on the survival of ES cells. Among this set of down-regulated targets is a gene expressed in skeletal muscle important for regulating leanness (18) and linked to human obesity (19) termed Tbc1d1, which is decreased in skeletal muscle of our conditional Tardbp-KO mouse model. Our findings suggest that TDP-43-dependent reduction of Tbc1d1 in skeletal muscle may be responsible for the increased fat metabolism and leanness observed in the conditional Tardbp-KO mice.…”

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confidence: 99%

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Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Chiang

Ling

Jeong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

265

250

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Tat activating regulatory DNA-binding protein (Tardbp or TDP-43), a highly conserved metazoan DNA/RNA binding protein thought to be involved in RNA transcription and splicing, has been linked to the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration and is essential for early embryonic development. However, neither the physiological role of TDP-43 in the adult nor its downstream targets are well defined. To address these questions, we developed conditional Tardbp-KO mice and embryonic stem (ES) cell models. Here, we show that postnatal deletion of Tardbp in mice caused dramatic loss of body fat followed by rapid death. Moreover, conditional Tardbp-KO ES cells failed to proliferate. Importantly, high-throughput DNA sequencing analysis on the transcriptome of ES cells lacking Tardbp revealed a set of downstream targets of TDP-43. We show that Tbc1d1, a gene known to mediate leanness and linked to obesity, is down-regulated in the absence of TDP-43. Collectively, our results establish that TDP-43 is critical for fat metabolism and ES cell survival.conditional knockout mice | amyotrophic lateral sclerosis | frontotemporal dementia | energy metabolism | RNA-sequencing I dentified initially as a cellular protein that regulates human immunodeficiency viral gene transcription (1), Tat activating regulatory DNA-binding protein (Tardbp or TDP-43) is a highly conserved DNA/RNA-binding protein thought to regulate alternative splicing of cystic fibrosis transmembrane conductance regulator (CFTR) and survival of motor neuron (SMN) through binding to heterogeneous nuclear ribonucleoprotein or (UG) n repeats of these target transcripts (2-4). Biophysical studies indicate that TDP-43 forms a dimer harboring two RNA-binding domains that preferentially bind to TG/UG repeats (5). Whereas TDP-43 is normally localized to the nucleus, it is redistributed as insoluble aggregates in neuronal nuclei, perikarya and neurites in amyotrophic lateral sclerosis (ALS) (6, 7) and frontotemporal lobar degeneration (FTLD) (8). The identification of missense mutations in TARDBP in familial and sporadic ALS (9, 10) supports the idea that this nuclear protein plays a critical role in the pathogenesis of these neurodegenerative disorders. Interestingly, most of these mutations identified to date are localized to the Cterminal domain of TDP-43, a heterogeneous nuclear ribonucleoprotein-interacting region that may be critical for the normal function of the protein. Although mutant TDP-43 mice showed evidence of neurodegeneration, no TDP-43-positive cytoplasmic aggregates were observed in neurons of these mutant mice, suggesting that altered RNA metabolism rather than TDP-43 aggregates underlies the pathogenesis of ALS or FTLD (11).To begin clarifying the molecular basis of mutant TDP-43-linked disease, it will be crucial to understand the physiological and cellular functions of TDP-43. Moreover, because increased expression of TDP-43 is also toxic to motor neurons (12, 13), it will be also important to identify a set ...

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“…The authors demonstrated a decrease in the expression of Tbc1d1 in mutant ES cells. Tbc1d1 is required for Glut4 translocation to the membrane of skeletal muscle cells and glucose uptake (90) and is involved in human obesity (91,92). We therefore examined TBC1D1 protein levels in hTDP-43 A315T mutants but did not detect any abnormalities in skeletal muscle or other tissues (not shown).…”

Section: A315tmentioning

confidence: 99%

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

Stribl

Samara

Trümbach

et al. 2014

Journal of Biological Chemistry

105

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Background: Mutations in TDP-43 are frequently found in ALS patients. Results: A315T TDP-43 protein is elevated from this transgenic knock-in allele due to disturbed feedback regulation. Conclusion: Elevation of A315T TDP-43 was insufficient to cause ALS in this mutant. Significance: This TDP-43 allele could be valuable in determining genetic or environmental factors that cause full-blown FTLD or ALS.

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R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population

Cited by 78 publications

References 28 publications

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

Deletion of TDP-43 down-regulates Tbc1d1 , a gene linked to obesity, and alters body fat metabolism

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

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