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

Po Min Chiang, Jonathan Ling, Yun Ha Jeong, Donald L. Price, Susan M. Aja, Philip C. Wong

Research output: Contribution to journalArticlepeer-review

175 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)16320-16324
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number37
DOIs
Publication statusPublished - 2010 Sep 14

All Science Journal Classification (ASJC) codes

  • General

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