ArticleProceedings of the National Academy of Sciences of the United States of America2016
Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 58 citations in OpenAlex.
- Obesity accelerates aging: Mechanisms and therapeutic implications.Genes & diseases · 2026Review
- Chitosan Oligosaccharides Suppress Adipogenesis and Lipid Accumulation in 3T3-L1 Preadipocytes via Multi-Pathway Transcriptomic Reprogramming.International journal of molecular sciences · 2026Article
- Golgi-associated TRAF6 as a regulator of protein convertase FURIN for insulin receptor precursor processing.Science China. Life sciences · 2025Article
- TBC1D1 functions as a negative regulator of satellite cells for muscle regeneration.Nature communications · 2025Article
- Targeting IGF1 to alleviate obesity through regulating energy expenditure and fat deposition.Science China. Life sciences · 2025Article
- Article
- Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes.The EMBO journal · 2024Article
- Rab8a restores diverse innate functions in CD11cNature communications · 2024Article
- AS160 is a lipid-responsive regulator of cardiac CaNature communications · 2024Article
- TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype.Cell death & disease · 2024Article
- TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity.Science China. Life sciences · 2024Article
- Fine-tuning AMPK in physiology and disease using point-mutant mouse models.Disease models & mechanisms · 2024Review
- AMPKγ3 Controls Muscle Glucose Uptake in Recovery From Exercise to Recapture Energy Stores.Diabetes · 2023Article
- The Anti-Obesity and Anti-Steatotic Effects of Chrysin in a Rat Model of Obesity Mediated through Modulating the Hepatic AMPK/mTOR/lipogenesis Pathways.Molecules (Basel, Switzerland) · 2023Article
- Anthocyanins as Promising Molecules Affecting Energy Homeostasis, Inflammation, and Gut Microbiota in Type 2 Diabetes with Special Reference to Impact of Acylation.Journal of agricultural and food chemistry · 2023Review
- Signaling pathways in obesity: mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2022Review
- The RalGAPα1-RalA signal module protects cardiac function through regulating calcium homeostasis.Nature communications · 2022Article
- TRIM24 is an insulin-responsive regulator of P-bodies.Nature communications · 2022Article
- Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ.PLoS biology · 2022Article
- AMPK-mediated phosphorylation enhances the auto-inhibition of TBC1D17 to promote Rab5-dependent glucose uptake.Cell death and differentiation · 2021Article
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser(231) by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1(Ser231Ala) knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.
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