Congratulations to Masahiro Morita, PhD and Sakie Katsumura, DDS, PhD on their publication in Cell Metabolism!
Congratulations to Dr. Masahiro Morita and Dr. Sakie Katsumura on their publication in Cell Metabolism. Dr. Morita is an Assistant Professor in the Department of Molecular Medicine and the Sam and Ann Barshop Institute for Longevity and Aging Studies. Dr. Katsumura is a postdoctoral fellow in the Morita lab.
Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure
Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H. Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H.-M. Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, Masahiro Morita.
Cell Metabolism. 34, 564–580, 5 April 2022. https://doi.org/10.1016/j.cmet.2022.03.005
- Hepatic CNOT6L controls food intake, energy expenditure, and fat utilization
- Gdf15 and Fgf21 mRNAs are degraded by CNOT6L deadenylase in response to stimuli
- GDF15 and FGF21 mediate the CNOT6L effects on food intake and energy expenditure
- Targeting CNOT6L has a therapeutic potential to treat diet-induced metabolic disorders
Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel how CNOT6L deadenylase switches off hepatokine expression after responding to stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting upregulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.
Keywords: hepatokine; GDF15; FGF21; mRNA degradation; CCR4-NOT deadenylase complex; inter-organ communication; food intake; energy expenditure; metabolic syndrome