pRb is an obesity suppressor in hypothalamus and high‐fat diet inhibits pRb in this location |
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Authors: | Zhonglei Lu Genevieve Marcelin Hao Fu Siok Le Dun Hongling Zhao Xiaosong Li Young‐Hwan Jo Sharon Wardlaw Nae Dun Streamson Chua Jr Liang Zhu |
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Institution: | 1. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, , Bronx, NY, USA;2. Department of Medicine, Albert Einstein College of Medicine, , Bronx, NY, USA;3. Department of Pharmacology, Temple University School of Medicine, , Philadelphia, PA, USA;4. Department of Molecular Pharmacology, Albert Einstein College of Medicine, , Bronx, NY, USA;5. Department of Medicine, Columbia University Medical Center, , New York, NY, USA |
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Abstract: | pRb is frequently inactivated in tumours by mutations or phosphorylation. Here, we investigated whether pRb plays a role in obesity. The Arcuate nucleus (ARC) in hypothalamus contains antagonizing POMC and AGRP/NPY neurons for negative and positive energy balance, respectively. Various aspects of ARC neurons are affected in high‐fat diet (HFD)‐induced obesity mouse model. Using this model, we show that HFD, as well as pharmacological activation of AMPK, induces pRb phosphorylation and E2F target gene de‐repression in ARC neurons. Some affected neurons express POMC; and deleting Rb1 in POMC neurons induces E2F target gene de‐repression, cell‐cycle re‐entry, apoptosis, and a hyperphagia‐obesity‐diabetes syndrome. These defects can be corrected by combined deletion of E2f1. In contrast, deleting Rb1 in the antagonizing AGRP/NPY neurons shows no effects. Thus, pRb‐E2F1 is an obesity suppression mechanism in ARC POMC neurons and HFD‐AMPK inhibits this mechanism by phosphorylating pRb in this location. |
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Keywords: | E2F1 high‐fat diet obesity POMC neurons pRb phosphorylation |
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