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Tytuł:
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Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.
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Autorzy:
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Yan C; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Zeng T; Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Lee K; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Nobis M; Invasion and Metastasis Lab, Cancer Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
Loh K; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
Gou L; Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Xia Z; Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Gao Z; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Bensellam M; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Institute of Experimental and Clinical Research, Pole of Endocrinology, Diabetes and Nutrition, Université catholique de Louvain, Brussels, Belgium.
Hughes W; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
Lau J; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Zhang L; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
Ip CK; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
Enriquez R; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Gao H; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Wang QP; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China.
Wu Q; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.
Haigh JJ; Research Institute in Oncology and Hematology, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada.
Laybutt DR; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
Timpson P; Invasion and Metastasis Lab, Cancer Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
Herzog H; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia. .; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia. .
Shi YC; Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia. .; Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia. .; Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia. .
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Źródło:
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Nature communications [Nat Commun] 2021 May 11; Vol. 12 (1), pp. 2622. Date of Electronic Publication: 2021 May 11.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [London] : Nature Pub. Group
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MeSH Terms:
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Arginine/*analogs & derivatives
Obesity/*prevention & control
Receptors, Neuropeptide Y/*antagonists & inhibitors
Thermogenesis/*drug effects
Adipocytes/drug effects ; Adipocytes/metabolism ; Adipose Tissue, Brown/cytology ; Adipose Tissue, Brown/drug effects ; Adipose Tissue, Brown/metabolism ; Adult ; Animals ; Arginine/pharmacology ; Arginine/therapeutic use ; Biopsy ; Cells, Cultured ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Energy Metabolism/drug effects ; Female ; Humans ; Male ; Mice ; Middle Aged ; Obesity/etiology ; Obesity/metabolism ; Primary Cell Culture ; Receptors, Neuropeptide Y/metabolism
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Substance Nomenclature:
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0 (Npy1r protein, mouse)
0 (Receptors, Neuropeptide Y)
0 (neuropeptide Y-Y1 receptor)
94ZLA3W45F (Arginine)
O35HK034KO (BIBO 3304)
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Entry Date(s):
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Date Created: 20210512 Date Completed: 20210526 Latest Revision: 20210526
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Update Code:
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20240105
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PubMed Central ID:
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PMC8113522
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DOI:
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10.1038/s41467-021-22925-3
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PMID:
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33976180
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Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.
