期刊
NATURE MEDICINE
卷 17, 期 1, 页码 55-U226出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2277
关键词
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资金
- US National Institutes of Health [R01-DK55758, R01-CA112023, RC1-DK086629, P01-DK088761, R01-DK56886, P01-DK49210, R21-DK073181]
- National Research Service Award [F32-DK083866, TL1-DK081181]
- University of Copenhagen
- [F32-DK085935]
- [T32-HL007360]
- [F32-DK081279]
- NATIONAL CANCER INSTITUTE [R01CA112023] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007360] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [F32DK085935, F32DK081279, RC1DK086629, R01DK056886, TL1DK081181, P01DK049210, F32DK083866, R21DK073181, P01DK088761, R01DK081456, R01DK055758] Funding Source: NIH RePORTER
The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite-sphingosine-1-phosphate (S1P)-independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.
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