期刊
CELL DEATH DISCOVERY
卷 7, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41420-021-00732-5
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资金
- Natural Science Foundation of Guangdong Province, China [2019A1515011927]
- Natural Science Foundation of Shenzhen City, China [JCYJ20190807145213180]
- Technology Research and Development Program of Shenzhen City, China [JCYJ20180507184647636]
- Guangdong Natural Science Foundation [2020A1515010347]
- Shenzhen STIC Research Foundation [JCYJ20180228162815750, JCYJ20190806164203496]
Microglial necroptosis plays a key role in obesity-related hypothalamic inflammation, impacting proinflammatory cytokine production. While the RIPK1 inhibitor does not suppress inflammation or prevent obesity, treatment with metformin effectively reduces obese phenotypes, offering a novel mechanism for obesity treatment.
Necroptosis, a form of programmed cell death, accounts for many inflammations in a wide range of diseases. Diet-induced obesity is manifested by low-grade inflammation in the mediobasal hypothalamus (MBH), and microglia are implicated as critical responsive components for this process. Here, we demonstrate that microglial necroptosis plays a pivotal role in obesity-related hypothalamic inflammation, facilitating proinflammatory cytokine production, such as TNF-alpha and IL-1 beta. Treatment with the anti-diabetic drug metformin effectively reduces the obese phenotypes in the high-fat diet (HFD)-fed mice, attributing to remission of hypothalamic inflammation partly through repressing microglial necroptosis. Importantly, using the receptor-interacting protein kinase 1 inhibitor, necrostatin-1s, could not suppress the microglial inflammation nor prevent body weight gain in the obese mice, indicating that the microglial necroptosis is RIPK1-independent. Altogether, these findings offer new insights into hypothalamic inflammation in diet-induced obesity and provide a novel mechanism of action for metformin in obesity treatment.
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