Metformin attenuates hypothalamic inflammation via downregulation of RIPK1-independent microglial necroptosis in diet-induced obese mice.

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-α and IL-1β. 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.