The vagus neurometabolic interface and clinical disease.

The nervous system both monitors and modulates body metabolism to maintain homoeostasis. In disease states such as obesity and diabetes, the neurometabolic interface is dysfunctional and contributes to clinical illness. The vagus nerve, in particular, with both sensory and motor fibres, provides an anatomical substrate for this interface. Its sensory fibres contain receptors for important circulating metabolic mediators, including leptin and cholecystokinin, and provide real-time information about these mediators to the central nervous system. In turn, efferent fibres within the vagus nerve participate in a brain-gut axis to regulate metabolism. In this review, we describe these vagus nerve-mediated metabolic pathways and recent clinical trials of vagus nerve stimulation for the management of obesity. These early studies suggest that neuromodulation approaches that employ electricity to tune neurometabolic circuits may represent a new tool in the clinical armamentarium directed against obesity.

Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death.

First recognized more than 30 years ago, glycine protects cells against rupture from diverse types of injury. This robust and widely observed effect has been speculated to target a late downstream process common to multiple modes of tissue injury. The molecular target of glycine that mediates cytoprotection, however, remains elusive. Here, we show that glycine works at the level of NINJ1, a newly identified executioner of plasma membrane rupture in pyroptosis, necrosis, and post-apoptosis lysis. NINJ1 is thought to cluster within the plasma membrane to cause cell rupture. We demonstrate that the execution of pyroptotic cell rupture is similar for human and mouse NINJ1 and that NINJ1 knockout functionally and morphologically phenocopies glycine cytoprotection in macrophages undergoing lytic cell death. Next, we show that glycine prevents NINJ1 clustering by either direct or indirect mechanisms. In pyroptosis, glycine preserves cellular integrity but does not affect upstream inflammasome activities or accompanying energetic cell death. By positioning NINJ1 clustering as a glycine target, our data resolve a long-standing mechanism for glycine-mediated cytoprotection. This new understanding will inform the development of cell preservation strategies to counter pathologic lytic cell death.