The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

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van der Horst GT, Oster H. High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice.

The hypothalamic–pituitary–thyroid (HPT) axis maintains circulating thyroid hormone levels in a narrow physiological range. As axons containing thyrotropin-releasing hormone (TRH) terminate on hypothalamic tanycytes, these specialized glial cells have been suggested to influence the activity of the HPT axis, but their exact role remained enigmatic. Here, we demonstrate that stimulation of the TRH receptor 1 increases intracellular calcium in tanycytes of the median eminence via Gαq/11 proteins. Activation of Gαq/11 pathways increases the size of tanycyte endfeet that shield pituitary vessels and induces the activity of the TRH-degrading ectoenzyme. Both mechanisms may limit the TRH release to the pituitary. Indeed, blocking TRH signaling in tanycytes by deleting Gαq/11 proteins in vivo enhances the response of the HPT axis to the chemogenetic activation of TRH neurons. In conclusion, we identify new TRH- and Gαq/11-dependent mechanisms in the median eminence by which tanycytes control the activity of the HPT axis.