: Medicine Articles
Letter: The Creb1 coactivator Crtc1 is required for energy balance and fertilityThe adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that act on the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element–binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction—Crtc1−/− mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice, while leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin's effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr, and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility. Nature Medicine, vol. 14 #10, pp1112-1117 |
Letter: Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer's disease–like pathologyBecause of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Aβ peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Aβ. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Aβ3(pE)–42 burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Aβx–40/42, diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Aβ3(pE)–42 acts as a seed for Aβ aggregation by self-aggregation and co-aggregation with Aβ1–40/42. Therefore, Aβ3(pE)–40/42 peptides seem to represent Aβ forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Aβ by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia. Nature Medicine, vol. 14 #10, pp1106-1111 |
News and Views: Autoantibodies vex the vasculatureInfections with fimbriated bacteria may trigger autoimmunity and cause a form of severe vasculitis that affects capillaries in the kidney and that can destroy the organ (pages 1088–1096). Nature Medicine, vol. 14 #10, pp1018-1019 |
News and Views: Immune alteration fends off AIDSComparative studies of the immune response to simian immunodeficiency virus in two nonhuman primate species provide insight into a central aspect of HIV infection—the ability of the virus to cause chronic activation of the immune system (pages 1077–1087). Nature Medicine, vol. 14 #10, pp1016-1018 |
News and Views: Portal to Alzheimer's diseaseGenetic inactivation of the mitochondrial self-destruction mechanism improves cognition in a mouse model of Alzheimer's disease (pages 1097–1105). Nature Medicine, vol. 14 #10, pp1020-1021 |
News and Views: Getting to the core of atherosclerosisFor years, researchers have debated whether the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), produced by inflammatory cells, is a 'good guy' or 'bad guy' in atherosclerosis. Work in pigs provides strong support for the view that Lp-PLA2 promotes the formation of atherosclerotic lesions and dangerous, unstable atherosclerotic plaques (pages 1059–1066). Nature Medicine, vol. 14 #10, pp1015-1016 |