Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging

Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging

Intercomparison of global river discharge simulations focusing on dam operation --- Part II: Multiple models analysis in two case-study river basins, Missouri-Mississippi and Green-Colorado

We performed a twofold intercomparison of river discharge regulated by dams under multiple meteorological forcings among multiple global hydrological models for a historical period by simulation. Paper II provides an intercomparison of river discharge simulated by five hydrological models under four meteorological forcings. This is the first global multimodel intercomparison study on dam-regulated river flow. Although the simulations were conducted globally, the Missouri-Mississippi and Green-Colorado Rivers were chosen as case-study sites in this study. The hydrological models incorporate generic schemes of dam operation, not specific to a certain dam. We examined river discharge on a longitudinal section of river channels to investigate the effects of dams on simulated discharge, especially at the seasonal time scale. We found that the magnitude of dam regulation differed considerably among the hydrological models. The difference was attributable not only to dam operation schemes but also to the magnitude of simulated river discharge flowing into dams. That is, although a similar algorithm of dam operation schemes was incorporated in different hydrological models, the magnitude of dam regulation substantially differed among the models. Intermodel discrepancies tended to decrease toward the lower reaches of these river basins, which means model dependence is less significant toward lower reaches. These case-study results imply that, intermodel comparisons of river discharge should be made at different locations along the river’s course to critically examine the performance of hydrological models because the performance can vary with the locations

Role of Toll-Like Receptor 9 in Atherogenesis

Background Toll-like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E–deficient (Apoe-/-) mice. Methods and Results Tlr9-deficient Apoe-/- (Tlr9-/-Apoe-/-) mice and Apoe-/- mice on a Western-type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double-stranded DNA, an endogenous ligand of TLR9, in these mice. Genetic deletion or pharmacologic blockade of TLR9 in angiotensin II–infused Apoe-/- mice attenuated atherogenesis in the aortic arch (P<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR9 in bone marrow in Tlr9-/-Apoe-/- mice promoted atherogenesis in the aortic arch (P<0.05). A TLR9 agonist markedly promoted proinflammatory activation of Apoe-/- macrophages, partially through p38 mitogen-activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe-/- macrophages than in Tlr9-/-Apoe-/- macrophages. Furthermore, in humans, circulating double-stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction (P<0.05). Conclusions TLR9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR9 may serve as a potential therapeutic target for atherosclerosis