Pancreatic Polypeptide Controls Energy Homeostasis via Npy6r Signaling in the Suprachiasmatic Nucleus in Mice

SummaryY-receptors control energy homeostasis, but the role of Npy6 receptors (Npy6r) is largely unknown. Young Npy6r-deficient (Npy6r−/−) mice have reduced body weight, lean mass, and adiposity, while older and high-fat-fed Npy6r−/− mice have low lean mass with increased adiposity. Npy6r−/− mice showed reduced hypothalamic growth hormone releasing hormone (Ghrh) expression and serum insulin-like growth factor-1 (IGF-1) levels relative to WT. This is likely due to impaired vasoactive intestinal peptide (VIP) signaling in the suprachiasmatic nucleus (SCN), where we found Npy6r coexpressed in VIP neurons. Peripheral administration of pancreatic polypeptide (PP) increased Fos expression in the SCN, increased energy expenditure, and reduced food intake in WT, but not Npy6r−/−, mice. Moreover, intraperitoneal (i.p.) PP injection increased hypothalamic Ghrh mRNA expression and serum IGF-1 levels in WT, but not Npy6r−/−, mice, an effect blocked by intracerebroventricular (i.c.v.) Vasoactive Intestinal Peptide (VPAC) receptors antagonism. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonlytreated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespanfor people living with ALS, and its precise mechanisms of action remainunclear. Most ALS cases are characterised by accumulation of cytoplasmicTAR DNA binding protein of 43 kDa (TDP-43), and understanding the effectsof riluzole in models that closely recapitulate TDP-43 pathology may provideinsights for development of improved therapeutics. We therefore investigatedthe effects of riluzole in female transgenic mice that inducibly express nuclearlocalisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, rNLS8, mice). Riluzole treatment from the first day ofhTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did notalter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8mice, riluzole did not ameliorate this disease-associated molecular phenotype.Likewise, riluzole did not alter the disease-associated atrophy of hindlimbmuscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease oranimal survival. Together, we demonstrate specific glutamatergic receptoralterations and muscle fibre-type changes reminiscent of ALS in female rNLS8mice, but riluzole had no effect on these or any other disease phenotypes.Future targeting of pathways related to accumulation of TDP-43 pathologymay be needed to develop better treatments for ALS