Biology subjects

Denys, M. E.

Publications and source records attributed to Denys, M. E..

3 recordsLinked to original sources

bioRxiv2023

Gene Deletion of the PACAP/VIP Receptor, VPAC2R, Alters Glycemic Responses During Metabolic and Psychogenic Stress in Adult Female Mice

Pituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. These opposing actions need further characterization, as does the role of VIP receptor 2 (VPAC2R) in the regulation of glucose metabolism. In this study, we examined the participation of VPAC2R on basal glycemia, fasted glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/-) female mice. The mean basal glycemia was significantly greater in Vipr2-/- in the fed state and after an 8h overnight fast as compared to wildtype (WT) mice. Insulin tolerance testing following a 5h fast (morning fast, 0.38 U/kg) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg), Vipr2-/- females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2-/-, but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate the action of upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels in Vipr2-/- mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2-/-: upregulated medullary tyrosine hydroxylase (Th) and downregulated hypothalamic Vip. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.

physiology↗

bioRxiv2022

Glucoregulatory Reprogramming in Male Mice Offspring Induced by Maternal Transfer of Indoor Flame Retardant Endocrine Disruptors

Polybrominated diphenyl ethers (PBDEs) are commercially used as indoor flame retardants that penetrate biota and bioaccumulate in human tissues, including breast milk. PBDEs have been associated with endocrine disruption, diabetes and metabolic syndrome (MetS) in humans and animals. However, their sex-specific diabetogenic effects are not completely understood. Our past works show diabetogenic effects of the commercial penta-mixture of PBDEs, DE-71, in perinatally exposed C57Bl/6 female mice. As a comparison, in the current study, the effects of DE-71 on glucose homeostasis in male offspring were examined. C57BL/6 dams were exposed to DE-71 at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71) or received corn oil vehicle (VEH/CON) for a total of 10 wks, including gestation and lactation. Male offspring were examined in adulthood and DE-71 exposure produced hypoglycemia upon extended fasting. In vivo glucose challenge testing showed marked intolerance (H-DE-71) and incomplete clearance (L- and H-DE-71). Moreover, L-DE-71-exposed mice showed altered glucose responses to insulin, especially incomplete glucose clearance and/or utilization. In addition, L-DE-71 produced elevated levels of plasma glucagon and the incretin GLP-1 but no changes were detected on insulin. These alterations, which represent relevant criteria used clinically to diagnose diabetes, were accompanied with reduced hepatic glutamate dehydrogenase enzymatic activity, elevated adrenal epinephrine and decreased thermogenic brown adipose tissue mass, which may indicate several organ system targets of PBDEs. Liver levels of several endocannabinoid species were not altered by perinatal exposure to DE-71 in males. Our findings demonstrate that chronic low exposure to PBDEs in mothers can reprogram glucose homeostasis and glucoregulatory hormones in male offspring. Previous findings using female offspring showed altered glucose homeostasis that aligned with a contrasting diabetogenic phenotype. We summarize the results of the current work generated in males in light of previous findings on females. Taken together, these findings, combined with our prior results, offer a comprehensive account of sex-dependent effects of maternally transferred environmentally relevant PBDEs on glucose homeostasis and glucoregulatory endocrine dysregulation.

pharmacology and toxicology↗

bioRxiv2021

Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display altered short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

neuroscience↗