Effects of Increased Central Cholinergic Activity on the Metabolic Challenge Induced by Submaximal Exercise in Rats: Adrenomedullary Secretion Influences

<b><i>Aim:</i></b> The aim of this study was to assess the influence of adrenomedullary secretion on the plasma glucose, lactate, and free fatty acids (FFAs) during running exercise in rats submitted to intracerebroventricular (i.c.v.) injection of physostigmine (PHY). PHY i.c.v. was used to activate the central cholinergic system. <b><i>Methods:</i></b> Wistar rats were divided into sham-saline (sham-SAL), sham-PHY, adrenal medullectomy-SAL, and ADM-PHY groups. The plasma concentrations of glucose, lactate, and FFAs were determined immediately before and after i.c.v. injection of 20 μL of SAL or PHY at rest and during running exercise on a treadmill. <b><i>Results:</i></b> The i.c.v. injection of PHY at rest increased plasma glucose in the sham group, but not in the ADM group. An increase in plasma glucose, lactate, and FFAs mobilization from adipose tissue was observed during physical exercise in the sham-SAL group; however, the increase in plasma glucose was greater with i.c.v. PHY. Moreover, the hyperglycemia induced by exercise and PHY in the ADM group were blunted by ADM, whereas FFA mobilization was unaffected. <b><i>Conclusion:</i></b> These results indicate that there is a dual metabolic control by which activation of the central cholinergic pathway increases plasma glucose but not FFA during rest and exercise, and that this hyperglycemic response is dependent on adrenomedullary secretion.

Disruption of O-Linked N-Acetylglucosamine Signaling in Placenta Induces Insulin Sensitivity in Female Offspring

Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain (p = 0.02) and an improved insulin tolerance (p = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment (p = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.

Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion ofReverbαdrives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the globalReverbα−/−mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.