Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis

Aims Glucokinase (GK) serves as a glucose sensor in several tissues including glucose‐sensitive neurons of the arcuate nucleus within the hypothalamus. We have previously demonstrated a role for arcuate GK in the regulation of food and glucose intake. However, its role in the regulation of glucose homeostasis is less clear. We therefore sought to investigate the role of arcuate GK in the regulation of glucose homeostasis. Materials and Methods Recombinant adeno‐associated virus expressing either GK or an antisense GK construct was used to alter GK activity specifically in the hypothalamic arcuate nucleus. GK activity in this nucleus was also increased by stereotactic injection of the GK activator, compound A. The effect of altered arcuate nucleus GK activity on glucose homeostasis was subsequently investigated using glucose and insulin tolerance tests. Results Increased GK activity specifically within the arcuate nucleus increased insulin secretion and improved glucose tolerance in rats during oral glucose tolerance tests. Decreased GK activity in this nucleus reduced insulin secretion and increased glucose levels during the same tests. Insulin sensitivity was not affected in either case. The effect of arcuate nucleus glucokinase was maintained in a model of type 2 diabetes. Conclusions These results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis

Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats

Background Obesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents. Objectives To investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats. Methods Recombinant adeno-associated virus bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1) respectively were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels. Results Compared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake. Conclusions Therefore, ARC corticosterone, regulated by 11βHSD1, may play a role in food intake and body weight regulation. These data have important implications for the development of centrally-acting 11βHSD1 inhibitors, which are currently being developed for the treatment of obesity, metabolic disorders and other conditions

Nuclear Factor 90(NF90) targeted to TAR RNA inhibits transcriptional activation of HIV-1

<p>Abstract</p> <p>Background</p> <p>Examination of host cell-based inhibitors of HIV-1 transcription may be important for attenuating viral replication. We describe properties of a cellular double-stranded RNA binding protein with intrinsic affinity for HIV-1 TAR RNA that interferes with Tat/TAR interaction and inhibits viral gene expression.</p> <p>Results</p> <p>Utilizing TAR affinity fractionation, North-Western blotting, and mobility-shift assays, we show that the C-terminal variant of nuclear factor 90 (NF90ctv) with strong affinity for the TAR RNA, competes with Tat/TAR interaction <it>in vitro</it>. Analysis of the effect of NF90ctv-TAR RNA interaction <it>in vivo </it>showed significant inhibition of Tat-transactivation of HIV-1 LTR in cells expressing NF90ctv, as well as changes in histone H3 lysine-4 and lysine-9 methylation of HIV chromatin that are consistent with the epigenetic changes in transcriptionally repressed gene.</p> <p>Conclusion</p> <p>Structural integrity of the TAR element is crucial in HIV-1 gene expression. Our results show that perturbation Tat/TAR RNA interaction by the dsRNA binding protein is sufficient to inhibit transcriptional activation of HIV-1.</p

Carbohydrate craving: not everything is sweet

Purpose of review: Cravings for carbohydrates have been known about for hundreds of years but the mechanisms behind it were unclear. This review will highlight recent advances in our knowledge of mechanisms to detect carbohydrates in the diet. Recent findings: Recent work has begun to identify the physiological mechanisms by which carbohydrates and glucose are detected and how this drives their intake. Recently, evidence has been found for systems that regulate carbohydrate and glucose intake via taste, hedonic, and homeostatic pathways. Summary: Identification of the physiological mechanisms that regulate carbohydrate intake will allow a better understanding of how their intake is regulated and responds to changes in dietary intake. Such an understanding will be a key for developing a more rational approach to the development of successful weight loss diets

Building healthy communities, Proceedings of The Third International Asian Health and Wellbeing Conference

The Third International Asian Health and Wellbeing Conference - Building Healthy Communities: North & South, Auckland, New Zealand, 8-9 September 2008link_to_OA_fulltex

Effects of moderate-dose omega-3 fish oil on cardiovascular risk factors and mood after ischemic stroke: A randomized, controlled trial

© 2009 American Heart Association, Inc.Background and purposeFish-derived omega-3 fatty acids have long been associated with cardiovascular protection. In this trial, we assessed whether treatment with a guideline-recommended moderate-dose fish oil supplement could improve cardiovascular biomarkers, mood- and health-related quality of life in patients with ischemic stroke.MethodsPatients with CT-confirmed stroke were randomized to 3 g/day encapsulated fish oil containing approximately 1.2 g total omega-3 (0.7 g docosahexaenoic acid; 0.3 g eicosapentaenoic acid) or placebo oil (combination palm and soy) taken daily over 12 weeks. Serum triglycerides, total cholesterol and associated lipoproteins, selected inflammatory and hemostatic markers, mood, and health-related quality of life were assessed at baseline and follow-up. The primary outcome was change in triglycerides. Compliance was assessed by capsule count and serum phospholipid omega-3 levels (Australian Clinical Trials Registration: ACTRN12605000207617).ResultsOne hundred two patients were randomized to fish oil or placebo. Intention-to-treat and per-protocol (>85% compliance) analyses showed no significant effect of fish oil treatment on any lipid, inflammatory, hemostatic, or composite mood parameters measured. Adherence to treatment based on pill count was good (89%) reflected by increased serum docosahexanoic acid (PConclusionsThere was no effect of 12 weeks of treatment with moderate-dose fish oil supplements on cardiovascular biomarkers or mood in patients with ischemic stroke. It is possible that insufficient dose, short duration of treatment, and/or oxidation of the fish oils may have influenced these outcomes.Sally D. Poppitt, Colin A. Howe, Fiona E. Lithander, Karen M. Silvers, Ruey-Bin Lin, John Croft, Yogini Ratnasabapathy, Robert A. Gibson, Craig S. Anderso

Auckland stroke outcomes study part 1: Gender, stroke types, ethnicity, and functional outcomes 5 years poststroke

Background: Studying long-term stroke outcomes including body functioning (neurologic and neuropsychological impairments) and activity limitations and participation is essential for long-term evidence-based rehabilitation and service planning, resource allocation, and improving health outcomes in stroke. However, reliable data to address these issues is lacking

Effects of peptide-YY on the hypothalamic-pituitary-gonadal axis in healthy men

Context Central and peripheral administration of peptide-YY (PYY) has potent anorectic effects, and PYY analogues are under development as anti-obesity treatments. Recent animal data suggest PYY may also influence the reproductive axis, however the effects of PYY on the human reproductive system are unknown. Objective To investigate the effects of PYY administration on the reproductive axis in healthy young men. Design Single-blind, randomised, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean age 24.1±0.9years, mean BMI 22.2±0.4kg/m2). Intervention Eight-hour intravenous infusion of 0.4pmol/kg/min PYY3-36 or rate-matched vehicle infusion. Results The number of LH pulses (mean number of LH pulses/8hours: PYY 4.4±0.3 vs vehicle 4.4±0.4, p>0.99), LH area under the curve (AUC) (PYY 1503±79IU.min/L vs vehicle 1574±86IU.min/L, p=0.36), FSH AUC (PYY 1158±513IU.min/L vs vehicle 1199±476IU.min/L, p=0.49) and testosterone AUC (PYY 10485±684IU.min/L vs vehicle 11133±803IU.min/L, p=0.24) were similar during PYY and vehicle infusions. Conclusions Acute intravenous infusion of 0.4pmol/kg/min PYY does not affect the reproductive axis in healthy men