Leptin fails to blunt the lipopolysaccharide-induced activation of the hypothalamic-pituitary-adrenal axis in rats

Copyright @ 2013 The authors. This work is licensed under a Creative Commons Attribution 3.0 Unported License.Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic-pituitary-adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis.We hypothesised that leptin would attenuate the HPA axis response to sepsis.We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1b secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.The section is funded by grants from the MRC, BBSRC, NIHR and an Integrative Mammalian Biology (IMB) Capacity Building Award, and by a FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. This work is supported by a BBSRC Doctoral Training-Strategic Skills Award grant (BB/F017340/1)

Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia

SUMMARY Melanocortin 4 receptors (Mc4rs) are expressed by extra-hypothalamic neurons including cholinergic autonomic pre-ganglionic neurons. However, whether Mc4rs in these neurons are required to control energy and glucose homeostasis is unclear. Here we report that Mc4rs in sympathetic, but not parasympathetic, pre-ganglionic neurons are required to regulate energy expenditure and body weight including brown and white adipose tissue thermogenic responses to diet and cold exposure. In addition, deletion of Mc4rs in both sympathetic and parasympathetic cholinergic neurons impairs glucose homeostasis

Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

10 Years of C-K Theory: A Survey on the Academic and Industrial Impacts of a Design Theory.

The goal of our research1 was to understand what is expected today from a design theory and what types of impact such type of scientific proposition may reach. To answer these questions with a grounded approach we chosed to study the developement of C-K theory as phenomenon per se that can inform our research work. C-K theory is clearly recognized as a design theory and it is a good representative of the level of generality and abstraction of contemporary design theory. Indeed, the validity of the theory as such has already been documented (e.g. Hatchuel & Weil 2002, 2003, 2008, 2009; Kazakçi 2009; Reich et al 2010; Le Masson et al 2010; Ullah et al 2012). Instead the current work sets out to understand the dissemination and the impact of the theory in both academic and industrial fields. The data collection overlooks the literature on C-K theory in English and in French, and includes interviews and feedbacks of students and industrial partners who applied C-K methodologies and tools. This research confirms the rapid diffusion and multiples impact of C-K theory. Beyond, such study signals that there are important expectations and potential impacts of a Design Theory within the field of knowledge at large. However there are strong conditions to meet these expectations: generality, generativity, and relatedness to contemporary sciences. A similar research could be done on Nam Suh's axiomatic approach to further test these conditions. It is impossible to say what will be the next generations of Design theory but it is sure that they should progress on these directions

Activation of Central Melanocortin Pathways by Fenfluramlne

D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN\u27s anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective antiobesity treatments

Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-p-dioxin

In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23 h after exposure to TCDD (100 mu g/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Going belowground: burying anthropomorphic biases on gustation and olfaction

Chemical signaling underpins behavioral interactions among organisms in the soil. Understanding chemical communication in the soil requires a paradigm shift in methodology and perspectives compared to aboveground ecosystems because olfaction and gustation, accepted modalities of chemosensation aboveground, may not accurately represent chemical communication in the soil. To fully understand chemical communication in the soil, it is essential to consider how soil properties, such as moisture, pH, and adsorption, affect the transport and perception of semiochemicals. De-anthropomorphizing the study of chemosensation can avoid potential biases, particularly in soil systems, where distinctions between olfaction and gustation are confounded by the heterogeneity of the soil environment and its effects on the mobility of chemical signals. In this perspective, we first explore how soil heterogeneity confounds the dichotomy between olfaction and gustation with hypothetical but ecologically relevant examples. Then we examine how anthropomorphic biases in aboveground chemical ecology have influenced soil chemical ecology. Our examples and discussion are prepared primarily in reference to soil arthropods. We conclude by discussing seven future research directions and outstanding questions. The soil is a premier example of a system where investigators should avoid anthropomorphisms when studying behavioral and chemical ecology. Research in soil chemical ecology should further efforts towards developing a unified view of chemosensation that could apply to all environments where chemical communication occurs

Reducing Eating Disorder Risk Factors: A Controlled Investigation of a Blended Task-Shifting/Train-the-Trainer Approach to Dissemination and Implementation

Recent advances in psychological intervention research have led to an increase in evidence-based interventions (EBIs), yet there remains a lag in dissemination and implementation of EBIs. Task-shifting and the train-the-trainer (TTT) model offer two potential strategies for enhancing reach of EBIs. The Body Project, an EBI found to prevent onset of eating disorders, served as the vehicle for this dissemination/implementation study. The primary aim of this study was to determine if training of peer-leaders for the Body Project could be task-shifted to undergraduate students using a hybrid task-shifting/TTT model. Our secondary aim was to determine if subgroups of participants evidenced different trajectories of change through 14-month follow-up. Regarding the first aim, we found almost no evidence to suggest that a presence of a doctoral-level trainer yielded superior participant outcomes compared to training by undergraduates alone. Regarding Aim 2, almost all classes for all variables evidenced improvement or a benign response. Additionally, for three key risk factors (thin-ideal internalization, body dissatisfaction, and ED symptoms) virtually all trajectories showed improvement. This study provides initial support for the use of a blended task-shifting/TTT approach to dissemination and implementation within prevention generally, and further support for broad dissemination of the Body Project specifically

Reducing Eating Disorder Risk Factors: A Controlled Investigation of a Blended Task-Shifting/Train-the-Trainer Approach to Dissemination and Implementation

Recent advances in psychological intervention research have led to an increase in evidence-based interventions (EBIs), yet there remains a lag in dissemination and implementation of EBIs. Task-shifting and the train-the-trainer (TTT) model offer two potential strategies for enhancing reach of EBIs. The Body Project, an EBI found to prevent onset of eating disorders, served as the vehicle for this dissemination/implementation study. The primary aim of this study was to determine if training of peer-leaders for the Body Project could be task-shifted to undergraduate students using a hybrid task-shifting/TTT model. Our secondary aim was to determine if subgroups of participants evidenced different trajectories of change through 14-month follow-up. Regarding the first aim, we found almost no evidence to suggest that a presence of a doctoral-level trainer yielded superior participant outcomes compared to training by undergraduates alone. Regarding Aim 2, almost all classes for all variables evidenced improvement or a benign response. Additionally, for three key risk factors (thin-ideal internalization, body dissatisfaction, and ED symptoms) virtually all trajectories showed improvement. This study provides initial support for the use of a blended task-shifting/TTT approach to dissemination and implementation within prevention generally, and further support for broad dissemination of the Body Project specifically