Showing papers in "Molecular metabolism in 2012"

Obesity and the gut microbiome: Striving for causality.

Abstract: The gut microbiome has been proposed to play a causal role in obesity. Here, we review the historical context for this hypothesis, highlight recent key findings, and critically discuss issues central to further progress in the field, including the central epistemological problem for the field: how to define causality in the relationship between microbiota and obesity phenotypes. Definition of such will be critical for the field to move forward.

High calorie diet triggers hypothalamic angiopathy

Abstract: Obesity, type 2 diabetes, and related diseases represent major health threats to modern society. Related pathophysiology of impaired neuronal function in hypothalamic control centers regulating metabolism and body weight has been dissected extensively and recent studies have started focusing on potential roles of astrocytes and microglia. The hypothalamic vascular system, however, which maintains the microenvironment necessary for appropriate neuronal function, has been largely understudied. We recently discovered that high fat/high sucrose diet exposure leads to increased hypothalamic presence of immunoglobulin G (IgG1). Investigating this phenomenon further, we have discovered a significant increase in blood vessel length and density in the arcuate nucleus (ARC) of the hypothalamus in mice fed a high fat/high sucrose diet, compared to matched controls fed standard chow diet. We also found a clearly increased presence of α-smooth muscle actin immunoreactive vessels, which are rarely present in the ARC and indicate an increase in the formation of new arterial vessels. Along the blood brain barrier, an increase of degenerated endothelial cells are observed. Moreover, such hypothalamic angiogenesis was not limited to rodent models. We also found an increase in the number of arterioles of the infundibular nucleus (the human equivalent of the mouse ARC) in patients with type 2 diabetes, suggesting angiogenesis occurs in the human hypothalamus of diabetics. Our discovery reveals novel hypothalamic pathophysiology, which is reminiscent of diabetic retinopathy and suggests a potential functional involvement of the hypothalamic vasculature in the later stage pathogenesis of metabolic syndrome.

Emerging role of glial cells in the control of body weight.

Abstract: Glia are the most abundant cell type in the brain and are indispensible for the normal execution of neuronal actions. They protect neurons from noxious insults and modulate synaptic transmission through affectation of synaptic inputs, release of glial transmitters and uptake of neurotransmitters from the synaptic cleft. They also transport nutrients and other circulating factors into the brain thus controlling the energy sources and signals reaching neurons. Moreover, glia express receptors for metabolic hormones, such as leptin and insulin, and can be activated in response to increased weight gain and dietary challenges. However, chronic glial activation can be detrimental to neurons, with hypothalamic astrocyte activation or gliosis suggested to be involved in the perpetuation of obesity and the onset of secondary complications. It is now accepted that glia may be a very important participant in metabolic control and a possible therapeutical target. Here we briefly review this rapidly advancing field.

Leptin action via LepR-b Tyr1077 contributes to the control of energy balance and female reproduction.

Abstract: Leptin action in the brain signals the repletion of adipose energy stores, suppressing feeding and permitting energy expenditure on a variety of processes, including reproduction. Leptin binding to its receptor (LepR-b) promotes the tyrosine phosphorylation of three sites on LepR-b, each of which mediates distinct downstream signals. While the signals mediated by LepR-b Tyr1138 and Tyr985 control important aspects of energy homeostasis and LepR-b signal attenuation, respectively, the role of the remaining LepR-b phosphorylation site (Tyr1077) in leptin action has not been studied. To examine the function of Tyr1077, we generated a “knock-in” mouse model expressing LepR-b F1077, which is mutant for LepR-b Tyr1077. Mice expressing LepR-b F1077 demonstrate modestly increased body weight and adiposity. Furthermore, females display impairments in estrous cycling. Our results suggest that signaling by LepR-b Tyr1077 plays a modest role in the control of metabolism by leptin, and is an important link between body adiposity and the reproductive axis.

Leptin reduces food intake via a dopamine D2 receptor-dependent mechanism

Abstract: Food intake is generally accepted to be regulated by the melanocortin system, however recent data suggests that mesolimbic dopaminergic neurons also influence food intake. Whether dopamine signaling is crucial for the acute effect of leptin on feeding is unknown. Using pharmacological and genetic strategies, we tested the hypothesis that the acute inhibitory effect of leptin on food intake is partially mediated by dopamine. Dopamine D2 but not D1 receptor blockade attenuated the acute hypophagic effect of leptin in fasted mice. Additionally, mice lacking the D2R (D2R KO) exhibited an attenuated response to leptin. Conversely, dopamine receptor blockade had no effect on the acute hypophagic effect of melanocortin stimulation or the hyperphagic effect of ghrelin. These findings suggest that dopaminergic pathways do not constitute a normal part of melanocortin-dependent feeding regulation and that the dopaminergic neurocircuitry typically associated with regulation of hedonic feeding likely contributes to feeding regulation by leptin.

A guide for measurement of circulating metabolic hormones in rodents: Pitfalls during the pre-analytical phase

Abstract: Researchers analyse hormones to draw conclusions from changes in hormone concentrations observed under specific physiological conditions and to elucidate mechanisms underlying their biological variability. It is, however, frequently overlooked that also circumstances occurring after collection of biological samples can significantly affect the hormone concentrations measured, owing to analytical and pre-analytical variability. Whereas the awareness for such potential confounders is increasing in human laboratory medicine, there is sometimes limited consensus about the control of these factors in rodent studies. In this guide, we demonstrate how such factors can affect reliability and consequent interpretation of the data from immunoassay measurements of circulating metabolic hormones in rodent studies. We also compare the knowledge about such factors in rodent studies to recent recommendations established for biomarker studies in humans and give specific practical recommendations for the control of pre-analytical conditions in metabolic studies in rodents.

Ghrelin-immunopositive hypothalamic neurons tie the circadian clock and visual system to the lateral hypothalamic arousal center

Abstract: Ghrelin, a circulating gut-hormone, has emerged as an important regulator of growth hormone release and appetite. Ghrelin-immunopositive neurons have also been identified in the hypothalamus with a unique anatomical distribution. Here, we report that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of the brain critical for arousal. Hypothalamic ghrelin mRNA oscillates in a circadian pattern peaking in the dark phase prior to the switch from arousal to sleep. Ghrelin inhibits the electrophysiological activity of identified orexin/hypocretin neurons in hypothalamic slices. These observations indicate that the hypothalamic neurons identified by ghrelin immunolabeling may be a key mediator of circadian and visual cues for the hypothalamic arousal system.

Uncovering the biology of FTO.

Abstract: Genome-wide association studies have revealed that SNPs in the first intron of FTO (Fat mass and Obesity related) are robustly associated with body mass index and obesity. Subsequently, it has become clear that this association with body weight, and increasingly food intake, is replicable across multiple populations and different age groups. However, to date, no conclusive link has been made between the risk alleles and FTO expression or its physiological role. FTO deficiency leads to a complex phenotype including postnatal mortality and growth retardation, pointing to some fundamental developmental role. Yet, the weight of evidence from a number of animal models where FTO expression has been perturbed indicates some role for FTO in energy homoeostasis. In addition, emerging data points to a role for FTO in the sensing of nutrients. In this review, we explore the in vivo and in vitro evidence detailing FTO's different faces and discuss how these might link to the regulation of body weight.

An inconvenient truth about obesity

Abstract: The 4-part Home Box Office (HBO) documentary on obesity entitled, “The Weight of the Nation” (theweightofthenation.hbo.com/) was aired in May of this year. Two years in the making, this timely documentary was produced in conjunction with two of the most prestigious biomedical institutions in the US – the Institute of Medicine and the National Institutes of Health (NIH) – and top US health officials were featured in the series and enlisted to promote it in media appearances. The documentary appropriately focuses on the health implications of obesity for current and future generations and explains how it results from complex interactions between inherited and environmental factors. It also highlights the important contributions to obesity risk made by unhealthy dietary and exercise habits and concludes with an impassioned plea for lifestyle change at the national level.

Neuroimaging the interaction of mind and metabolism in humans.

Abstract: Hormonal and metabolic signals interact with neural circuits orchestrating behavior to guide food intake. Neuroimaging techniques such as functional magnetic resonance imaging (fMRI) enable the identification of where in the brain particular mental processes like desire, satiety and pleasure occur. Once these neural circuits are described it then becomes possible to determine how metabolic and hormonal signals can alter brain response to influence psychological states and decision-making processes to guide intake. Here, we provide an overview of the contributions of functional neuroimaging to the understanding of how subjective and neural responses to food and food cues interact with metabolic/hormonal factors.

TOSO promotes β-cell proliferation and protects from apoptosis.

Abstract: Decreased β-cell mass reflects a shift from quiescence/proliferation into apoptosis, it plays a crucial role in the pathophysiology of diabetes. A major attempt to restore β-cell mass and normoglycemia is to improve β-cell survival. Here we show that switching off the Fas pathway using Fas apoptotic inhibitory protein (Faim/TOSO), which regulates apoptosis upstream of caspase 8, blocked β-cell apoptosis and increased proliferation in human islets. TOSO was clearly expressed in pancreatic β-cells and down-regulated in T2DM. TOSO expression correlated with β-cell turnover; at conditions of improved survival, TOSO was induced. In contrast, TOSO downregulation induced β-cell apoptosis. Although TOSO overexpression resulted in a 3-fold induction of proliferation, proliferating β-cells showed a very limited capacity to undergo multiple rounds of replication. Our data suggest that TOSO is an important regulator of β-cell turnover and switches β-cell apoptosis into proliferation.

Mapping leptin's link to reproduction.

Abstract: Lack of leptin action due to null mutations of either leptin or the leptin receptor results in increased appetite, decreased metabolic rate, infertility, immune dysfunction, and insulin resistance both in humans and rodents. Consistent with a major role for leptin action in the CNS, mice with a neuron-specific deletion of the leptin receptor closely resemble the phenotype of mice that lack the leptin receptor in the whole body (db /db) [3]. On the other hand, expression of LepR-b in the brain of db/db mice rescues obesity, diabetes, and completely restores

Our evolving understanding of the interaction between leptin and dopamine system to regulate ingestive behaviors.

Abstract: Dopamine (DA) has been with us scientifically for a long time. Dopamine's function as a neurotransmitter was first recognized in 1958, a finding that eventually led to Arvid Carlsson being awarded the Nobel Prize in 2000. Among its numerous identified physiological roles, dopaminergic signaling is well known to regulate ingestive behaviors [1]. This is not surprising. Eating food is a pleasurable act and the DA projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) clearly play a role in many aspects of reward that shape behavior. Consequently, a number of investigators have hypothesized a role for the DA system to interact with key peripheral signals that regulate food intake such as leptin [2,3] and ghrelin [4]. Literally thousands of papers have focused on the hypothalamic pathways mediating the anorectic effect of leptin. However, leptin receptors are also expressed in the VTA, and leptin decreases the firing rate of DA neurons and decreases feeding behavior independently of hypothalamic mechanisms [2,3]. In this issue, Billes and colleagues report that the systemic injection of DA receptor 2 antagonists before leptin treatment blunts the anorexigenic action of leptin [5]. Supporting those pharmacological findings, the administration of leptin to mice lacking DA receptor 2 showed an attenuated effect of leptin on feeding [5]. Conversely, DA receptor blockade had no effect on the acute hypophagic effect of melanocortin receptor agonists or the increased food intake caused by exogenous ghrelin administration [5]. This work lays another important brick in the foundation that leptin and the DA system have important interactions that are critical for the regulation of food intake and points the finger squarely at the D2 receptor as a key component of this interaction. This leaves open several interesting questions. First, which neuronal population is responsible for the interaction between leptin and DA receptor 2. Since both leptin and DA receptors are located within the VTA and different hypothalamic nuclei, other methodologies will need to be applied to give us clues as to the key neuroanatomical locations that mediate these effects. This question remains important since a previous study reported that DA receptor 2-deficient mice showed an increased response to central leptin administration [6]. Therefore, it is plausible to hypothesize that the manipulation of DA receptor 2 in specific neuronal populations might differentially affect leptin's actions. A second important question concerns the molecular pathway mediating the interaction between leptin and D2R. It could be hypothesized that the long isoform of the leptin receptor heterodimerizes with D2R. Interestingly, such heterodimers have been identified for ghrelin receptor (GHS-R1a) and D2R, and preventing such heterodimers alters the DRD2 signal transduction [7]. Answering this question could identify potential new downstream targets modulating the anorectic action of leptin. Finally, a key question concerns the possibility that leptin's actions on the DA system impact not only ingestive behaviors but have an important role in a wide range of other behaviors. For example, the dopaminergic system plays an important role as a mediator of the actions of ghrelin on food intake [4], spatial memories [8], and locomotor activity [9]. The findings of Billes et al. highlight the relevance of the dopaminergic system as a physiological mediator of feeding behavior and as a regulator of leptin's actions. Given that this interaction is independent of the melanocortin system it highlights the need to continue to explore new pathways that may underlie leptin's effects on energy balance, reproduction and peripheral fuel utilization. Revealing such pathways allows for new insights that can provide for better understanding of how dysregulation of body weight can occur and novel therapeutic strategies to make it easier for individuals to sustain meaningful weight loss.

Welcome to molecular metabolism

Abstract: Metabolic diseases including obesity, diabetes and related comorbidities remain on the rise Impaired cellular metabolism is emerging as an etiological factor for an increasing number of illnesses, such as cancer, cardiovascular diseases or neurodegenerative disorders More than ever before, research efforts across the globe are aiming to improve our understanding of the molecular pathophysiology of and expand the therapeutic options for these diseases To fill an unmet need for an ambitious, open access journal focusing solely on mechanistic metabolism research, we established Molecular Metabolism Our main goal is to publish breakthrough discoveries with unprecedented speed For example, the review process of Molecular Metabolism does not offer an option for reviewers to recommend major revision Rather, we encourage reviewers to quickly accept the very highest quality submissions within days without attempting to reshape the scientific work of the authors It is our pledge that your breakthrough findings will not be held up at Molecular Metabolism, with reviews completed and editorial decisions made within approximately one week Accepted manuscripts will then be published online in preliminary format within approximately another week The Editors of Molecular Metabolism will be open and accessible Please approach us, or the Regional and Topic editors of the journal, at any time by phone, e-mail, or at conferences Introduce us to your latest discoveries Our website at wwwmolecularmetabolismcom will offer information regarding which editors will be present at which scientific conferences We are looking forward to hearing from you, reading about your latest work, and publishing your breakthroughs in Molecular Metabolism