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Biomedical subjects

Sabrina Diano

Publications and source records attributed to Sabrina Diano.

At least 19 recordsLinked to original sources
PubMed2007

A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2.

The active thyroid hormone, triiodothyronine (T3), regulates mitochondrial uncoupling protein activity and related thermogenesis in peripheral tissues. Type 2 deiodinase (DII), an enzyme that catalyzes active thyroid hormone production, and mitochondrial uncoupling protein 2 (UCP2) are also present in the hypothalamic arcuate nucleus, where their interaction and physiological significance have not been explored. Here, we report that DII-producing glial cells are in direct apposition to neurons coexpressing neuropeptide Y (NPY), agouti-related protein (AgRP), and UCP2. Fasting increased DII activity and local thyroid hormone production in the arcuate nucleus in parallel with increased GDP-regulated UCP2-dependent mitochondrial uncoupling. Fasting-induced T3-mediated UCP2 activation resulted in mitochondrial proliferation in NPY/AgRP neurons, an event that was critical for increased excitability of these orexigenic neurons and consequent rebound feeding following food deprivation. These results reveal a physiological role for a thyroid-hormone-regulated mitochondrial uncoupling in hypothalamic neuronal networks.

Agouti-Related Protein↗
PubMed2006

Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals.

Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.

Animals↗
PubMed2006

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor.

Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of POMC cells and normal energy homeostasis under standard and high fat diet. Endotoxin (LPS) and stress-induced anorexia and adrenocorticotropin regulation were unaffected in these animals. Strikingly, the anorectic effect of centrally administered CNTF was abolished in POMC-specific gp130 knockout mice. Correspondingly, in these animals, CNTF failed to activate STAT3 phosphorylation in POMC neurons and to induce c-Fos expression in the paraventricular nucleus. These data reveal POMC neurons as a critical site of CNTF action in mediating its anorectic effect.

Acute Disease↗
PubMed2006

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Animals↗
PubMed2005

Leptin induces nitric oxide synthase type II in C6 glioma cells. Role for nuclear factor-kappaB in hormone effect.

Astrocytes in the CNS produce inflammatory mediators in response to several stimuli and cytokines. Here we investigated the in vitro effect of leptin on inducible nitric oxide synthase (iNOS) expression in a glioma cell line (C6). After hormone stimulation, culture media were analysed for accumulated stable oxidation products of NO (NO2(-) and NO3(-), designated as NO(x)), cellular RNA was extracted to determine iNOS mRNA level by RT-PCR and cellular lysates were prepared for protein expression. Leptin induced a concentration-dependent increase of NO release, related to iNOS induction. This effect was potentiated by IFN-gamma, or TNF-alpha, or IFN-gamma plus IL-1beta. Pyrrolidine dithiocarbamate (PDTC) and N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), two inhibitors of NF-kappaB activation, as well as the specific proteasome inhibitor MG132, blocked leptin-induced iNOS. The role of NF-kappaB was also confirmed by time course studies on degradation of IkappaB-alpha, which began to degrade 5 min after treatment with leptin and returned to basal level after 30-60 min. Pre-incubation of cells with MG132 inhibited leptin-induced IkappaB-alpha degradation. These results confirm the pro-inflammatory role of leptin and identify it as a potential up-regulator of cytokine-induced inflammatory response in the CNS.

Animals↗
PubMed2005

A novel growth hormone secretagogue-1a receptor antagonist that blocks ghrelin-induced growth hormone secretion but induces increased body weight gain.

Ghrelin, the natural ligand for the growth hormone secretagogue-1a (GHS-1a) receptor, has received a great deal of attention due to its ability to stimulate weight gain and the hope that an antagonist of the GHS-1a receptor could be a treatment for obesity. We have discovered an analog of full-length human ghrelin, BIM-28163, which fully antagonizes GHS-1a by binding to but not activating the receptor. We further demonstrate that BIM-28163 blocks ghrelin activation of the GHS-1a receptor, and inhibits ghrelin-induced GH secretion in vivo. Unexpectedly, however, BIM-28163 acts as an agonist with regard to stimulating weight gain. These results may suggest the presence of an unknown ghrelin receptor that modulates ghrelin actions on weight gain. In keeping with our results on growth hormone (GH) secretion, BIM-28163 acts as an antagonist of ghrelin-induced Fos protein immunoreactivity (Fos-IR) in the medial arcuate nucleus, an area involved in the ghrelin modulation of GH secretion. However, in the dorsal medial hypothalamus (DMH), a region associated with regulation of food intake, both ghrelin and BIM-28163 act as agonists to upregulate Fos-IR. The observation that ghrelin and BIM-28163 have different efficacies in inducing Fos-IR in the DMH, and that concomitant administration of ghrelin and an excess of BIM-28163 results in the same level of Fos-IR as BIM-28163 administered alone may demonstrate that in the DMH both ghrelin and BIM-28163 act via the same receptor. If so, it is unlikely that this receptor is GHS-1a. Collectively, our findings suggest that the action of ghrelin to stimulate increased weight gain may be mediated by a novel receptor other than GHS-1a, and further imply that GHS-1a may not be the appropriate target for anti-obesity strategies.

Animals↗
PubMed2005

Suppression of hypothalamic deiodinase type II activity blunts TRH mRNA decline during fasting.

Fasting is characterized by disrupted thyroid feedback, with suppressed levels of thyroid hormones and paraventricular thyrotropin releasing hormone (TRH). We found that third ventricle administration of the deiodinase inhibitor, iopanoic acid, dose-dependently reduced deiodinase type II (DII) activity selectively in the hypothalamus. This suppression of DII by iopanoic acid during fasting prevented elevated DII activity and blunted the decline in hypothalamic TRH mRNA levels. Because fasting-induced elevation in hypothalamic DII activity is paralleled by increased hypothalamic T3 concentration, our study suggests that T3 formation by DII in the hypothalamus is the cause of disrupted thyroid feedback during fasting.

Animals↗
PubMed2005

Inverse shift in circulating corticosterone and leptin levels elevates hypothalamic deiodinase type 2 in fasted rats.

During food deprivation, plasma T(4) and T(3) levels are decreased. Under this metabolic condition, hypothalamic deiodinase type 2 (D2) activity and mRNA levels are elevated, whereas TRH mRNA levels are suppressed. Systemic T(4) administration does not reverse these hypothalamic changes. The mechanism(s) that underlies this paradoxical regulation of D2 during fasting is unknown. We hypothesize that leptin and/or glucocorticoids play a role in these mechanisms, and their interactions may be an important regulator of the hypothalamic-pituitary-thyroid axis. Thus, we assessed the effects of these hormones on D2 activity levels of food-deprived as well as fed animals using enzyme activity measurements. In food-deprived animals, corticosterone replacement reversed the inhibitory effect of adrenalectomy (ADX) on D2 induction, whereas ADX and ADX plus corticosterone replacement did not significantly affect D2 activity levels in rats fed ad libitum. Leptin administration to fed animals did not change D2 activity, whereas in fasted rats, leptin decreased D2 activity by reducing corticosterone plasma levels. When leptin was administered to fasted animals that were either ADX or ADX plus corticosterone treated at a high dose, D2 activity did not increase. Our results show that during fasting, diminishing leptin levels play a permissive role to enable glucocorticoid-induced up-regulation of D2. Thus, our observations suggest that appropriate induction of D2 activity during negative energy balance is dependent upon both leptin and glucocorticoid signaling.

Adrenalectomy↗
PubMed2005

Agouti-related protein-deficient mice display an age-related lean phenotype.

Endogenous modulators of the central melanocortin system, such as the agouti-related protein (AgRP), should hold a pivotal position in the regulation of energy intake and expenditure. Despite this, AgRP-deficient mice were recently reported to exhibit normal food intake, body weight gain, and energy expenditure. Here we demonstrate that 2- to 3-month-old Agrp null mice do in fact exhibit subtle changes in response to feeding challenges (fasting and MCR agonists) but, of more significance and magnitude, exhibit reduced body weight and adiposity after 6 months of age. This age-dependent lean phenotype is correlated with increased metabolic rate, body temperature, and locomotor activity and increased circulating thyroid hormone (T4 and T3) and BAT UCP-1 expression. These results provide further proof of the importance of the AgRP neuronal system in the regulation of energy homeostasis.

Adipose Tissue↗
PubMed2005

Mitochondrial uncoupling proteins in the CNS: in support of function and survival.

Mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1) is classically associated with non-shivering thermogenesis by brown fat. Recent evidence indicates that UCP family proteins are also present in selected neurons. Unlike UCP1, these proteins (UCP2, UCP4 and BMCP1/UCP5) are not constitutive uncouplers and are not crucial for non-shivering thermogenesis. However, they can be activated by free radicals and free fatty acids, and their activity has a profound influence on neuronal function. By regulating mitochondrial biogenesis, calcium flux, free radical production and local temperature, neuronal UCPs can directly influence neurotransmission, synaptic plasticity and neurodegenerative processes. Insights into the regulation and function of these proteins offer unsuspected avenues for a better understanding of synaptic transmission and neurodegeneration.

Animals↗
PubMed2005

Obesity and the neuroendocrine control of energy homeostasis: the role of spontaneous locomotor activity.

Obesity represents one of the most urgent global health threats as well as one of the leading causes of death throughout industrialized nations. Efficacious and safe therapies remain at large. Attempts to decrease fat mass via pharmacological reduction of energy intake have had limited potency or intolerable side effects. Increasingly widespread sedentary lifestyle is often cited as a major contributor to the increasing prevalence of obesity. Moreover, low levels of spontaneous physical activity (SPA) are a major predictor of fat mass accumulation during overfeeding in humans, pointing to a substantial role for SPA in the control of energy balance. Despite this, very little is known about the molecular mechanisms by which SPA is regulated. The overview will attempt to summarize available information on neuroendocrine factors regulating SPA.

Animals↗
PubMed2004

Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response.

The hypothalamic neuropeptides hypocretins (orexins) play a crucial role in the stability of arousal and alertness. We tested whether the hypocretinergic system is a critical component of the stress response activated by the corticotropin-releasing factor (CRF). Our results show that CRF-immunoreactive terminals make direct contact with hypocretin-expressing neurons in the lateral hypothalamus and that numerous hypocretinergic neurons express the CRF-R1/2 receptors. We also demonstrate that application of CRF to hypothalamic slices containing identified hypocretin neurons depolarizes membrane potential and increases firing rate in a subpopulation of hypocretinergic cells. CRF-induced depolarization was tetrodotoxin insensitive and was blocked by the peptidergic CRF-R1 antagonist astressin. Moreover, activation of hypocretinergic neurons in response to acute stress was severely impaired in CRF-R1 knock-out mice. Together, our data provide evidence of a direct neuroanatomical and physiological input from CRF peptidergic system onto hypocretin neurons. We propose that, after stressor stimuli, CRF stimulates the release of hypocretins and that this circuit contributes to activation and maintenance of arousal associated with the stress response.

Action Potentials↗
PubMed2004

Rapid rewiring of arcuate nucleus feeding circuits by leptin.

The fat-derived hormone leptin regulates energy balance in part by modulating the activity of neuropeptide Y and proopiomelanocortin neurons in the hypothalamic arcuate nucleus. To study the intrinsic activity of these neurons and their responses to leptin, we generated mice that express distinct green fluorescent proteins in these two neuronal types. Leptin-deficient (ob/ob) mice differed from wild-type mice in the numbers of excitatory and inhibitory synapses and postsynaptic currents onto neuropeptide Y and proopiomelanocortin neurons. When leptin was delivered systemically to ob/ob mice, the synaptic density rapidly normalized, an effect detectable within 6 hours, several hours before leptin's effect on food intake. These data suggest that leptin-mediated plasticity in the ob/ob hypothalamus may underlie some of the hormone's behavioral effects.

Animals↗
PubMed2004

Brain circuits regulating energy homeostasis.

For decades, increasingly sophisticated methods have been designed to address the problem of the involvement of the brain in the physiology of energy homeostasis and the pathogenesis of obesity. A vast number of experimental observations have been made from novel genetic and physiologic approaches that allowed the identification of metabolic hormones and their relationship to key peptidergic systems in the brain. Although the central integration of afferent signals reflecting acute and chronic energy requirements is becoming clearer, the blueprint of the central regulation of energy expenditure is not known. This review offers a look at central neuronal circuitries that are implicated in metabolism regulation and strongly suggests that without a blueprint, attempts to intervene and control energy balance will remain futile.

Animals↗
PubMed2004

Novel analogs of ghrelin: physiological and clinical implications.

Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both normal physiology and specific pathologies.

Animals↗
PubMed2003

Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning.

The mitochondrial uncoupling protein (UCP2) is expressed in selected regions of the brain. Here we demonstrate that up-regulation of UCP2 is part of a neuroprotective set of responses to various cellular stresses in vitro and in vivo. PC12 cells, when transfected with UCP2, were protected against free radical-induced cell death. Seizure activity was associated with elevated UCP2 levels and mitochondrial uncoupling activity. In transgenic mice that expressed UCP2 constitutively in the hippocampus before seizure induction, a robust reduction in cell death was seen. Because UCP2 increased mitochondrial number and ATP levels with a parallel decrease in free radical-induced damage, it is reasonable to suggest that mitochondrial UCPs precondition neurons by dissociating cellular energy production from that of free radicals to withstand the harmful effects of cellular stress occurring in a variety of neurodegenerative disorders, including epilepsy.

Adenosine Diphosphate↗
PubMed2003

Hypothalamic type II iodothyronine deiodinase: a light and electron microscopic study.

In the central nervous system, the active form of thyroid hormone, T3, derives from the cellular uptake and intracellular 5'-monodeiodination of T4 by type II 5'-monodeiodinase (DII). Here, we report that using an antiserum raised against the C-terminus of the full-length SeDII, immunolabeled cells were found in the rat hypothalamus in agreement with the DII mRNA distribution. Light and electron microscopy shows that DII is localized in astrocytes and tanycytes, supporting the hypothesis that these cells play an important role in the mediation peripheral signals, such as thyroid hormones, on hypothalamic functions.

Animals↗