Showing papers on "Hypothalamus published in 2004"
TL;DR: The results suggest that leptin plays a neurotrophic role during the development of the hypothalamus and that this activity is restricted to a neonatal critical period that precedes leptin's acute regulation of food intake in adults.
Abstract: In adult mammals, the adipocyte-derived hormone leptin acts on the brain to reduce food intake by regulating the activity of neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we report that neural projection pathways from the ARH are permanently disrupted in leptin-deficient (Lepob/Lepob) mice and leptin treatment in adulthood does not reverse these neuroanatomical defects. However, treatment of Lepob/Lepob neonates with exogenous leptin rescues the development of ARH projections, and leptin promotes neurite outgrowth from ARH neurons in vitro. These results suggest that leptin plays a neurotrophic role during the development of the hypothalamus and that this activity is restricted to a neonatal critical period that precedes leptin's acute regulation of food intake in adults.
1,139 citations
TL;DR: Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54, and it is concluded that kisspeptin-GPR54 signaling may be part of the hypothalamus circuitry that governs the hypothalamic secretion of GnRH.
Abstract: Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.
1,090 citations
TL;DR: 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, suggesting that leptin-mediated plasticity in the Ob/ob hypothalamus may underlie some of the hormone's behavioral effects.
Abstract: 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.
944 citations
TL;DR: Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogOnadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.
Abstract: The first known step in sexual maturation at puberty is the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. Pubertal changes also include accelerated linear growth and adrenal maturation. The authors used complementary genetic approaches in both humans and mice to study a gen
754 citations
TL;DR: It is demonstrated that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake, and that AMPK is identified as a novel target for anti-obesity drugs.
724 citations
TL;DR: The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus.
Abstract: Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.
703 citations
TL;DR: The current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.
Abstract: The gonadotropic axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals that is activated at puberty. Recently, loss of function mutations of the gene encoding G protein-coupled receptor 54 (GPR54), the putative receptor for the KiSS-1-derived peptide metastin, have been associated with lack of puberty onset and hypogonadotropic hypogonadism. Yet the pattern of expression and functional role of the KiSS-1/GPR54 system in the rat hypothalamus remain unexplored to date. In the present work, expression analyses of KiSS-1 and GPR54 genes were conducted in different physiological and experimental settings, and the effects of central administration of KiSS-1 peptide on LH release were assessed in vivo. Persistent expression of KiSS-1 and GPR54 mRNAs was detected in rat hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female rats. Hypothalamic expression of KiSS-1 and GPR54 genes changed throughout the estrous cycle and was significantly increased after gonadectomy, a rise that was prevented by sex steroid replacement both in males and females. Moreover, hypothalamic expression of the KiSS-1 gene was sensitive to neonatal imprinting by estrogen. From a functional standpoint, intracerebroventricular administration of KiSS-1 peptide induced a dramatic increase in serum LH levels in prepubertal male and female rats as well as in adult animals. In conclusion, we provide novel evidence of the developmental and hormonally regulated expression of KiSS-1 and GPR54 mRNAs in rat hypothalamus and the ability of KiSS-1 peptide to potently stimulate LH secretion in vivo. Our current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.
695 citations
TL;DR: Using tritiated amino acid autoradiography, the efferent projections of the anterior hypothalamic area (AHA) were studied in albino rats.
Abstract: Using tritiated amino acid autoradiography, the efferent projections of the anterior hypothalamic area (AHA) were studied in albino rats.
Axons from AHA neurons were not confined to local projections in the hypothalamus. Ascending AHA axons ran through the preoptic region, joined the diagonal band and distributed in the lateral septum. Descending AHA efferents within the hypothalamus coursed in a bundle ventromedial to the fornix. Projections were observed to the dorsomedial, ventromedial, arcuate and dorsal premammillary nuclei, and to the median eminence. Sweeping dorsomedially in the posterior hypothalamus, some AHA axons distributed in the central grey. AHA axons staying ventral projected to the supramammillary region, ventral tegmental area, raphe nuclei and midbrain reticular formation. Other AHA efferents distributed to the periventricular thalamus, to the medial amygdala via the stria terminalis or supraoptic commissure, and to the lateral habenula through the stria medullaris.
For comparison with the AHA, efferent projections from the paraventricular nucleus (PVN) and from the ventromedial nucleus and adjacent basal hypothalamus (VMR) were studied. Projections from PVN neurons were not restricted to the median eminence and neurohypophysis. PVN efferents also distributed to many of the same regions as did those of the AHA but had somewhat different fiber trajectories and longer descending projections. VMR efferents were more widespread than those of the AHA, with projections extending into the lateral zona incerta and pontine reticular formation.
Projections from the AHA were distinct from those of the medial preoptic area (mPOA). For example, while AHA axons descended in a bundle ventromedial to the fornix, mPOA axons ran in the medial forebrain bundle. Such anatomical differences may underlie experimentally demonstrated functional differences between the mPOA and AHA, for instance, in mediation of male and female sex behaviors.
628 citations
TL;DR: New insight is provided into development of hypothalamic circuits and an anatomical basis for the delayed postnatal regulation of food intake and body weight by leptin is suggested.
Abstract: The arcuate nucleus of the hypothalamus (ARH) is a critical component of forebrain pathways that regulate a variety of neuroendocrine functions, including an important role in relaying leptin signals to other parts of the hypothalamus. However, neonatal rodents do not lose weight in response to leptin treatment in the same way as do adults, suggesting that certain aspects of leptin signaling pathways in the hypothalamus may not be mature. We tested this possibility by using DiI axonal labeling to examine the development of projections from the ARH to other parts of the hypothalamus in neonatal mice, paying particular attention to the innervation of the paraventricular nucleus (PVH), the dorsomedial nucleus (DMH), and the lateral hypothalamic area (LHA), each of which have been implicated in the regulation of feeding. The results indicate that ARH projections are quite immature at birth and appear to innervate the DMH, PVH, and LHA in succession, within distinct temporal domains. The projections from the ARH to the DMH develop rapidly and are established by the sixth postnatal day (P6), whereas those to the PVH develop significantly later, with the mature pattern of innervation first apparent between postnatal day 8 (P8)-P10. Furthermore, the ability of leptin to activate Fos in the PVH, DMH, and LHA appears to be age-dependent and correlates with the arrival of ARH projections to each nucleus. Taken together, these findings provide new insight into development of hypothalamic circuits and suggest an anatomical basis for the delayed postnatal regulation of food intake and body weight by leptin.
531 citations
TL;DR: Kisspeptin therefore potently stimulates the hypothalamic‐pituitary‐gonadal axis and is likely to be mediated via the hypothalamate LHRH system.
Abstract: Kisspeptin is the peptide product of the KiSS-1 gene and the endogenous agonist for the GPR54 receptor. Recent evidence suggests the kisspeptin/GPR54 system is a key regulator of the reproductive system. We examined the effect of intracerebroventricular (i.c.v.) and peripheral administration of the active kisspeptin fragment, kisspeptin-10, on circulating gonadotrophins and total testosterone levels in adult male rats. The effect of kisspeptin-10 in vitro on the release of hypothalamic peptides from hypothalamic explants and gonadotrophins from anterior pituitary fragments was also determined. The i.c.v. administration of kisspeptin-10 dose-dependently increased plasma luteinizing hormone (LH) and increased plasma follicle stimulating hormone (FSH) and total testosterone at 60 min postinjection. In a separate study investigating the time course of this response, i.c.v. administered kisspeptin-10 (3 nmol) significantly increased plasma LH at 10, 20 and 60 min, FSH at 60 min and total testosterone at 20 and 60 min postinjection. Kisspeptin-10 stimulated the release of luteinizing hormone-releasing hormone (LHRH) from in vitro hypothalamic explants. Peripheral administration of kisspeptin-10 increased plasma LH, FSH and total testosterone. However, doses of 100-1000 nM kisspeptin-10 did not influence LH or FSH release from pituitary fragments in vitro. Kisspeptin therefore potently stimulates the hypothalamic-pituitary-gonadal axis. These effects are likely to be mediated via the hypothalamic LHRH system.
471 citations
TL;DR: Data indicate that e CB signaling negatively modulates HPA axis function in a context-dependent manner and suggest that pharmacological augmentation of eCB signaling could serve as a novel approach to the treatment of anxiety-related disorders.
Abstract: Activation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for the adaptation and survival of animals upon exposure to stressful stimuli, and data suggest that endocannabinoid (eCB) signaling modulates neuroendocrine function. We have explored the role of eCB signaling in the modulation of stress-induced HPA axis activation. Administration of the CB1receptor antagonist/inverse agonist SR141716 (0.01, 0.1, 1, and 5 mg/kg, ip) to male mice produced a small, dosedependent increase in the serum corticosterone (CORT) concentration. Despite this effect, the highest dose of SR141716 did not significantly increase neuronal activity within the paraventricularnucleusofthehypothalamus,asmeasuredby the induction of Fos protein. Similarly, exposure of mice to 30 min of restraint increased serum CORT concentrations, but did not produce a consistent, statistically significant increase in Fos expression within the PVN. However, pretreatment of mice with SR141716 before restraint stress robustly potentiated restraint-induced CORT release and Fos expression within the PVN. Pretreatment of mice with either the CB1 receptor agonist CP55940, the eCB transport inhibitor AM404, or the fatty acid amide hydrolase inhibitor URB597 significantly decreased or eliminated restraint-induced CORT release. Upon exposure to acute restraint, hypothalamic 2-arachidonylglycerol content was reduced compared with the control value; however, afte r5do frestraint exposure (which resulted in an attenuated CORT response), the hypothalamic 2-arachidonylglycerol content was increased compared with the control value. These data indicate that eCB signaling negatively modulates HPA axis function in a context-dependent manner and suggest that pharmacological augmentation of eCB signaling could serve as a novel approach to the treatment of anxiety-related disorders. (Endocrinology 145: 5431–5438, 2004)
TL;DR: It is reported that chronic central administration of KiSS‐1 peptide to immature female rats induced the precocious activation of the gonadotrophic axis, as estimated by advanced vaginal opening, elevated uterus weight, and increased serum levels of luteinizing hormone (LH) and oestrogen.
Abstract: The awakening of the gonadotrophic axis at puberty is the end-point of a complex cascade of sex developmental events that leads to the attainment of reproductive capacity. Recently, loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been linked to hypogonadotrophic hypogonadism, both in rodents and humans. However, the actual role of the KiSS-1/GPR54 system in the timing of puberty onset remains unexplored. We report herein that chronic central administration of KiSS-1 peptide to immature female rats induced the precocious activation of the gonadotrophic axis, as estimated by advanced vaginal opening, elevated uterus weight, and increased serum levels of luteinizing hormone (LH) and oestrogen. The central effect of KiSS-1 upon LH release appeared to be mediated via the hypothalamic LH-releasing hormone. In contrast, despite the well-documented permissive role of body fat stores and the adipocyte-derived hormone leptin in puberty maturation, acute activation of the gonadotrophic axis by KiSS-1 was persistently observed in pubertal animals under food deprivation, after central immunoneutralization of leptin, and in a model of leptin resistance. Overall, the present results, together with our recent data on maximum expression of KiSS-1 and GPR54 genes in the hypothalamus at puberty, provide novel evidence for a role of the KiSS-1 system as a downstream element in the hypothalamic network triggering the onset of puberty.
TL;DR: Rat ARC neurons containing neuropeptide Y and agouti-related protein, which are conditional pacemakers, are activated by orexigens and inhibited by the anorexigen leptin to propose a neuron-specific signaling mechanism through which central and peripheral signals engage the central neural anabolic drive.
Abstract: The hypothalamic arcuate nucleus (ARC) integrates and responds to satiety and hunger signals and forms the origins of the central neural response to perturbations in energy balance. Here we show that rat ARC neurons containing neuropeptide Y (NPY) and agouti-related protein (AgRP), which are conditional pacemakers, are activated by orexigens and inhibited by the anorexigen leptin. We propose a neuron-specific signaling mechanism through which central and peripheral signals engage the central neural anabolic drive.
TL;DR: The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.
Abstract: Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc-/- mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc-/- mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc-/- and Pomc+/- mice. The effects of leptin on food intake and body weight were blunted in obese Pomc-/- mice whereas nonobese Pomc-/- mice were sensitive to leptin. Surprisingly, we found that Pomc-/- mice maintained their acute anorectic response to peptide-YY3-36 (PYY3-36). However, 7 days of PYY3-36 administration had no effect on cumulative food intake or body weight in wild-type or Pomc-/- mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY3-36 or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.
TL;DR: Data demonstrate that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release, indicating that AVP and apelin are conversely regulated to facilitate systemic AVPrelease and suppress diuresis.
Abstract: Apelin, a recently isolated neuropeptide that is expressed in the supraoptic and the paraventricular nuclei, acts on specific receptors located on vasopressinergic neurons. The increased phasic pattern of these neurons facilitates sustained antidiuresis during dehydration or lactation. Here, we investigated whether apelin interacts with arginine vasopressin (AVP) to maintain body fluid homeostasis. We first characterized the predominant molecular forms of endogenous hypothalamic and plasma apelin as corresponding to apelin 13 and, to a lesser extent, to apelin 17. We then demonstrated that, in lactating rats, apelin was colocalized with AVP in supraoptic nucleus magnocellular neurons and given intracerebroventricularly inhibited the phasic electrical activity of AVP neurons. In lactating mice, intracerebroventricular administration of apelin 17 reduced plasma AVP levels and increased diuresis. Moreover, water deprivation, which increases systemic AVP release and causes depletion of hypothalamic AVP stores, decreased plasma apelin concentrations and induced hypothalamic accumulation of the peptide, indicating that AVP and apelin are conversely regulated to facilitate systemic AVP release and suppress diuresis. Opposite effects of AVP and apelin are likely to occur at the hypothalamic level through autocrine modulation of the phasic electrical activity of AVP neurons. Altogether, these data demonstrate that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. The coexistence of apelin and AVP in magnocellular neurons, their opposite biological effects, and regulation are likely to play a key role for maintaining body fluid homeostasis.
TL;DR: The results indicate that the BSTal and BSTsc are parts of the same cell group, which plays a role in coordinating visceral and somatic motor responses (during ingestive behaviors, for example), especially in response to noxious stimuli.
Abstract: The anterolateral group of the bed nuclei of the stria terminalis (BSTalg) contains four distinct cell groups embedded within an undifferentiated anterolateral area (BSTal) that architectonically resembles a subjacent subcommissural zone (BSTsc). The overall distributions of axonal projections from various regions of the BSTal and from the BSTsc were determined with the Phaseolus vulgaris-leucoagglutinin (PHAL) anterograde tracer method and found to be identical. The BSTal and BSTsc share dense bidirectional connections, and also project heavily within the BST to the rhomboid and fusiform nuclei and the anteroventral and anterodorsal areas. They project less densely to the juxtacapsular, oval, magnocellular, ventral, and interfascicular BST nuclei. Outside the BST, brain areas receiving strong to moderate inputs from the BSTal and BSTsc fall into several functional groups: somatomotor system (nucleus accumbens, substantia innominata, ventral tegmental area, and retrorubral area and adjacent midbrain reticular nucleus), central autonomic control system (central amygdalar nucleus, dorsal lateral hypothalamic area, ventrolateral periaqueductal gray, parabrachial nucleus, and nucleus of the solitary tract), neuroendocrine system (paraventricular and supraoptic nuclei, hypothalamic visceromotor pattern generator network), and thalamocortical feedback loops (midline, medial, and intralaminar nuclei). The results indicate that the BSTal and BSTsc are parts of the same cell group (dorsal and ventral to the anterior commissure), which plays a role in coordinating visceral and somatic motor responses (during ingestive behaviors, for example), especially in response to noxious stimuli (learned anorexia associated with noxious stimuli). BSTal projections are distinct from those of the adjacent juxtacapsular, oval, fusiform, and rhomboid nuclei.
TL;DR: It is suggested that release of oxytocin from a descending pPVN-to-NTS pathway contributes to leptin's attenuation of food intake by a mechanism that involves the activation of pPvN oxytoc in neurons by leptin, resulting in increased sensitivity of NTS neurons to satiety signals.
Abstract: Hindbrain projections of oxytocin neurons in the parvocellular paraventricular nucleus (pPVN) are hypothesized to transmit leptin signaling from the hypothalamus to the nucleus of the solitary trac...
TL;DR: Modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the amygdala, which regulates feeding behavior and mediates the anorexic effects of C75.
TL;DR: Structural data may be interpreted to suggest that the bed nuclei posterior division forms part (pallidal) of a corticostriatopallidal system involved in controlling two major classes of social (defensive and reproductive) behavior.
Abstract: The posterior division of the bed nuclei of the stria terminalis has three major nuclei: principal, interfascicular, and transverse, which receive topographically ordered inputs from the medial amygdalar nucleus The overall pattern of axonal projections from each nucleus was determined in male rats with the Phaseolus vulgaris-leucoagglutinin method Together, these nuclei project topographically back to the medial amygdalar nucleus, to the adjacent lateral septal nucleus, to the nucleus accumbens and substantia innominata, to hypothalamic parts of the behavior control column, and to the hypothalamic periventricular region, which controls patterned neuroendocrine and autonomic responses The principal nucleus preferentially innervates septal and hypothalamic regions that control reproductive behavior and visceromotor responses, confirming a similar analysis by Gu et al (J Comp Neurol [2003] 460:542-562) In contrast, the interfascicular and transverse nuclei differentially innervate septal and hypothalamic regions that control defensive as well as reproductive behaviors In addition, the transverse nucleus projects significantly to midbrain parts of the behavior control column concerned with foraging/exploratory behavior All three posterior division nuclei also project to thalamocortical feedback loops (by means of the nucleus reuniens and paraventricular nucleus) These structural data may be interpreted to suggest that the bed nuclei posterior division forms part (pallidal) of a corticostriatopallidal system involved in controlling two major classes of social (defensive and reproductive) behavior
TL;DR: It appears that hypothalamic leptin resistance, possibly due to defective nutritional regulation of leptin receptor expression and/or reduced STAT3 signaling in the hypothalamus, contributes to the development of obesity associated with high-fat feeding and aging.
Abstract: The hypothalamus is a major site for integration of central and peripheral signals that regulate energy homeostasis. Within the hypothalamus, neurons residing in the ARC (arcuate nucleus)-PVN (paraventricular)-PF/LH (perifornical/ lateral hypothalamus) axis communicate among each other and are subjected to the influence of several peripheral factors, including leptin and insulin. Proper signaling in the hypothalamus by leptin, a long-sought peripheral factor that relays the status of fat stores, is critical to normal regulation of food intake and body weight. Leptin action in the hypothalamus is mediated by a large number of orexigenic and anorectic peptide-producing neurons of the ARC-PVN-PF/LH axis. Not only the classical JAK2 (Janus kinase 2)-STAT3 (signal transducer and activator of transcription 3) pathway, but also the phosphatidylinositol-3 kinase-phosphodiesterase 3BcAMP pathway mediates hypothalamic leptin receptor signaling. It appears that hypothalamic leptin resistance, possibly due to defective nutritional regulation of leptin receptor expression and/or reduced STAT3 signaling in the hypothalamus, contributes to the development of obesity associated with high-fat feeding and aging. Interestingly, hypothalamic neurons may develop leptin resistance despite an intact JAK2STAT3 signaling path. The role of suppressor of cytokine signaling 3 and other negative regulators of leptin signaling in central leptin resistance needs to be established, an important area of future investigation. Further understanding of the neural circuitry and leptin signaling in the hypothalamus is critical not only for the advancement of our knowledge on the hypothalamic role in energy balance but also for future development of drugs for the attenuation or treatment of obesity and related disorders in humans. (Endocrinology 145: 2613–2620, 2004)
TL;DR: A preexisting reduction in hypothalamic but not brain stem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased.
Abstract: Rats selectively bred to develop diet-induced obesity (DIO) were compared with those bred to be diet resistant (DR) on a 31% fat high-energy diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15 mg/kg ip) into lean 4- to 5-wk-old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21, 63, and 64% less leptin-induced immunoreactive phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24-h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4- to 5-wk-old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23 wk of age on low-fat chow or after 6 wk on high-energy diet. In addition, leptin receptor mRNA expression was 23% lower in the arcuate nuclei of 4- to 5-wk-old DIO compared with DR rats. Thus a preexisting reduction in hypothalamic but not brain stem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased. Defects in leptin transport appear to be an acquired defect associated with the development of obesity and possibly age.
TL;DR: Data suggest that ARC glucose-excited neurons may serve an integrative role in the regulation of energy balance and the glucokinase inhibitor alloxan increases KATP single-channel currents in glucose- Excited neurons in a manner similar to low glucose.
Abstract: Glucosensing neurons in the hypothalamic arcuate nucleus (ARC) were studied using electrophysiological and immunocytochemical techniques in neonatal male Sprague-Dawley rats. We identified glucose-excited and -inhibited neurons, which increase and decrease, respectively, their action potential frequency (APF) as extracellular glucose levels increase throughout the physiological range. Glucose-inhibited neurons were found predominantly in the medial ARC, whereas glucose-excited neurons were found in the lateral ARC. ARC glucose-excited neurons in brain slices dose-dependently increased their APF and decreased their ATP-sensitive K+ channel (KATP channel) currents as extracellular glucose levels increased from 0.1 to 10 mmol/l. However, glucose sensitivity was greatest as extracellular glucose decreased to <2.5 mmol/l. The glucokinase inhibitor alloxan increases KATP single-channel currents in glucose-excited neurons in a manner similar to low glucose. Leptin did not alter the activity of ARC glucose-excited neurons. Although insulin did not affect ARC glucose-excited neurons in the presence of 2.5 mmol/l (steady-state) glucose, they were stimulated by insulin in the presence of 0.1 mmol/l glucose. Neuropeptide Y (NPY) inhibited and alpha-melanocyte-stimulating hormone stimulated ARC glucose-excited neurons. ARC glucose-excited neurons did not show pro-opiomelanocortin immunoreactivity. These data suggest that ARC glucose-excited neurons may serve an integrative role in the regulation of energy balance.
TL;DR: It seems the psychogenic responses to stress are gated by discrete sets of GABAergic neurons in the basal forebrain and hypothalamus, which may play a major role in HPA dysfunction seen in affective disease states and aging.
Abstract: GABA and glutamate play a major role in central integration of hypothalamo-pituitary-adrenocortical (HPA) stress responses. Recent work in our group has focused on mechanisms whereby GABAergic and glutamatergic circuits interact with parvocellular paraventricular nucleus (PVN) neurons controlling the HPA axis. GABAergic neurons in the bed nucleus of the stria terminalis, preoptic area, and hypothalamus can directly inhibit PVN outflow and thereby reduce ACTH secretion. In contrast, glutamate activates the HPA axis, presumably by way of hypothalamic and brainstem projections to the PVN. These inhibitory and excitatory PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including glutamatergic neurons of the ventral subiculum, prefrontal cortex, and GABAergic cells from the amygdala and perhaps septum. Lesion studies indicate that the ventral subiculum and prefrontal cortex are involved in inhibition of HPA axis responses to psychogenic stimuli, whereas the amygdala is positioned to enhance hormone secretion by way of GABA-GABA disinhibitory connections. Thus, it seems the psychogenic responses to stress are gated by discrete sets of GABAergic neurons in the basal forebrain and hypothalamus. As such, these neurons are positioned to summate limbic inputs into net inhibitory tone on the PVN and may thus play a major role in HPA dysfunction seen in affective disease states and aging.
TL;DR: The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/depression.
TL;DR: The results support the role of the PH in the nociceptive processing of meningeal input as orexinergic mechanisms in the PH may provide a link for endocrine and autonomic changes as well as nocICEptive phenomena seen in primary headache disorders.
Abstract: The novel neuropeptides orexin A and B are selectively synthesised in the lateral and posterior hypothalamus and are involved in hypothalamic regulation of autonomic and neuroendocrine functions. Recent findings point also to a role in nociception. As the posterior hypothalamus is involved in the central modulation of nociception we studied the effects of hypocretin/orexin receptor activation in the posterior hypothalamic area (PH) of the rat on dural nociceptive input. Orexins were microinjected into the PH and the effects on responses of neurones in the caudal trigeminal nucleus studied. Injection of orexin A decreased the A- and C-fibre responses to dural electrical stimulation as well as spontaneous activity. Responses to noxious thermal stimulation of the facial skin were also decreased by orexin A. Injection of orexin B into the PH, however, elicited increased responses to dural stimulation in A- and C-fibre responses and resulted in increased spontaneous activity. Responses to facial thermal stimulation were also increased by orexin B. Control injection of saline into the PH had no significant effect. The results show a differential modulation of dural nociceptive input by orexin A and B receptor activation in the PH. The results support the role of the PH in the nociceptive processing of meningeal input. As both peptides are also involved in hypothalamic regulation of neuroendocrine and autonomic functions, orexinergic mechanisms in the PH may provide a link for endocrine and autonomic changes as well as nociceptive phenomena seen in primary headache disorders.
TL;DR: Evidence for the existence of a similar network of neurons in the NTS and a model by which this information from the ARC and NTS centers may be integrated directly or via adipostatic centers such as the paraventricular nucleus of the hypothalamus (PVH).
Abstract: The importance of the central melanocortin system in the regulation of energy balance is highlighted by studies in transgenic animals and humans with defects in this system Mice that are engineered to be deficient for the melanocortin-4 receptor (MC4R) or pro-opiomelanocortin (POMC) and those that overexpress agouti or agouti-related protein (AgRP) all have a characteristic obese phenotype typified by hyperphagia, increased linear growth, and metabolic defects Similar attributes are seen in humans with haploinsufficiency of the MC4R The central melanocortin system modulates energy homeostasis through the actions of the agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), a POMC cleavage product, and the endogenous antagonist AgRP on the MC3R and MC4R POMC is expressed at only two locations in the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the tractus solitarius (NTS) of the brainstem This chapter will discuss these two populations of POMC neurons and their contribution to energy homeostasis We will examine the involvement of the central melanocortin system in the incorporation of information from the adipostatic hormone leptin and acute hunger and satiety factors such as peptide YY (PYY(3-36)) and ghrelin via a neuronal network involving POMC/cocaine and amphetamine-related transcript (CART) and neuropeptide Y (NPY)/AgRP neurons We will discuss evidence for the existence of a similar network of neurons in the NTS and propose a model by which this information from the ARC and NTS centers may be integrated directly or via adipostatic centers such as the paraventricular nucleus of the hypothalamus (PVH)
TL;DR: It is demonstrated that orexins directly regulate NPY, POMC and glucose‐responsive neurons in the ARC and VMH, in a manner reciprocal to leptin, as well as neural pathways and intracellular signaling mechanisms that may play key roles in the orexigenic action of orexlins.
Abstract: Orexin-A and -B (hypocretin-1 and -2) have been implicated in the stimulation of feeding. Here we show the effector neurons and signaling mechanisms for the orexigenic action of orexins in rats. Immunohistochemical methods showed that orexin axon terminals contact with neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-positive neurons in the arcuate nucleus (ARC) of the rats. Microinjection of orexins into the ARC markedly increased food intake. Orexins increased cytosolic Ca 2 + concentration ([Ca 2 + ] i ) in the isolated neurons from the ARC, which were subsequently shown to be immunoreactive for NPY. The increases in [Ca 2 + ] i were inhibited by blockers of phospholipase C (PLC), protein kinase C (PKC) and Ca 2 + uptake into endoplasmic reticulum. The stimulation of food intake and increases in [Ca 2 + ] i in NPY neurons were greater with orexin-A than with orexin-B, indicative of involvement of the orexin-1 receptor (OX 1 R). In contrast, orexin-A and -B equipotently attenuated [Ca 2 + ] i oscillations and decreased [Ca 2 + ] i levels in POMC-containing neurons. These effects were counteracted by pertussis toxin, suggesting involvement of the orexin-2 receptor and Gi/Go subtypes of GTP-binding proteins. Orexins also decreased [Ca 2 + ] i levels in glucose-responsive neurons in the ventromedial hypothalamus (VMH), a satiety center. Leptin exerted opposite effects on these three classes of neurons. These results demonstrate that orexins directly regulate NPY, POMC and glucose-responsive neurons in the ARC and VMH, in a manner reciprocal to leptin. Orexin-A evokes Ca 2 + signaling in NPY neurons via OX 1 R-PLC-PKC and IP 3 pathways. These neural pathways and intracellular signaling mechanisms may play key roles in the orexigenic action of orexins.
TL;DR: In this article, the authors showed that the daily rise in plasma glucose concentrations is caused by an SCN-mediated withdrawal of GABAergic inputs to sympathetic preautonomic neurons in the paraventricular nucleus of the hypothalamus, resulting in an increased hepatic glucose production.
Abstract: Daily peak plasma glucose concentrations are attained shortly before awakening. Previous experiments indicated an important role for the biological clock, located in the suprachiasmatic nuclei (SCN), in the genesis of this anticipatory rise in plasma glucose concentrations by controlling hepatic glucose production. Here, we show that stimulation of NMDA receptors, or blockade of GABA receptors in the paraventricular nucleus of the hypothalamus (PVN) of conscious rats, caused a pronounced increase in plasma glucose concentrations. The local administration of TTX in brain areas afferent to the PVN revealed that an important part of the inhibitory inputs to the PVN was derived from the SCN. Using a transneuronal viral-tracing technique, we showed that the SCN is connected to the liver via both branches of the autonomic nervous system (ANS). The combination of a blockade of GABA receptors in the PVN with selective removal of either the sympathetic or parasympathetic branch of the hepatic ANS innervation showed that hyperglycemia produced by PVN stimulation was primarily attributable to an activation of the sympathetic input to the liver. We propose that the daily rise in plasma glucose concentrations is caused by an SCN-mediated withdrawal of GABAergic inputs to sympathetic preautonomic neurons in the PVN, resulting in an increased hepatic glucose production. The remarkable resemblance of the presently proposed control mechanism to that described previously for the control of daily melatonin rhythm suggests that the GABAergic control of sympathetic preautonomic neurons in the PVN is an important pathway for the SCN to control peripheral physiology.
TL;DR: Previous findings of sex differences in brain E(2) levels perinatally are corroborated and extended and reveal an unexpected regional heterogeneity in E( 2) synthesis and/or metabolism.
Abstract: Accurate assessment of gonadal steroid levels in the developing brain is critical for understanding naturally occurring steroid-mediated sexual differentiation as well as determining the physiological relevance of exogenous steroid treatments commonly used in the study of this phenomenon Using RIA, we measured the estradiol (E(2)) content of six regions of the developing brain immediately post partum, 1 d post partum, and after injection of exogenous estradiol benzoate, testosterone propionate, or the aromatase inhibitor formestane We found sexually dimorphic E(2) content in several regions of the newborn brain At 2 h of life, there was significantly higher E(2) content in males vs females in the frontal cortex, hypothalamus and preoptic area but not in the hippocampus, brainstem, or cerebellum Surprisingly, the female hippocampus had significantly higher E(2) content than all other female regions examined By d 1 post partum, E(2) levels had decreased precipitously in most brain regions, and only the hypothalamus maintained a sex difference Injection of female pups with estradiol benzoate raised tissue levels to that of the male in the hypothalamus but 2- to 3-fold higher in the other five regions Testosterone administration increased E(2) content exclusively in the preoptic area, suggesting local variation in aromatase activity and/or substrate availability Central administration of formestane decreased estrogen content in the male cortex, hypothalamus, and preoptic area Formestane treatment also decreased endogenous E(2) in female cortex and hippocampus, suggesting de novo synthesis selectively in these brain regions These data corroborate and extend previous findings of sex differences in brain E(2) levels perinatally and reveal an unexpected regional heterogeneity in E(2) synthesis and/or metabolism
TL;DR: This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness and suggests that this alteration in pulsatility is important for the differences in stress responsiveness when comparing males and females.
Abstract: Enhanced corticosterone release by female compared to male rats under basal and stress conditions is well documented. The demonstration that gonadectomy enhances stress-induced corticosterone secretion in male rats, but reduces such levels in female rats, suggests a causal association between gonadal steroids and corticosterone release. The present study examined the corticosterone profile of sham gonadectomized and gonadectomized female and male rats under basal and stress conditions. An automated sampling system collected blood from each freely moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide, LPS). Plasma was analysed for corticosterone content using radioimmunoassay. Castration resulted in a significant increase in basal corticosterone release compared to the sham-castrated male rats. Pulsar analysis revealed a significant two-fold increase in the number of corticosterone pulses over 24 h. Corticosterone increases in response to noise stress and to LPS injection were enhanced following castration. Conversely, ovariectomy resulted in a two-fold reduction in the number of corticosterone pulses as well as the stress response compared to shamovariectomized female rats. Arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary were analysed post-LPS administration by in situ hybridization. Significantly higher values were found for AVP, CRH and POMC mRNAs examined for sham females and castrated males compared to sham males and ovariectomized females. This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness. The present results extend these observations to the regulation of the dynamic pattern of corticosterone release under basal conditions and suggests that this alteration in pulsatility is important for the differences in stress responsiveness when comparing males and females. Circadian variation in basal levels of corticosterone in the rat (cortisol in the human) is widespread across species and has been particularly well studied in rats (1) and humans (2). In nocturnal rats, this rhythm is characterized by peak corticosterone levels in the evening (waking phase) and a trough 12 h later (sleeping phase) (3). In humans, who sleep at night, this pattern is reversed. In times of psychological or physical stress, corticosterone secretion in rats is increased above basal levels due to enhanced activation of the hypothalamicpituitary-adrenal (HPA) axis. There is increased secretion of adrenocorticotrophic hormone (ACTH) driving the heightened corticosterone release and a subsequent increase in production of hypothalamic corticotrophin-releasing hor