The evolution of organic material on Asteroid 162173 Ryugu and its delivery to Earth.

The recent return of samples from asteroid 162173 Ryugu provides a first insight into early Solar System prebiotic evolution from known planetary bodies. Ryugu's samples are CI chondrite-like, rich in water and organic material, and primarily composed of phyllosilicate. This phyllosilicate surrounds micron to submicron macromolecular organic particles known as insoluble organic matter. Using advanced microscopy techniques on Hayabusa-2 samples, we find that aqueous alteration on Ryugu produced organic particles richer in aromatics compared to less altered carbonaceous chondrites. This challenges the view that aromatic-rich organic matter formed pre-accretion. Additionally, widespread diffuse organic material occurs in phyllosilicate more aliphatic-, carboxylic-rich, and aromatic-poor than the discrete organic particles, likely preserving the soluble organic material. Some organic particles evolved to encapsulate phyllosilicate, indicating that aqueous alteration on Ryugu led to the containment of soluble organic matter within these particles. Earth therefore has been, and continues to be, delivered micron-sized polymeric organic objects containing biologically relevant molecules.

Pebbles and sand on asteroid (162173) Ryugu: In situ observation and particles returned to Earth.

The Hayabusa2 spacecraft investigated the C-type (carbonaceous) asteroid (162173) Ryugu. The mission performed two landing operations to collect samples of surface and subsurface material, the latter exposed by an artificial impact. We present images of the second touchdown site, finding that ejecta from the impact crater was present at the sample location. Surface pebbles at both landing sites show morphological variations ranging from rugged to smooth, similar to Ryugu's boulders, and shapes from quasi-spherical to flattened. The samples were returned to Earth on 6 December 2020. We describe the morphology of >5 grams of returned pebbles and sand. Their diverse color, shape, and structure are consistent with the observed materials of Ryugu; we conclude that they are a representative sample of the asteroid.

Nesfatin-1 ameliorates type-2 diabetes-associated reproductive dysfunction in male mice.

PURPOSE: The present study was aimed to demonstrate the recuperative effect of nesfatin-1 on testicular dysfunction in the high-fat diet (HFD)/streptozotocin (STZ)-induced type-2 diabetes mellitus (T2DM) mice. METHOD AND RESULTS: Three experimental groups were formed: (1) vehicle control (VC), (2) T2DM mice, (3) T2DM + nesf-1. The mice with blood glucose level higher than 300 mg/dL following HFD and a single dose of STZ were used for the experiment. The T2DM mice showed increases in body mass, blood glucose and insulin levels, reductions in spermatogenesis and steroidogenesis, production of antioxidative enzymes, and disturbed lipid profile. These alterations were all ameliorated by administration of nesfatin-1 at 20 µg/Kg BW for 15 days. Nesfatin-1 treatment also increased the production of testosterone (T), improved insulin sensitivity, and effectively ameliorated the testicular aberrations, and increased spermatogenesis and steroidogenesis. In addition, nesfatin-1 treatment upregulated the PCNA and Bcl2 expression and inhibited the caspase-3 and prohibitin expression in T2DM mice. Nesfatin-1 increased insulin receptor (IR) and GLUT8 expressions, and lactate production, the changes that further substantiate the increase of energy influx to the testis. CONCLUSION: Altogether, the results suggest the ameliorative effect of nesfatin-1 against T2DM-associated testicular dysfunctions and improved insulin sensitivity along with promoting T production and fertility in T2DM mice.

Thermal and impact histories of 25143 Itokawa recorded in Hayabusa particles.

Understanding the origin and evolution of near-Earth asteroids (NEAs) is an issue of scientific interest and practical importance because NEAs are potentially hazardous to the Earth. However, when and how NEAs formed and their evolutionary history remain enigmas. Here, we report the U-Pb systematics of Itokawa particles for the first time. Ion microprobe analyses of seven phosphate grains from a single particle provide an isochron age of 4.64 ± 0.18 billion years (1σ). This ancient phosphate age is thought to represent the thermal metamorphism of Itokawa's parent body, which is identical to that of typical LL chondrites. In addition, the incorporation of other particles suggests that a significant shock event might have occurred 1.51 ± 0.85 billion years ago (1σ), which is significantly different from the shock ages of 4.2 billion years of the majority of shocked LL chondrites and similar to that of the Chelyabinsk meteorite. Combining these data with recent Ar-Ar studies on particles from a different landing site, we conclude that a globally intense impact, possibly a catastrophic event, occurred ca. 1.4 Ga ago. This conclusion enables us to establish constraints on the timescale of asteroid disruption frequency, the validity of the crater chronology and the mean lifetime of small NEAs.

Weaning stage hyperglycemia induces glucose-insensitivity in arcuate POMC neurons and hyperphagia in type 2 diabetic GK rats.

Hyperphagia triggers and accelerates diabetes, and prevents proper dietary control of glycemia. Inversely, the impact of hyperglycemia on hyperphagia and possible mechanistic cause common for these two metabolic disorders in type 2 diabetes are less defined. The present study examined the precise developmental process of hyperglycemia and hyperphagia and explored the alterations in the hypothalamic arcuate nucleus (ARC), the primary feeding and metabolic center, in Goto-Kakizaki (GK) rats with type 2 diabetes and nearly normal body weight. At mid 3 to 4 weeks of age, GK rats first exhibited hyperglycemia, and then hyperphagia and reduced mRNA expressions for anorexigenic pro-opiomelanocortin (POMC) and glucokinase in ARC. Furthermore, [Ca2+]i responses to high glucose in ARC POMC neurons were impaired in GK rats at 4 weeks. Treating GK rats from early 3 to mid 6 weeks of age with an anti-diabetic medicine miglitol not only suppressed hyperglycemia but ameliorated hyperphagia and restored POMC mRNA expression in ARC. These results suggest that the early hyperglycemia occurring in weaning period may lead to impaired glucose sensing and neuronal activity of POMC neurons, and thereby induce hyperphagia in GK rats. Correction of hyperglycemia in the early period may prevent and/or ameliorate the progression of hyperphagia in type 2 diabetes.

Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin.

BACKGROUND: Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN: Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

Seasonal changes in gene expression of corticoid receptors in anadromous and non-anadromous strains of rainbow trout Oncorhynchus mykiss.

To clarify the regulation of expression of corticoid receptor (CR) genes during period of parr-smolt transformation of salmonids, seasonal changes in mRNA levels of glucocorticoid receptor (GR)-1, GR-2 and mineralocorticoid receptor (MR) were examined in gill, leucocytes, spleen and brain of anadromous and non-anadromous forms of Oncorhynchus mykiss. Increases in gill Na(+) , K(+) ATPase activity, plasma thyroxine levels and hypo-osmoregulatory ability assessed by 24 h seawater challenge test represented characteristics of smoltification in anadromous O. mykiss from May to June, whereas there was no apparent increase in the values of non-anadromous O. mykiss. Plasma cortisol levels of anadromous O. mykiss were higher than levels of non-anadromous O. mykiss from April to June. In gill of non-anadromous O. mykiss, there were significant increases in mRNA levels of three types of CR in spring. Although there were significant seasonal variations of CR mRNA levels in gill of anadromous O. mykiss, they appear to be less clear than those variations in non-anadromous O. mykiss. In anadromous O. mykiss, significant elevations in mRNA levels of the three types of CR were observed especially in the spleen. In both preoptic area and basal hypothalamus of the brain, there were tendencies to increase in CR mRNA levels from spring to summer in both anadromous and non-anadromous O. mykiss. These results showed difference in regulation of CR gene expression between the two forms of O. mykiss for osmoregulatory, immune and central nervous systems.

Ghrelin signalling in ß-cells regulates insulin secretion and blood glucose.

Insulin secretion from pancreatic islet ß-cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach in 1999 as the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in the stomach and to a lesser extent in the intestine, pancreas and brain. Ghrelin, initially identified as a potent stimulator of GH release and feeding, has been shown to suppress glucose-induced insulin release. This insulinostatic action is mediated by Gα(i2) subtype of GTP-binding proteins and delayed outward K⁺ (Kv) channels. Interestingly, ghrelin is produced in pancreatic islets. The ghrelin originating from islets restricts insulin release and thereby upwardly regulates the systemic glucose level. Furthermore, blockade or elimination of ghrelin enhances insulin release, which can ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the insulinostatic action of ghrelin, its signal transduction mechanisms in islet ß-cells, ghrelin's status as an islet hormone, physiological roles of ghrelin in regulating systemic insulin levels and glycaemia, and therapeutic potential of the ghrelin-GHS-R system as the target to treat type 2 diabetes.

Predictive value of endoscopic findings in the diagnosis of active intestinal amebiasis.

Endoscopic diagnosis of amebic colitis can be difficult because its appearance may mimic other forms of colonic disease. The aim of this study was to identify predictive endoscopic findings for amebic colitis. Patients with suspected amebic colitis based on distinctive endoscopic findings such as aphthae or erosions, ulcers, exudates, or a bump, were included in the study. A total of 157 patients were selected, 50 of whom had amebic colitis. The sensitivity and specificity of endoscopic findings that were significantly associated with amebic colitis were: cecal lesions (80% and 54%), multiple number of lesions (96% and 29%), presence of aphthae or erosions (84% and 37%), and presence of exudate (88% and 74%). Multivariate analysis revealed that the best combination of findings to predict amebic colitis was the presence of cecal lesions, multiple lesions, and exudates, which corresponded to an area under the receiver operating characteristic curve of 0.89 (95% confidence interval 0.82-0.95).

Physiological and molecular endocrine changes in maturing wild sockeye salmon, Oncorhynchus nerka, during ocean and river migration.

Maturing adult sockeye salmon Oncorhynchus nerka were intercepted while migrating in the ocean and upstream in freshwater over a combined distance of more than 1,300 km to determine physiological and endocrine changes associated with ionoregulation. Sockeye migrating through seawater and freshwater showed consistent declines in gill Na+/K+ -ATPase (NKA) activity, plasma osmolality and plasma chloride concentration. In contrast, plasma sodium concentration became elevated in seawater as fish approached the river mouth and was then restored after sockeye entered the river. Accompanying the movement from seawater to freshwater was a significant increase in mRNA for the NKA α1a subunit in the gill, with little change in the α1b subunit. Potential endocrine signals stimulating the physiological changes during migration were assessed by measuring plasma cortisol and prolactin (Prl) concentrations and quantifying mRNA extracted from the gill for glucocorticoid receptors 1 and 2 (GR1 and GR2), mineralocorticoid receptor (MR), growth hormone 1 receptor (GH1R), and prolactin receptor (PrlR). Plasma cortisol and prolactin concentrations were high in seawater suggesting a preparatory endocrine signal before freshwater entry. Generally, the mRNA expression for GR1, GR2 and MR declined during migration, most notably after fish entered freshwater. In contrast, PrlR mRNA increased throughout migration, particularly as sockeye approached the spawning grounds. A highly significant association existed between gill PrlR mRNA and gill NKA α1a mRNA. GH1R mRNA also increased significantly, but only after sockeye had migrated beyond tidal influence in the river and then again just before the fish reached the spawning grounds. These findings suggest that cortisol and prolactin stimulate ionoregulation in the gill as sockeye salmon adapt to freshwater.

Incipient space weathering observed on the surface of Itokawa dust particles.

The reflectance spectra of the most abundant meteorites, ordinary chondrites, are different from those of the abundant S-type (mnemonic for siliceous) asteroids. This discrepancy has been thought to be due to space weathering, which is an alteration of the surfaces of airless bodies exposed to the space environment. Here we report evidence of space weathering on particles returned from the S-type asteroid 25143 Itokawa by the Hayabusa spacecraft. Surface modification was found in 5 out of 10 particles, which varies depending on mineral species. Sulfur-bearing Fe-rich nanoparticles exist in a thin (5 to 15 nanometers) surface layer on olivine, low-Ca pyroxene, and plagioclase, which is suggestive of vapor deposition. Sulfur-free Fe-rich nanoparticles exist deeper inside (<60 nanometers) ferromagnesian silicates. Their texture suggests formation by metamictization and in situ reduction of Fe(2+).

Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.

Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.

Long-term infusion of brain-derived neurotrophic factor reduces food intake and body weight via a corticotrophin-releasing hormone pathway in the paraventricular nucleus of the hypothalamus.

Brain-derived neurotrophic factor (BDNF) has been implicated in learning, depression and energy metabolism. However, the neuronal mechanisms underlying the effects of BDNF on energy metabolism remain unclear. The present study aimed to elucidate the neuronal pathways by which BDNF controls feeding behaviour and energy balance. Using an osmotic mini-pump, BDNF or control artificial cerebrospinal fluid was infused i.c.v. at the lateral ventricle or into the paraventricular nucleus of the hypothalamus (PVN) for 12 days. Intracerebroventricular BDNF up-regulated mRNA expression of corticotrophin-releasing hormone (CRH) and urocortin in the PVN. TrkB, the receptor for BDNF, was expressed in the PVN neurones, including those containing CRH. Both i.c.v. and intra-PVN-administered BDNF decreased food intake and body weight. These effects of BDNF on food intake and body weight were counteracted by the co-administration of alpha-helical-CRH, an antagonist for the CRH and urocortin receptors CRH-R1/R2, and partly attenuated by a selective antagonist for CRH-R2 but not CRH-R1. Intracerebroventricular BDNF also decreased the subcutaneous and visceral fat mass, adipocyte size and serum triglyceride levels, which were all attenuated by alpha-helical-CRH. Furthermore, BDNF decreased the respiratory quotient and raised rectal temperature, which were counteracted by alpha-helical-CRH. These results indicate that the CRH-urocortin-CRH-R2 pathway in the PVN and connected areas mediates the long-term effects of BDNF to depress feeding and promote lipolysis.

Positional effects of polymorphisms in probe-target sequences on genoplot images of oligonucleotide microarrays.

Single nucleotide polymorphisms (SNPs) present in probe-target sequences (SPTS) have been shown to be associated with abnormal genoplot images. We explored the effects of SPTS positions on genoplot images using a data set from a genome-wide association study typed on an Illumina Human Hap300 platform. We screened the physical genomic positions of 308,330 autosomal probes to identify SPTS candidates deposited in dbSNP. The genoplot images across 293 individuals were inspected further in SNPs bearing an SPTS candidate. We identified 35,185 SNPs bearing a single SPTS candidate, including 264 SNPs showing abnormal genoplot images. The frequencies of SPTS at distances within 10 bases from the target SNP were significantly higher in the 264 SNPs showing abnormal genoplot images, than in the remaining 34,921 SNPs (49.62 vs 12.87%; Fisher exact test; P = 2.2 x 10(-16)). Of these 264 SNPs, we randomly selected 20 SNPs and resequenced them in 97 individuals. An SPTS within 10 bases of the target SNP was confirmed in all 20 SNPs, except for one SNP with a small deletion (7 bases) in the probe-target sequence. Taken together, these results suggest an association of a proximal SPTS with an abnormal genoplot image, which could result in spurious genotype detections, highlighting the importance of minimizing systematic errors in microarray experiments.

Effect of pituitary adenylate cyclase-activating polypeptide in islet transplantation.

INTRODUCTION: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an islet substance serving as an intra-islet amplifier of glucose-induced insulin secretion similar to exendin-4. It has been reported that systemic administration of PACAP maintained beta-cell mass, delayed the onset of hyperglycemia, and protected beta cells from glucose toxicity. Moreover, PACAP increases glucose-stimulated insulin release in vitro and in vivo. In this study, we investigated the possibility of PACAP use in human islet transplantation. METHODS: Human islets were cultured in the presence or absence of PACAP (10(-12) mol/L) for 48 hours. We assessed beta-cell viability using FACS, cellular composition analysis by iCys/LSC, and glucose-stimulated insulin secretion. In vivo, islets were transplanted beneath the kidney capsule of Streptozotocin-induced diabetic immunodeficient mice. An intravenous glucose tolerance test (IVGTT) was also performed in the presence or absence of PACAP (Peptide International, Louisville, Ky, United States; 1.3 nmol/kg). RESULTS: There were significant improvements in terms of beta-cell viability and cellular composition between islets cultured with or without PACAP, respectively (P < .05). Moreover, glucose-stimulated insulin secretion significantly improved in islets cultured with PACAP compared with controls, respectively (P < .05). Treatment of recipient mice with PACAP resulted in beneficial effects on insulin secretion (PACAP vs control, 13.2 vs 1.9 mU/L), in IVGTT. However, no significant difference was observed in glucose levels between the 2 groups. CONCLUSIONS: Our study indicated that PACAP significantly improved beta-cell viability and survival during culture, and increased insulin secretion in vitro and in vivo. However, blood glucose levels in vivo after an IVGTT did not significantly improve, probably due to increased glucagon secretion from alpha cells. PACAP supplementation to culture medium could be of assistance to improve clinical islet transplantation outcomes.

Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism.

Nesfatin-1 is a novel satiety molecule in the hypothalamus and is also present in peripheral tissues. Here we sought to identify the active segment of nesfatin-1 and to determine the mechanisms of its action after peripheral administration in mice. Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner. Nesfatin-1 has three distinct segments; we tested the effect of each segment on food intake. Injection of the midsegment decreased food intake under leptin-resistant conditions such as db/db mice and mice fed a high-fat diet. After injection of the midsegment, expression of c-Fos was significantly activated in the brainstem nucleus tractus solitarius (NTS) but not in the hypothalamic arcuate nucleus; the nicotinic cholinergic pathway to the NTS contributed to midsegment-induced anorexia. Midsegment injection significantly increased expression of proopiomelanocortin and cocaine- and amphetamine-regulated transcript genes in the NTS but not in the arcuate nucleus. Investigation of mutant midsegments demonstrated that a region with amino acid sequence similarity to the active site of agouti-related peptide was indispensable for anorexigenic induction. Our findings indicate that the midsegment of nesfatin-1 causes anorexia, possibly by activating POMC and CART neurons in the NTS via a leptin-independent mechanism after peripheral stimulation.

Reconstruction of transcription-translation dynamics with a model of gene networks.

A transcription-translation model of gene networks and a method to reconstruct it from gene expression data are proposed. The model is a hybrid system based on the Glass network with continuous-time dynamics and logical interactions. Transcription-translation dynamics is introduced into the Glass network. The reconstruction of gene networks is reduced to the problem of estimating logical functions from binary representations of quantities of mRNAs and proteins. The reconstruction method is applied to the gene expression data of circadian rhythms. The response characteristics of the reconstructed gene network to periodic stimuli are analyzed. The results suggest the existence of a receiver gene that responds to an external signal, consistently with biological knowledge.

Young adult-specific hyperphagia in diabetic Goto-kakizaki rats is associated with leptin resistance and elevation of neuropeptide Y mRNA in the arcuate nucleus.

The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.

Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats.

Leptin, an adipocytokine encoded by an obesity gene and expressed in adipose tissue, affects feeding behavior, thermogenesis, and neuroendocrine status via leptin receptors distributed in the brain, especially in the hypothalamus. Leptin may also modulate the synaptic plasticity and behavioral performance related to learning and memory since: leptin receptors are found in the hippocampus, and both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines that modulate long-term potentiation (LTP) in the hippocampus. We therefore examined the effect of leptin on (1) behavioral performance in emotional and spatial learning tasks, (2) LTP at Schaffer collateral-CA1 synapses, (3) presynaptic and postsynaptic activities in hippocampal CA1 neurons, (4) the intracellular Ca(2+) concentration ([Ca(2+)](i)) in CA1 neurons, and (5) the activity of Ca(2+)/calmodulin protein kinase II (CaMK II) in the hippocampal CA1 tissue that exhibits LTP. Intravenous injection of 5 and/or 50mug/kg, but not of 500mug/kg leptin, facilitated behavioral performance in passive avoidance and Morris water-maze tasks. Bath application of 10(-12)M leptin in slice experiments enhanced LTP and increased the presynaptic transmitter release, whereas 10(-10)M leptin suppressed LTP and reduced the postsynaptic receptor sensitivity to N-methyl-d-aspartic acid. The increase in the [Ca(2+)](i) induced by 10(-10)M leptin was two times greater than that induced by 10(-12)M leptin. In addition, the facilitation (10(-12)M) and suppression (10(-10)M) of LTP by leptin was closely associated with an increase and decrease in Ca(2+)-independent activity of CaMK II. Our results show that leptin not only affects hypothalamic functions (such as feeding, thermogenesis, and neuroendocrine status), but also modulates higher nervous functions, such as the behavioral performance related to learning and memory and hippocampal synaptic plasticity.