Feeding and GLP-1 receptor activation stabilize ß-catenin in specific hypothalamic nuclei in male rats.

ß-catenin is a multifunctional protein that can act in the canonical Wnt/ß-catenin pathway to regulate gene expression but can also bind to cadherin proteins in adherens junctions where it plays a key role in regulating cytoskeleton linked with these junctions. Recently, evidence has been presented indicating an essential role for ß-catenin in regulating trafficking of insulin vesicles in ß-cells and showing that changes in nutrient levels rapidly alter levels of ß-catenin in these cells. Given the importance of neuroendocrine hormone secretion in the regulation of whole body glucose homeostasis, the objective of this study was to investigate whether ß-catenin signalling is regulated in the hypothalamus during the normal physiological response to food intake. Rats were subjected to a fasting/re-feeding paradigm, and then samples collected at specific timepoints for analysis of ß-catenin expression by immunohistochemistry and Western blotting. Changes in gene expression were assessed by RT-qPCR. Using immunohistochemistry, feeding acutely increased detectable cytoplasmic levels of ß-catenin ('stabilized ß-catenin') in neurons in specific regions of the hypothalamus involved in metabolic regulation, including the arcuate, dorsomedial and paraventricular nuclei of the hypothalamus. Feeding-induced elevations in ß-catenin in these nuclei were associated with increased transcription of several genes that are known to be responsive to Wnt/ß-catenin signalling. The effect of feeding was mimicked by administration of the GLP-1 agonist exendin-4, and was characterized by cAMP-dependent phosphorylation of ß-catenin at serine residues 552 and 675. The data suggest that ß-catenin/TCF signalling is involved in metabolic sensing in the hypothalamus. This article is protected by copyright. All rights reserved.

Deletion of Suppressor of Cytokine Signaling 3 from Forebrain Neurons Delays Infertility and Onset of Hypothalamic Leptin Resistance in Response to a High Caloric Diet.

UNLABELLED: The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction. SIGNIFICANCE STATEMENT: Obesity is commonly associated with infertility in humans and other animals. Treatments for human infertility show a decreased success rate with increasing body mass index. A hallmark of obesity is an increase in circulating leptin levels; despite this, the brain responds as if there were low levels of leptin, leading to increased appetite and suppressed fertility. Here we show that leptin resistant infertility is caused in part by the leptin signaling molecule SOCS3. Deletion of SOCS3 from brain neurons delays the onset of diet-induced infertility.

Neurocognitive impairments associated with ambiguous handedness in the chronically mentally ill.

One form of atypical handedness, ambiguous handedness, is found in roughly one-quarter of chronic schizophrenic patients. Despite its prevalence, relatively little is known about the neurocognitive underpinnings of ambiguous handedness. In the present study we examined the performance of ambiguous (n = 19) and non-ambiguous (n = 39) handed chronically mentally ill inpatients on selected measures of verbal learning, motor learning and manual dexterity. The results revealed that ambiguous handers were more impaired than non-ambiguous handers in verbal learning, but not motor learning. Group differences in manual dexterity were significant for the entire sample, but not when analyses were limited to males. These findings suggest that impairments in verbal learning may be linked to the pathogenesis of ambiguous handedness in chronic psychiatric patients.

Solar and thermal radiation in Jupiter's atmosphere: initial results of the Galileo probe net flux radiometer.

The Galileo probe net flux radiometer measured radiation within Jupiter's atmosphere over the 125-kilometer altitude range between pressures of 0.44 bar and 14 bars. Evidence for the expected ammonia cloud was seen in solar and thermal channels down to 0.5 to 0.6 bar. Between 0.6 and 10 bars large thermal fluxes imply very low gaseous opacities and provide no evidence for a deep water cloud. Near 8 bars the water vapor abundance appears to be about 10 percent of what would be expected for a solar abundance of oxygen. Below 8 bars, measurements suggest an increasing water abundance with depth or a deep cloud layer. Ammonia appears to follow a significantly subsaturated profile above 3 bars. Unexpectedly high absorption of sunlight was found at wavelengths greater than 600 nanometers.

Prediction of response to haloperidol dose reduction by Span of Apprehension measures for treatment-refractory schizophrenic patients.

Thirteen treatment-refractory schizophrenic patients participated in a haloperidol reduction study. Two of the subjects were unable to tolerate medication reduction. These subjects were comparable to the other patients in terms of initial clinical variables but were outliers on baseline accuracy and reaction time measures from the Span of Apprehension. The results suggest that aspects of basic visual processing and motor response speed may identify patients who require higher neuroleptic doses.

Successful behavioral treatment of polydipsia in a schizophrenic patient.

Behavioral treatment of a 35 year old female with chronic schizophrenia and water intoxication with seizures was conducted on an inpatient psychiatric unit. Treatment included frequent daily weights, restricted fluid intake, positive reinforcement for program compliance, and time-out from reinforcement following significant weight gain or other specified program violations. The final 6 months of the 30 month treatment program were a maintenance phase during which most contingencies were faded and all fluid restrictions were removed. There was no reported recurrence of polydipsia after 18 months of community placement.