New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism

Hypothalamic over-expression of VGF in the Siberian hamster increases energy expenditure and reduces body weight gain

VGF (non-acronymic) was first highlighted to have a role in energy homeostasis through experiments involving dietary manipulation in mice. Fasting increased VGF mRNA in the Arc and levels were subsequently reduced upon refeeding. This anabolic role for VGF was supported by observations in a VGF null (VGF-/-) mouse and in the diet-induced and gold-thioglucose obese mice. However, this anabolic role for VGF has not been supported by a number of subsequent studies investigating the physiological effects of VGF-derived peptides. Intracerebroventricular (ICV) infusion of TLQP-21 increased resting energy expenditure and rectal temperature in mice and protected against diet-induced obesity. Similarly, ICV infusion of TLQP-21 into Siberian hamsters significantly reduced body weight, but this was due to a decrease in food intake, with no effect on energy expenditure. Subsequently NERP-2 was shown to increase food intake in rats via the orexin system, suggesting opposing roles for these VGF-derived peptides. Thus to further elucidate the role of hypothalamic VGF in the regulation of energy homeostasis we utilised a recombinant adeno-associated viral vector to over-express VGF in adult male Siberian hamsters, thus avoiding any developmental effects or associated functional compensation. Initially, hypothalamic over-expression of VGF in adult Siberian hamsters produced no effect on metabolic parameters, but by 12 weeks post-infusion hamsters had increased oxygen consumption and a tendency to increased carbon dioxide production; this attenuated body weight gain, reduced interscapular white adipose tissue and resulted in a compensatory increase in food intake. These observed changes in energy expenditure and food intake were associated with an increase in the hypothalamic contents of the VGF-derived peptides AQEE, TLQP and NERP-2. The complex phenotype of the VGF-/- mice is a likely consequence of global ablation of the gene and its derived peptides during development, as well as in the adult

Is using the strengths and difficulties questionnaire in a community sample the optimal way to assess mental health functioning?

An important characteristic of a screening tool is its discriminant ability or the measure’s accuracy to distinguish between those with and without mental health problems. The current study examined the inter-rater agreement and screening concordance of the parent and teacher versions of SDQ at scale, subscale and item-levels, with the view of identifying the items that have the most informant discrepancies; and determining whether the concordance between parent and teacher reports on some items has the potential to influence decision making. Cross-sectional data from parent and teacher reports of the mental health functioning of a community sample of 299 students with and without disabilities from 75 different primary schools in Perth, Western Australia were analysed. The study found that: a) Intraclass correlations between parent and teacher ratings of children’s mental health using the SDQ at person level was fair on individual child level; b) The SDQ only demonstrated clinical utility when there was agreement between teacher and parent reports using the possible or 90% dichotomisation system; and c) Three individual items had positive likelihood ratio scores indicating clinical utility. Of note was the finding that the negative likelihood ratio or likelihood of disregarding the absence of a condition when both parents and teachers rate the item as absent was not significant. Taken together, these findings suggest that the SDQ is not optimised for use in community samples and that further psychometric evaluation of the SDQ in this context is clearly warranted

Physical and Sexual Abuse and Early-Onset Bipolar Disorder in Youths Receiving Outpatient Services: Frequent, but Not Specific

The objective of this study was to determine if physical and sexual abuse showed relationships to early-onset bipolar spectrum disorders (BPSD) consistent with findings from adult retrospective data. Participants (N=829, M= 10.9 years old ±3.4 SD, 60 % male, 69 % African American, and 18 % with BPSD), primarily from a low socio-economic status, presented to an urban community mental health center and a university research center. Physical abuse was reported in 21 %, sexual abuse in 20 %, and both physical and sexual abuse in 11 % of youths with BPSD. For youths without BPSD, physical abuse was reported in 16 %, sexual abuse in 15 %, and both physical and sexual abuse in 5 % of youths. Among youth with BPSD, physical abuse was significantly associated with a worse global family environment, more severe depressive and manic symptoms, a greater number of sub-threshold manic/hypomanic symptoms, a greater likelihood of suicidality, a greater likelihood of being diagnosed with PTSD, and more self-reports of alcohol or drug use. Among youth with BPSD, sexual abuse was significantly associated with a worse global family environment, more severe manic symptoms, a greater number of sub-threshold manic/hypomanic symptoms, greater mood swings, more frequent episodes, more reports of past hospitalizations, and a greater number of current and past comorbid Axis I diagnoses. These findings suggest that if physical and/or sexual abuse is reported, clinicians should note that abuse appears to be related to increased severity of symptoms, substance use, greater co-morbidity, suicidality, and a worse family environment

An Intact Dorsomedial Hypothalamic Nucleus, but Not the Subzona Incerta or Reuniens Nucleus, Is Necessary for Short-Day Melatonin Signal-Induced Responses in Siberian Hamsters

Siberian hamsters provide a useful model to define mechanisms underlying obesity reversal as they naturally transition from their extreme seasonal obesity in long ‘summer-like’ days (LDs) to a leaner state in short ‘winter-like’ days (SDs). These day length changes are coded into durational melatonin (MEL) signals by the pineal gland resulting in stimulation of MEL receptors (MEL1a-Rs). MEL1a-R mRNA is colocalized centrally in sympathetic nervous system (SNS) outflow neurons comprising a chain of neurons that ultimately innervates white adipose tissue (WAT). Neural components in this circuit include the subzona incerta (subZI), dorsomedial hypothalamic nucleus (DMH) and thalamic reuniens nucleus (ReN). SD, long-duration MEL signals induce gonadal regression and increase WAT SNS drive triggering lipolysis and thereby reversing LD obesity. We attempted to block the reversal of SD MEL signal-induced obesity by making electrolytic or sham lesions of the subZI, ReN or DMH in LD-housed hamsters. To create SD-like, long-duration MEL signals, we injected MEL 3 h before lights out, thereby lengthening the naturally occurring nocturnal duration of circulating MEL. ReN and subZI lesions did not block SD-like MEL signal-induced decreases in body, WAT, testicular masses or food intake; by contrast, DMH lesions blocked decreases in WAT and testicular mass. This nonresponsiveness was not due to lesion-induced inappropriate nocturnal LD MEL secretion that would have altered our creation of SD-like signals. Therefore, the DMH appears to participate in the control of both SD energy and reproductive responses, and joins the suprachiasmatic nucleus as sites necessary for SD responses in this species