GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Neural mediator of the schizotypy-antisocial behavior relationship.

Prior studies have established that schizotypal personality traits (schizotypy) were associated with antisocial behavior (crime), but it is unclear what neural factors mediate this relationship. This study assessed the mediating effect that sub-regional prefrontal gray, specifically the orbitofrontal gray matter volume, has on the schizotypy-antisocial behavior relationship. Five prefrontal sub-regional (superior, middle, inferior, orbitofrontal and rectal gyral) gray matter volumes were assessed using structural magnetic resonance imaging in 90 adults from the community, together with schizotypy and antisocial behavior. Among all five prefrontal sub-regions, the orbitofrontal cortex (OFC) was the major region-of-interest in the present study. Mediation analyses showed that orbitofrontal gray fully mediated the association between schizotypy and antisocial behavior. After having controlled the sex, age, socio-economic statuses, whole brain volumes and substance abuse/dependence of test subjects, the orbitofrontal gray still significantly mediated the effect of schizotypy on antisocial behavior by 53.5%. These findings are the first that document a neural mediator of the schizotypy-antisocial behavior relationship. Findings also suggest that functions subserved by the OFC, including impulse control and inhibition, emotion processing and decision-making, may contribute to the above comorbidity.

Identification of the global transcriptomic response of the hypothalamic arcuate nucleus to fasting and leptin.

Leptin plays a major role in coordinating the integrated response of the brain to changes in nutritional state. Leptin receptor expressing neurones within the arcuate nucleus (ARC) of the hypothalamus sense circulating leptin and densely innervate other regions of the hypothalamus, including the paraventricular nucleus (PVN). In the ARC, leptin is known to alter the expression of genes with important roles in the control of energy balance, and the aim of the present study was to obtain a more comprehensive picture of the action of leptin in these nuclei. Mice were ad libitum fed, or fasted for 48 h when receiving either sham or i.p. leptin treatment. We used laser capture microdissection and microarrays to identify leptin-regulated transcripts within the ARC. Expression of 639 genes are increased and 452 decreased within the fasted ARC. Leptin regulates 15% and 20% of these genes, respectively. In addition to expected changes in Pomc, Agrp, Npy and Cart, pathway analysis indicated that leptin regulated other genes concerned with energy homeostasis and endocrine function. As previously reported for the PVN, leptin also altered the expression of genes involved in nervous system development and synaptic function. However, aside from a small number of such genes (e.g. Gap43), leptin influenced the expression of different sets of neuronal developmental genes in the ARC and PVN. In conclusion, the present study identifies a set of genes that are regulated, at least in part, by leptin in the ARC, highlighting these as candidates for possible roles in leptin action and resistance.

A yang-promoting Chinese herbal suppository preparation enhances the antioxidant status of red cells in male human subjects.

In the 16-week pilot study, the effect of a Yang-promoting Chinese herbal suppository preparation (VI-28) on the red cell antioxidant status was examined in 31 healthy male subjects aged 41-66 years old. VI-28 treatment for 12 weeks (one suppository (0.3 g) daily for week 1-4; one every 2 days for week 5-8; one every 3 days for week 9-12) produced a time/dose-dependent alteration in red cell antioxidant status. The VI-28-induced change is characterized by a slight depletion in cellular reduced glutathione (GSH) level and a decrease in susceptibility to peroxide-induced lipid peroxidation as well as increases in catalase (CAT) and Cu-Zn-superoxide dismutase (SOD) activities. While a reversal trend of change was observed in cellular GSH level, the susceptibility to lipid peroxidation as well as the CAT activity after the cessation of treatment for 4 weeks, the SOD activity exhibited a protracted increase. The results indicate that VI-28 treatment enhances red cell antioxidant status in male subjects. The beneficial effect of VI-28 treatment on red cells may re fl ect a corresponding change in antioxidant status of peripheral tissues.

Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice.

Tanshinones are the major lipid soluble pharmacological constituents of Danshen, the dried roots of Salvia miltiorrhiza Bunge (Labiatae), a well known traditional Chinese medicine used for the treatment of cerebrovascular diseases including stroke. Potential neuroprotective effects of tanshinones IIA (TsIIA) and IIB (TsIIB) were examined in adult mice subjected to transient focal cerebral ischemia caused by middle cerebral artery occlusion (MCAo). Our results revealed that TsIIA (16 mg/kg) readily penetrated the blood brain barrier reaching a peak concentration of 0.41 nmol/g brain wet weight 60 minutes after intraperitoneal injection and decreased slowly over several hours. Twenty-four hours after middle cerebral artery occlusion, brain infarct volume was reduced by 30% and 37% following treatment with TsIIA and TsIIB, respectively. The reduction in brain infarct volume was accompanied by a significant decrease in the observed neurological deficit. Tanshinones or other structurally related compounds may have potential for further development as neuroprotective drugs.

Schisandrin B protects against tacrine- and bis(7)-tacrine-induced hepatotoxicity and enhances cognitive function in mice.

Intragastric administration (100-200 micromol/kg) of tacrine (THA) or bis(7)-THA could cause an acute and dose-dependent increase in plasma alanine aminotransferases activity in mice at 6 h after the drug administration. The increase in plasma enzyme activity was associated with an increase in hepatic malondialdehyde level, an indirect index of oxidative tissue damage. Pretreating mice with schisandrin B (Sch B), an active dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, at a daily dose of 0.125-0.5 mmol/kg for 3 days protected against the THA/bis(7)-THA induced hepatic oxidative damage in a dose-dependent manner. Sch B treatment (0.025-0.5 mmol/kg/day x 5) also enhanced the passive avoidance-response in mice as assessed by the step-through task experiment. The ensemble of results suggests that Sch B may be useful for reducing the potential hepatotoxicity of THA/bis(7)-THA in anti-Alzheimer's therapy.