Malnutrition is prevalent in elderly hospitalised patients and has been associated with longer lengths of stay (LOS), higher rates of complications and increased hospital costs. Feeding assistance has traditionally been the role of nurses, however with an ageing population and an ever-increasing workload there may not be sufficient time to ensure the nutritional care of all patients. A program in which trained volunteers assist, socialise and feed nutritionally vulnerable patients at lunch on weekdays has been initiated in a major suburban hospital in Sydney. The pilot study reported here aimed to evaluate the lunchtime assistance program in terms of dietary intakes by comparing data from weekdays (with volunteers) and that from weekends (no volunteers). Nine patients (mean age+(SD): 89±4.6 years) participated in the study. Observations and weighed plate waste were recorded for each patient at lunch on two weekdays and two weekend days. When volunteers were present, the average protein intake increased by 10.1 g at lunch (p<0.05) and 10.7g over the whole day (p<0.05). There was also a trend to increased energy intake. Observations indicated that the volunteers, when compared to the nurses, socialised more with patients, encouraged them to eat more often and spent more time feeding them. Trialing volunteer assistance in a larger study would be useful. Observations and weighed plate waste were recorded for each patient at lunch on two weekdays and two weekend days. When volunteers were present, the average protein intake increased by 10.1 g at lunch (p<0.05) and 10.7g over the whole day (p<0.05). There was also a trend to increased energy intake. Observations indicated that the volunteers, when compared to the nurses, socialised more with patients, encouraged them to eat more often and spent more time feeding them. Trialing volunteer assistance in a larger study would be useful.

Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.

Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.

Excessive weight gain has been identified as a serious metabolic side-effect of second-generation antipsychotics (SGAs), including olanzapine. While hyperphagia has been suggested to be the main contributor for this side-effect in the short term, reduced energy expenditure, in particular thermogenesis and locomotor activity, has been considered to contribute to the maintenance of heavy weight under long-term SGA treatments. Recent studies have identified metabolically active brown adipose tissues (BAT) in adult humans, suggesting potential clinical significance for the involvement of BAT thermogenesis in SGA-induced weight gain. However, to date there has been little research elucidating the central neuronal pathways affecting BAT thermogenesis or the morphological changes of the BAT. The present study aimed to investigate the role of BAT thermogenesis and locomotor activity in olanzapine-induced weight gain during the prolonged time courses of olanzapine treatment in an established female rat model. Although short- to mid-term olanzapine treatment had no effect on BAT temperature, we observed that long-term olanzapine treatment (from day 18 to 34) induced a significant reduction in BAT temperature, with an acute effect being observed between 45 and 150 min post-treatment in the long-term cohort. Additionally, in the long-term olanzapine group, the reduced BAT temperature was accompanied by decreased UCP1 and PGC-1α expressions in the BAT. Moreover, TH mRNA expressions in both hypothalamus and brainstem were also downregulated after mid- to long-term olanzapine treatment. Further, olanzapine led to reduced percentage of brown adipocytes in BAT during mid- to long-term treatments. Finally, locomotor activity was reduced throughout the three treatment cohorts. In summary, our results suggest that the reduction of BAT thermogenesis plays an important role during the long-term of olanzapine-induced weight gain, which was accompanied by an earlier onset of BAT adipocyte morphological changes and biochemical changes in the hypothalamus and the brainstem, while locomotor activity contributes to the entire olanzapine treatment courses.

Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome. ABSTRACTBased on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGAinduced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium.Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/ agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome.

High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/ day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF dietinduced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, antineuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rheinenriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation. Disciplines Medicine and Health Sciences Publication DetailsWang, S., Huang, X., Zhang, P., Wang, H., Zhang, Q., Yu, S. & Yu, Y. (2016). Chronic rhein treatment improves recognition memory in high-fat diet-induced obese male mice. Journal of Nutritional Biochemistry, 36 42-50. High-fat (HF) diet modulates gut microbiota and increases plasma concentration of 2 lipopolysaccharide (LPS), metabolic endotoxemia, which is associated with obesity and its 3 related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the 4 rhubarb plant which has been used as an anti-inflammatory agent for several millennia. 5 However, the potential effects of rhein against HF diet-induced obesity and its associated 6 alteration of gut microbiota, inflammation and cognitive decline have not been studied. In 7 this study, C57BL/6J male mice were fed a HF diet for 8 weeks to induce obesity, and then 8 treated with oral rhein (120 mg/kg body weight per day in HF diet) for a further 6 weeks.

Deficits in neurite outgrowth and synaptogenesis have been recognized as an underlying developmental aetiology of psychosis. Electrical stimulation promotes neuronal induction including neurite outgrowth and branching. However, the effect of electrical stimulation using 3D electrodes on neurite outgrowth and synaptogenesis has not been explored. This study examined the effect of 3D electrical stimulation on 3D primary cortical neuronal cultures. 3D electrical stimulation improved neurite outgrowth in 3D neuronal cultures from both wild-type and NRG1-knockout (NRG1-KO) mice. The expression of synaptophysin and PSD95 were elevated under 3D electrical stimulation. Interestingly, 3D electrical stimulation also improved neural cell aggregation as well as the expression of PSA-NCAM. Our findings suggest that the 3D electrical stimulation system can rescue neurite outgrowth deficits in a 3D culturing environment, one that more closely resembles the in vivo biological system compared to more traditionally used 2D cell culture, including the observation of cell aggregates as well as the upregulated PSA-NCAM protein and transcript expression. This study provides a new concept for a possible diagnostic platform for neurite deficits in neurodevelopmental diseases, as well as a viable platform to test treatment options (such as drug delivery) in combination with electrical stimulation.

Deficits in neurite outgrowth, possibly involving dysregulation of risk genes neuregulin-1 (NRG1) and disrupted in schizophrenia 1 (DISC1) have been implicated in psychiatric disorders including schizophrenia. Electrical stimulation using conductive polymers has been shown to stimulate neurite outgrowth of differentiating human neural stem cells. This study investigated the use of the electroactive conductive polymer polypyrrole (Ppy) to counter impaired neurite outgrowth of primary pre-frontal cortical (PFC) neurons from NRG1-knock out (NRG1-KO) and DISC1-locus impairment (DISC1-LI) mice. Whereas NRG1-KO and DISC1-LI exhibited reduced neurite length and number of neurite branches compared to wild-type controls, this was not apparent for cultures on electroactive Ppy. Additionally, the use of the Ppy substrate normalised the synaptophysin and PSD95 protein and mRNA expression whereas both are usually reduced by NRG1-KO or DISC1-LI. Our findings support the utility of Ppy mediated electrical stimulation to prevent the reduction of neurite outgrowth and related synaptic protein expression in the primary PFC neurons from NRG1-KO and DISC1-LI mice, providing proof-of-concept for treating neurodevelopmental diseases including schizophrenia.