Induced Weight Gain Research Articles

T37. THE LONELY MOUSE: A MODEL FOR STUDYING MATERNAL PSYCHOLOGICAL STRESS AND ITS CONSEQUENCES IN THE OFFSPRING

BackgroundIt is well established that antenatal psychopathology affects obstetric outcomes and maternal behavior, and that it has long-term consequences on the offspring’s wellbeing and mental health, which are relevant for multiple psychiatric disorders. Against this background, it is of pivotal importance to investigate the precise mechanisms that underlie such association, and evaluate the potential beneficial and/or detrimental impact of pharmacological treatment during pregnancy and the postpartum period. To date, rodent models rely mainly on exposure to chronic or acute unpredictable stress during pregnancy, which is mainly based on physical stressors characterized by medium translational value. Therefore, we propose the use of a social isolation-rearing paradigm to investigate the effects of antenatal maternal stress on the offspring. This model has the advantage of implementing psychological stressors, as opposed to physical stressors, to induce depressive-like behaviours in female mice. Moreover, the depressive-like state can be induced and assessed before pregnancy, thus eliminating possible confounding factors that arise from physical stressful manipulations applied during pregnancy.MethodsC57BL/6 female mice were socially isolated, or group housed, from weaning (PND21) to adulthood (PND91). After 5 weeks of social isolation, the animals were tested to confirm the development of a depressive-like phenotype. At PND91, both group housed and socially isolated mice were bred and left undisturbed during pregnancy. The offspring were subjected to cognitive and behavioral testing in adulthood. A subgroup of socially isolated and grouped females were treated with the antidepressant Fluoxetine (10mg/kg) for the last 3 weeks of social isolation, pregnancy and weaning, and the offspring were once again subjected to cognitive and behavioral testing in adulthood.ResultsSocial isolation rearing induced weight gain, basal plasma corticosterone reduction and depressive-like behavioural traits, such as reduced social interaction and increased anxiety. Both female and male offspring of socially isolated mothers displayed a variety of behavioural abnormalities relevant to different psychiatric disorders, such as increased anxiety and altered fear expression. Male offspring also presented metabolic alterations and cognitive deficits in the form of spatial working memory and recognition memory. Prenatal fluoxetine was effective in rescuing some of the above-mentioned behavioural abnormalities but detrimental for others.DiscussionOur results demonstrate, for the first time, that long-lasting psychological stress preceding pregnancy is sufficient for inducing long-term behavioural and metabolic alterations in the offspring. Specifically, social isolation can be considered a strong etiological factor for stress in rodents, just as loneliness is a significant precursor to depression in humans. The social isolation-rearing model could thus offer a translationally-relevant setting in which to further investigate the mechanisms underlying the association between prenatal stress and psychopathology in the offspring, and the contribution of pharmacological treatments.

F98. HYPOVITAMINOSIS D IN SCHIZOPHRENIA: ASSOCIATED CARDIOVASCULAR RISK

BackgroundVitamin D modulate the course of many neurologic diseases and conditions. Moreover, the prevalence of vitamin D deficiency might be higher in psychiatric patients, in particular with schizophrenia.Likewise, there is an inverse relationship between vitamin D levels and several cardiovascular risk factors, including the metabolic syndrome, that patients with schizophrenia are predisposed to develop. It is within this framework that this study aims to explore the relationship between vitamin D levels in a cohort of Tunisian patients with schizophrenia and to determine the cardiovascular risk according to whether they had hypovitaminosis D or not.MethodsA cross-sectional and retrospective descriptive study was conducted at the “F” psychiatry department at the Razi Hospital, Manouba over a twelve-month period from June 1st, 2015 to May 31st, 2016, including 80 patients with schizophrenia in period of clinical remission. The evaluation focused on anthropometric parameters and cardiovascular risk factors. A dosage of vitamin D was performed.ResultsThe patients had an average age of 42.5 years and 70% were male. 25 patients had metabolic syndrome. 49% of patients had vitamin D insufficiency and 51% had vitamin D deficiency. Vitamin D levels had not been affected by the clinical characteristics of the disease. However, there was no significant association between vitamin D levels and metabolic syndrome. A significant negative correlation was found between the total sum of the various cardiovascular risk factors and the vitamin D deficiency (p <0.001).DiscussionIn our study, all patients had vitamin D levels below the recommended levels. 25 patients (31%) met the criteria for metabolic syndrome. All our patients had at least one cardiovascular risk factor. The majority (33% and 27%) had respectively three or four FRCV. 10% had more than five concurrent FRCVs. This result has been described in many studies. Indeed, in patients with schizophrenia, the cardiometabolic risk seems to increase continuously. Several European studies have reported a prevalence of metabolic syndrome ranging from 28% to 37% in patients with schizophrenia. Higher rates of 43% and 46% were reported respectively in the United States and Canada. Moreover, with schizophrenia have an increased risk of sudden death and are 2 to 4 times more likely to die prematurely compared to the general population. These results have been explained with a multicausal model focusing on genetics, lifestyle, smoking, diet and sedentary behavior as well as by the side effects of antipsychotics known to induce weight gain and aggravate symptoms. risk factors for cardiometabolic disease, although studies in naïve patients reflect various abnormalities early on. However, several studies confirm that certain metabolic abnormalities may occur in schizophrenic patients naive to any antipsychotic treatment.This result is consistent with current literature data that highlight increased metabolic and cardiovascular risk in vitamin D deficiency. Indeed, in the general population, vitamin D deficiency is an important risk factor for cardiometabolic disease. The majority of cohort studies have reported an increase in the incidence of cardiovascular disease in people with low vitamin D levels.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

The prevalence of diabetes mellitus is increasing and is associated with a range of complications including nephropathy. New antidiabetic agents are sought which also have positive effects to diminish diabetic complications. Examples of promising new classes of such agents are glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. In addition to cardiovascular protective effects such as weight loss and decreased blood pressure of some of these agents, there is evidence for renoprotective effects with these agents. This review elaborates on the main results of renoprotective effects of these 3 treatment classes. In conclusion, currently available trials have demonstrated renoprotective effects for certain glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, and the sodium-glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin. Dipeptidyl peptidase-4 inhibitors did not show a significant renoprotective effect. Nevertheless, larger studies with respect to renoprotective effects of these 3 drug classes are currently being performed, and thus, no conclusions for all of these agents can yet be made.

P.1.015 - Influence of prebiotic intake on olanzapine-mediated weight gain, central receptors, peripheral biomarkers, and gut microbiota

Olanzapine is the first-line antipsychotic treatment for schizophrenia, but often leads to secondary health concerns such as metabolic syndrome and weight gain. Studies in rats have shown that chronic olanzapine administration induces weight gain [1] and reduces hippocampal glutamate N-methyl-D-Aspartate receptor (NMDAR) levels, the latter which may hinder the recovery of cognitive function in schizophrenia patients. We have shown that dietary augmentation of beneficial gut bacteria using the commercially available prebiotic Bimuno ™ galacto-oligosaccharides (B-GOS ® ) increases central levels of NMDAR subunits in rodents [2,3]. The aim of this study was to determine whether the effects of olanzapine on weight gain and peripheral effects are influenced by B-GOS® intake in rats. Adult female Sprague-Dawley rats were provided with a B-GOS ® (0.5g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. Weight gain and water intake were monitored daily. We determined whether B-GOS ® influenced olanzapine-associated weight gain, and central NMDAR and serotonin receptor expression. Circulating levels of acetate, IL-1β, IL-8 and TNFα as well as liver acetyl-CoA Carboxylase (ACC), white adipose tissue acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Two-way ANOVAs were used to analyse all data, with repeated measures included to explore weight gain. Olanzapine induced significant weight gain (p ® -fed rats. Significant effect of treatment was observed on hippocampal GluN1 mRNA abundance (p = 0.034), where olanzapine significantly increased (+17%) levels in the absence of B-GOS ® (p = 0.040). Plasma acetate concentrations increased following B-GOS ® or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS ® . Co-administration of B-GOS ® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS ® elevated faecal Bifidobacterium Spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS ® , was without effect. The current study demonstrates a potential strategy to reduce olanzapine-mediated weight gain in schizophrenia without compromising a key central pharmacological action of this antipsychotic. We also demonstrate a NMDAR augmenting effect, supporting a potential pro-cognitive effect of the prebiotic. Our data also implies that elevated TNFα in B-GOS ® /olanzapine rats may contribute to the reduction in olanzapine-induced weight gain as pro-inflammatory TNFα is a recognised appetite suppressant. These data suggest that inclusion of B-GOS ® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis.

Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo.

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Latent Toxoplasma gondii infection is associated with decreased serum triglyceride to high-density lipoprotein cholesterol ratio in male patients with schizophrenia

BackgroundPrevious studies suggested a complex association between Toxoplasma gondii (TG) infection and host lipid metabolism. Both TG infection and metabolic disturbances are very common in patients with schizophrenia, but this relationship is not clear. MethodsIn this cross-sectional study, we evaluated the association between TG seropositivity, serum lipid levels, body mass index (BMI) and metabolic syndrome (MetS) in 210 male inpatients with schizophrenia. ResultsIn our sample of schizophrenia patients, with the mean age of 43.90 ± 12.70 years, the rate of TG seropositivity was 52.38% and the prevalence of MetS was 17%. Patients with the TG antibodies had lower serum triglyceride levels and body weight compared to TG seronegative patients, despite having more frequently received antipsychotics (clozapine, olanzapine risperidone and quetiapine), which are well known to induce weight gain and metabolic abnormalities. However, the only significant change in metabolic parameters, observed in TG seropositive patients with schizophrenia, was decreased serum triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio. No associations were observed between TG seropositivity and serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and glucose levels, waist circumference, BMI and the rate of MetS. ConclusionThis is the first report of the association between TG infection and decreased serum triglyceride to HDL-C ratio in a sample of carefully selected men with chronic schizophrenia.

Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain.

Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.

Metformin-A drug of plant origin

Galega officinalis is a summer-flowering perennial herb found in most temperate regions. One of the first use of this herb was to cure the frequent urination associated with the disease, now called as diabetes mellitus. In 1926, polymethethylene diguanides had been introduced for the treatment of diabetes and due to its debilitating effect on the liver, it had been withdrawn in the 1940s. On working with dicyanodiamide and dimethylammonium, Dublin chemists, Emil Werner and James Bell had discovered a compound in 1922. They found out that dicyanodiamide on reaction with dimethyl ammonium chloride yielded dimethyldiguanide, i.e., metformin. The Food and Drugs Administration approves metformin to be used for the treatment of Type 2 Diabetes Mellitus. Metformin was approved for the treatment of Type 2 Diabetes Mellitus in 1958 for UK, in 1972 for Canada and in 1995 by FDA in USA. Although metformin was initially proven to treat high sugar levels, there are many uses of metformin proven to be effective. Metformin not only for diabetes, but also for gestational diabetes mellitus, obesity, hypersecretion of ovarian androgens, polycystic ovary syndrome (PCOS), antipsychotic therapy induced weight gain, cancer treatment and anti-aging. Metformin is the drug of choice for patients who are obese and have type 2 diabetes mellitus. It works by decreasing hepatic glucose production and decreasing peripheral insulin resistance. Metformin acts on obesity by causing a decrease in the appetite. The other action of metformin is reduction of circulating levels of insulin and insulin like growth factor 1 (IGF-1) which is associated with anticancer action. There are ongoing research about the effect of metformin on anti-aging properties and proved that metformin is linked with anti-aging factors. Three main factors that are related with aging are oxidation, glycation and methylation.

A study on Olanzapine induced weight gain among patients of Schizophrenia at a Tertiary Care Medical College Hospital in Deccan Plateau

A study on Olanzapine induced weight gain among patients of Schizophrenia at a Tertiary Care Medical College Hospital in Deccan Plateau

High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity.

The contribution of high fructose corn syrup (HFCS) to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high-fat diets are widely accepted as a rodent model of diet-induced obesity (DIO) and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6) received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets.

Decision-making Capacity for Treatment of Psychotic Patients on Long Acting Injectable Antipsychotic Treatment

ObjectiveProviding informed, consent requires patients' Decision-Making Capacity for treatment. We evaluated the Decision Making Capacity of outpatients diagnosed with schizophrenia and schizoaffective disorder on treatment with Long Acting Injectable Antipsychotic medication. MethodThis is a retrospective, cross-sectional, correlational study conducted at two Depot Clinics in Athens, Greece. Participants included 65 outpatients diagnosed with schizophrenia and schizoaffective disorder on treatment with Long Acting Injectable Antipsychotics. ResultsOver half of the participants showed poor understanding of the information given regarding their disease and treatment (Understanding subscale), however >70% seemed to comprehend the relevance of this information to their medical condition (Appreciation subscale). Moreover, half of the participants reported adequate reasoning ability (Reasoning subscale), whilst patients who gained >7% of their body weight scored statistically significantly higher in the subscales of Understanding and Appreciation. ConclusionOur results suggest that there is a proportion of patients with significantly diminished Decision Making Capacity, hence a full assessment is recommended in order to track them down. Further research is needed to better interpret the association between antipsychotic induced weight gain and Decision Making Capacity in patients suffering from schizophrenia or schizoaffective disorder.

Risperidone-induced metabolic dysfunction is attenuated by Curcuma longa extract administration in mice.

Antipsychotics, such as risperidone, increase food intake and induce alteration in glucose and lipid metabolism concomitantly with overweight and body fat increase, these biological abnormalities belong to the metabolic syndrome definition (high visceral adiposity, hypertriglyceridemia, hyperglycemia, low HDL-cholesterol and high blood pressure). Curcumin is a major component of traditional turmeric (Curcuma longa) which has been reported to improve lipid and glucose metabolism and to decrease weight in obese mice. We questioned the potential capacity of curcumin, contained in Curcuma longa extract (Biocurcuma™), to attenuate the risperidone-induced metabolic dysfunction. Two groups of mice were treated once a week, for 22weeks, with intraperitoneal injection of risperidone (Risperdal) at a dose 12.5 mpk. Two other groups received intraperitoneal injection of the vehicle of Risperdal following the same schedule. Mice of one risperidone-treated groups and of one of vehicle-treated groups were fed a diet with 0.05% Biocurcuma™ (curcumin), while mice of the two other groups received the standard diet. Curcumin limited the capacity of risperidone to reduce spontaneous motricity, but failed to impede risperidone-induced increase in food intake. Curcumin did not reduce the capacity of risperidone to induce weight gain, but decreased visceral adiposity and decreased the risperidone-induced hepatomegaly, but not steatosis. Furthermore, curcumin repressed the capacity of risperidone to induce the hepatic over expression of enzymes involved in lipid metabolism (LXRα, FAS, ACC1, LPL, PPARγ, ACO, SREBP2) and decreased risperidone-induced glucose intolerance and hypertriglyceridemia. Curcumin decreased risperidone-induced increases in serum markers of hepatotoxicity (ALAT, ASAT), as well as of one major hepatic pro-inflammatory transcription factor (NFκB: p105 mRNA and p65 protein). These findings support that nutritional doses of curcumin contained in Curcuma longa extract are able to partially counteract the risperidone-induced metabolic dysfunction in mice, suggesting that curcumin ought to be tested to reduce the capacity of risperidone to induce the metabolic syndrome in human.

Oroxin A from Oroxylum indicum prevents the progression from prediabetes to diabetes in streptozotocin and high-fat diet induced mice

BackgroundOroxylum indicum (L.) Kurz (Bignoniaceae) has been widely used for the treatment of respiratory infections and gastrointestinal disorders. Our previous study showed that an ethanol–water O. indicum seed extract (OISE), when combined with acarbose, reduced the risk of diabetes by 75% and effectively prevented the associated complications. Oroxin A, a major component of OISE, can activate PPARγ and inhibit α-glucosidase and it represents a promising candidate for diabetes intervention. PurposeThe aim of this study is to investigate the effect of oroxin A from O. indicum on the progression of prediabetes to diabetes and the underlying mechanisms in streptozotocin and high-fat-diet induced prediabetic mice. MethodsOroxin A was purified from OISE and its PPARγ transcriptional activation was determined in vitro and in vivo. The prediabetic mice were established by high-fat diet and streptozotocin, which was followed by treatment with oroxin A. The effect of oroxin A was determined by analysis of the lipid profiles, oxidative stress, hepatic function and histology. The mechanism of oroxin A was also investigated. ResultsOroxin A is a compound with low toxicity that has reduced the relative risk of progression from prediabetes to diabetes by 66.7% without inducing weight gain or hepatotoxicity. Oroxin A also improved the complications of prediabetes, such as lipid metabolism dysfunction and liver injury. Results of mechanism studies suggested that oroxin A is a partial PPARγ agonist that can activate PPARγ transcriptional activation in vitro and in vivo. Oroxin A also exhibited an inhibitory activity against α-glucosidase and an antioxidant capacity. ConclusionOroxin A prevents the progression from prediabetes to diabetes through a multi-pathway intervention mechanism.

P.3.e.007 - Does genetics of obesity overlap with pharmacogenetics of antipsychotic induced weight gain? A molecular pathway analysis

P.3.e.007 - Does genetics of obesity overlap with pharmacogenetics of antipsychotic induced weight gain? A molecular pathway analysis

Association of MTHFR C677T polymorphism with weight gain induced by risperidone in schizophrenia

Objective To explore the association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with weight gain induced by risperidone. Methods 356 patients with schizophrenia according to the DSM-IV criteria in this study. The height and body weight of the patients were measured before starting risperidone treatment and 8-week later. The MTHFRC677T polymorphism was genotyped using direct DNA sequencing method. Results A significant association was found between MTHFR gene C677T and body weight mass index (BMI) change after 8-week risperidone treatment. CC-carriers experienced higher BMI gain than CT/TT-carriers (CC(4.47±1.09), CT(4.54±1.27), TT(2.31±0.75), F=5.634, P 7%) was higher than that in non-bodyweight gain groups (48.4% vs 32.4%, χ2=11.342, P<0.01). Conclusion MTHFRC677T polymorphism is associated with risperidone induced weight gain in Chinese Han population. Key words: Schizophrenia; MTHFR gene; Antipsychotics; Body weight gain

Effects of obesity on metabolic and cardiovascular outcomes following insulin initiation in patients with type 2 diabetes

Insulin therapy induces weight gain but whether it causes long term adverse metabolic and CV outcomes in obese patients remains unclear. A retrospective cohort study of 12,725 insulin initiators with T2D derived from UK General Practices. Multivariate linear, logistic regression analyses and Cox proportional hazard models were used to estimate HbA1c, BMI, risk of composite CV events between baseline BMI categories at 5 years. Mean age was 58.6±13.8years. The proportion of patients achieving HbA1c targets decreased across increasing BMI categories at 6 and at 12 months; p=0.0001, but not significant beyond 24 months. 1095 composite events of all-cause mortality, non-fatal stroke and MI occurred with an adjusted hazard risk (aHR) relative to normal of: (1.10; 95%CI: 0.90-1.35) in the overweight, (1.05; 95%CI: 0.86-1.29) in the obese class I, (1.03; 95%CI: 0.83-1.29) in the obese class II and (1.30; 95%CI: 1.02-1.66) in the obese class III BMI categories. Among patients with T2D insulin initiators, obesity adversely influences HbA1c up to 12 months, but not beyond 24 months and is associated with a decrease in BMI compared to non-obese groups. Morbidly obese patients initiating insulin have 30% increased risk of composite CV events after 5 years.

Prior Endurance Training Enhances Beta-Adrenergic Signaling in Epidydimal Adipose from Mice Fed a High-Fat Diet.

Adipose tissue beta-adrenergic signaling is attenuated in obesity and insulin resistance. It has been previously demonstrated that prior exercise training protects against short-term, high-fat diet (HFD)-induced weight gain and glucose intolerance. This study aimed to determine whether prior exercise training results in altered beta-adrenergic and lipolytic signaling in adipose tissue when challenged with a HFD. Male C57BL/6J mice underwent 4 weeks of treadmill training (1 h/d, 5 d/wk). Twenty-four hours after the final bout of exercise, mice were fed a HFD (60% kcal lard) for 4 days. Serum fatty acids, beta-adrenergic signaling (phosphorylated ERK, hormone-sensitive lipase, and p38), and perilipin 1 content were greater in epididymal white adipose tissue (eWAT) from previously trained mice. These changes were not evident in eWAT from trained mice prior to the HFD and were not secondary to alterations in insulin responsiveness or catecholamine concentrations. CL 316,243-mediated increases in hormone-sensitive lipase phosphorylation and fatty acid accumulation in the media were greater in adipose tissue explants from previously trained mice fed a HFD. These findings suggest that previous training increases adipose tissue beta-adrenergic responsiveness to a short-term HFD. This may help to explain the protective effect of prior exercise training against the deleterious effects of a HFD.

ErbB signaling antagonist ameliorates behavioral deficit induced by phencyclidine (PCP) in mice, without affecting metabolic syndrome markers

Schizophrenia is a severe syndrome that affects about 1% of the world population. Since the mid-1950s, antipsychotics have been used to treat schizophrenia with preference for treating positive symptoms; however, their tolerance level is low, there are numerous side effects, and only some patients respond to the treatment. Antipsychotic medications that are more effective, better tolerated, and with fewer adverse effects are urgently needed. Given the accumulating evidence of the role filled by the ErbB signaling network in the biology of the dopamine, GABA, and glutamate systems, and in the etiology of schizophrenia, we hypothesized that the ErbB network is a candidate for development of a novel agent through which various symptoms of schizophrenia and other psychiatric disorders might be treated.Herein, we studied, in mice, the capability of blocking the ErbB signaling, in comparison with the atypical antipsychotic drug clozapine, to counter schizophrenia-like behavior induced by acute and sub-chronic phencyclidine (PCP), and determined whether inhibition of the ErbB networks induced weight gain and affected social and exploratory behavior, and metabolic syndrome markers. We demonstrated that administration of the pan-ErbB inhibitor JNJ28871063 (JNJ) reduced the level of activity in the open field induced by an acute injection of PCP. Moreover, the ability of JNJ to attenuate the effect of PCP is as effective as clozapine. In addition and like clozapine, JNJ normalized social behavior impairment induced by sub-chronic PCP and stress. Adult JNJ-treated mice displayed normal sociability and exploratory behavior, and their serum cholesterol, LDL, and HDL levels were lower than in the saline-treated mice. Sub-chronic treatment did not affect weight gain, glucose levels, and the activity of hepatic enzymes catalase and SOD.These data suggest that treatment with JNJ attenuates abnormal behaviors induced by PCP, and has similar effects as the antipsychotic drug clozapine, with no adverse effects. Thus, the ErbB signaling can serve as a new starting point for non-dopaminergic-based drug development of schizophrenia.

A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain

Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes and the mitochondrial DNA (mtDNA) in conferring risk for AIWG. We selected 168 European-Caucasian individuals from the CATIE sample based upon meeting criteria of multiple weight measures while taking selected antipsychotics (risperidone, quetiapine or olanzapine). We tested the association of 670 nuclear-encoded mitochondrial genes with weight change (%) using MAGMA software. Thirty of these genes showed nominally significant P-values (<0.05). We were able to replicate the association of three genes, CLPB, PARL, and ACAD10, with weight change (%) in an independent prospectively assessed AIWG sample. We analyzed mtDNA variants in a subset of 74 of these individuals using next-generation sequencing. No common or rare mtDNA variants were found to be significantly associated with weight change (%) in our sample. Additionally, analysis of mitochondrial haplogroups showed no association with weight change (%). In conclusion, our findings suggest nuclear-encoded mitochondrial genes play a role in AIWG. Replication in larger sample is required to validate our initial report of mtDNA variants in AIWG.

Association of variants in SH2B1 and RABEP1 with worsening of low-density lipoprotein and glucose parameters in patients treated with psychotropic drugs

Genetic factors associated with Body Mass Index (BMI) have been widely studied over the last decade. We examined whether genetic variants previously associated with BMI in the general population are associated with cardiometabolic parameter worsening in the psychiatric population receiving psychotropic drugs, a high-risk group for metabolic disturbances. Classification And Regression Trees (CARTs) were used as a tool capable of describing hierarchical associations, to pinpoint genetic variants best predicting worsening of cardiometabolic parameters (i.e total, HDL and LDL-cholesterol, triglycerides, body mass index, waist circumference, fasting glucose, and blood pressure) following prescription of psychotropic drugs inducing weight gain in a discovery sample of 357 Caucasian patients. Significant findings were tested for replication in a second Caucasian psychiatric sample (n=140).SH2B1 rs3888190C>A was significantly associated with LDL levels in the discovery and in the replication sample, with A-allele carriers having 0.2mmol/l (p=0.005) and 0.36mmol/l (p=0.007) higher LDL levels compared to others, respectively. G-allele carriers of RABEP1 rs1000940A>G had lower fasting glucose levels compared to others in both samples (−0.16mmol/l; p<0.001 and −0.77mmol/l; p=0.03 respectively). The present study is the first to observe such associations in human subjects, which may in part be explained by a high risk towards dyslipidemia and diabetes in psychiatric patients receiving psychotropic treatments compared to population-based individuals. These results may therefore give new insight into the etiology of LDL-cholesterol and glucose regulation in psychiatric patients under psychotropic drug therapy.