| 1 | PLoS ONE 2011 -1 6: e20571 |
|---|---|
| PMID | 21695181 |
| Title | Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. |
| Abstract | The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AGRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance. |
| SCZ Keywords | schizophrenia |
| 2 | J Clin Psychopharmacol 2012 Dec 32: 767-72 |
| PMID | 23131879 |
| Title | Trajectories of agouti-related protein and leptin levels during antipsychotic-associated weight gain in patients with schizophrenia. |
| Abstract | Some but not all second-generation antipsychotics can induce considerable weight gain and metabolic syndrome. Although the exact biochemical mechanisms for these adverse effects are unclear, appetite-regulating neuropeptides of the central nervous system are thought to be implicated in this process. The hypothalamic mediator Agouti-related protein (AGRP) is inhibited by leptin and was shown to increase food intake. The aim of the present study was to investigate the trajectory of AGRP levels during antipsychotic-induced weight gain. As part of a controlled prospective clinical study, we determined indicators of body fat mass, plasma AGRP, and leptin levels in 16 patients with schizophrenia treated with ziprasidone and 21 patients with schizophrenia treated with olanzapine. Measurements by enzyme-linked immunosorbent assay were obtained before treatment (T0), after 4 weeks (T1), and after 3 months (T2) of treatment. Whereas body mass index and leptin levels increased in patients treated with olanzapine compared to patients treated with ziprasidone, plasma AGRP levels did not differ among the treatment groups and did not change over time. Associations between AGRP and fat mass as well as appetite were disrupted in the olanzapine-treated patients but not in the ziprasidone group. Future studies are needed to test whether the lack of a decrease in AGRP levels during weight gain in patients treated with olanzapine could perpetuate adverse metabolic long-term effects. |
| SCZ Keywords | schizophrenia |
| 3 | World J. Biol. Psychiatry 2014 Apr 15: 251-8 |
| PMID | 24564533 |
| Title | Investigation of melanocortin system gene variants in antipsychotic-induced weight gain. |
| Abstract | The use of second-generation antipsychotic medications may result in substantial weight gain in a subset of schizophrenia patients. Distinct populations of neurons expressed in the hypothalamus, including the cocaine- and amphetamine-regulated transcript (CART), the polypeptide pro-opiomelanocortin (POMC) and the agouti-related protein (AGRP), have regulatory roles in weight control and energy homeostasis. Thus, we investigated the potential role of CART, POMC and AGRP genetic variants in antipsychotic-induced weight gain (AIWG). Five CART single nucleotide polymorphisms (SNPs) (rs10515115, rs3763153, rs3857384, rs11575893, rs16871471), three POMC SNPs (rs6713532, rs1047521, rs3754860) and one AGRP SNP (rs1338993), were genotyped in 218 patients treated with antipsychotics for chronic schizophrenia and evaluated for AIWG. We compared weight change (%) across genotypic groups using analysis of covariance. None of the SNPs in POMC, CART, AGRP were significantly associated with AIWG in the refined samples stratified by ethnicity and medication treatment. In this exploratory study, we observed that POMC, CART and AGRP gene variants are not a major contributor to AIWG. However larger samples are required to completely rule out their effect on AIWG. |
| SCZ Keywords | schizophrenia |
| 4 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94 |
| PMID | 23085507 |
| Title | Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. |
| Abstract | Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 5 | Brain Res. 2015 Jan 1596: 146-55 |
| PMID | 25449893 |
| Title | Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats. |
| Abstract | Although the use of atypical antipsychotic drugs has been successful in the treatment of schizophrenia, they can cause some complications in the long-term use, including weight gain. Patients using these drugs tend to disrupt treatment primarily due to side effects. The atypical antipsychotic mechanism of action regulates a number of highly disrupted neurotransmitter pathways in the brains of psychotic patients but may also cause impairment of neurohormonal pathways in different brain areas. In this study, we investigated the circulating levels of hypothalamic neurohormones, which are related to appetite regulation; neuropeptide Y (NPY); alpha melanocyte stimulating hormone (?-MSH); cocaine and amphetamine regulated transcript (CART); agouti-related peptide (AGRP); and leptin in male Wistar rats, which were treated with risperidone, a serotonin antagonist, for four weeks. Alterations in the mRNA expression levels of these candidate genes in the hypothalamus were also analyzed. We hypothesized that risperidone treatment might alter both hypothalamic and circulating levels of neuropeptides through serotonergic antagonism, resulting in weight gain. Gene expression studies revealed that the mRNA expression levels of proopiomelanocortin (POMC), AGRP, and NPY decreased as well as their plasma levels, except for NPY. Unexpectedly, CART mRNA levels increased when their plasma levels decreased. Because POMC neurons express the serotonin receptor (5HT2C), the serotonergic antagonism of risperidone on POMC neurons may cause an increase in appetite and thus increase food consumption even in a short-term trial in rats. |
| SCZ Keywords | schizophrenia |
| 6 | Metab Brain Dis 2015 Apr 30: 529-35 |
| PMID | 25034457 |
| Title | Serum levels of AgRP protein in patients with schizophrenia on clozapine monotherapy. |
| Abstract | Agouti-related peptide (AGRP) is one of the hypothalamic hormones that works by increasing appetite and decreasing metabolism, thus leading to weight gain. The aim of the study was to find out if AGRP level in subjects with schizophrenia on clozapine monotherapy is higher compared with healthy controls. We determined fasting serum AGRP levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition analysis. There was no difference for AGRP levels between patients taking clozapine and control group (15.00±8.65 vs. 15.33±6.82 pg/mL, p?=0.37). We found negative correlations between AGRP levels and total body fat (r?=-0.34 and -0.48 in the whole study group and clozapine group, respectively) and positive correlations with lean body mass (r?=0.38 and 0.49 in the whole study group and clozapine group, respectively), body water (r?=0.34 and 0.49 in the whole study group and clozapine group, respectively) and basal metabolic rate (r?=0.42 both in the clozapine and control groups). There were no correlations with age, height, weight, body mass index, fat mass index, abdominal, waist or hip circumferences, waist-hip ratio, blood pressure, total cholesterol, HDL, LDL, triglycerides, uric acid, glucose, insulin, clozapine dose or treatment duration, duration of treatment with antipsychotics and markers for insulin resistance. We cannot conclude that treatment with clozapine is associated with increased level of AGRP. We did not find previously described differences in AGRP levels between obese and non-obese subjects or associations between AGRP and various metabolic parameters. |
| SCZ Keywords | schizophrenia |