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1.
J Clin Psychopharmacol ; 38(6): 622-626, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30300290

ABSTRACT

BACKGROUND: Second-generation antipsychotics (SGAs) are commonly used to treat children with mental health conditions (MHCs) but are associated with adverse effects including obesity, hypertension, dyslipidemia, and type 2 diabetes. The mechanisms underlying these complications are unknown, but it has been suggested that SGAs increase appetite leading to weight gain. The present objective was to perform a pilot study to investigate appetite and satiety hormones in SGA-treated (risperidone or quetiapine) and SGA-naive children with similar mental health conditions. METHODS: Oral glucose tolerance tests (OGTTs) were conducted in SGA-naive (n = 18), risperidone-treated (n = 20), and quetiapine-treated (n = 16) children recruited from the British Columbia Children's Hospital Psychiatry Department. Over 5 time-points during the OGTT, appetite questionnaires using a visual analogue scale were administered, and blood was collected to measure ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, glucagon-like protein 1, leptin, and adiponectin. Mixed model analyses were conducted to examine between-group differences. RESULTS: The children were similar in age, psychiatric diagnosis, and global assessment of functioning scores. Body mass index z-scores were also similar between groups. Appetite was increased during the OGTT in the risperidone-treated compared with the SGA-naive group for 2 questions ("How strong is your desire to eat"; P = 0.003 and "How much food do you think you can eat"; P = 0.028). No differences in satiety hormones were observed between the 3 groups. CONCLUSIONS: Risperidone treatment in youth is associated with elevated appetite during an OGTT, with no differences in gut peptides or adipocytokines to explain risperidone's effect on appetite. Further research is needed to explore other mediators of weight gain and metabolic dysfunction in SGA-treated youth.


Subject(s)
Antipsychotic Agents/adverse effects , Appetite/drug effects , Mental Disorders/drug therapy , Peptide Hormones/drug effects , Quetiapine Fumarate/adverse effects , Risperidone/adverse effects , Satiation/drug effects , Adolescent , Child , Cross-Sectional Studies , Female , Humans , Male , Mental Disorders/blood , Peptide Hormones/blood , Pilot Projects
2.
Am J Physiol Regul Integr Comp Physiol ; 309(5): R613-22, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26180184

ABSTRACT

Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE.


Subject(s)
Alcohol Drinking/adverse effects , Ethanol/toxicity , Hippocampus/drug effects , Hypothalamus/drug effects , Prenatal Exposure Delayed Effects , Receptors, Glucocorticoid/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Age Factors , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , DNA Methylation/drug effects , Early Growth Response Protein 1/genetics , Early Growth Response Protein 1/metabolism , Female , Gene Expression Regulation, Developmental , Gene Expression Regulation, Enzymologic , Gestational Age , Hippocampus/growth & development , Hippocampus/metabolism , Hypothalamus/growth & development , Hypothalamus/metabolism , Male , Maternal Exposure , Pregnancy , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Sex Factors
3.
J Clin Psychopharmacol ; 34(3): 359-64, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24633003

ABSTRACT

Second-generation antipsychotics (SGAs) are commonly prescribed to youth but are associated with metabolic effects including obesity and diabetes. The mechanisms underlying diabetes development are unclear. The purpose of this study was to compare glucose homeostasis, insulin sensitivity, insulin secretion, and overall ß-cell function in risperidone-treated, quetiapine-treated, and SGA-naive youth with mental illness. We conducted a cross-sectional study in which youth aged 9 to 18 years underwent a 2-hour oral glucose tolerance test. Indices for insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), and ß-cell function (insulin secretion-sensitivity index-2 [ISSI-2]) were calculated. A total of 18 SGA-naive, 20 risperidone-treated, and 16 quetiapine-treated youth participated. The 3 groups were similar in age, sex, ethnicity, body mass index standardized for age and sex, pubertal status, degree of psychiatric illness, psychiatric diagnoses, and other medications. The median treatment duration was 17 months (range, 3-91 months) for risperidone-treated youth and 10 months (range, 3-44 months) for quetiapine-treated youth. The quetiapine-treated group had lower insulinogenic index (P < 0.01) and lower ISSI-2 (P < 0.01) compared with that in the SGA-naive group. Only the body mass index standardized for age and sex was negatively associated with Matsuda index (ß = -0.540, P < 0.001) in all youth. Quetiapine treatment was negatively associated with insulinogenic index (ß = -0.426, P = 0.007) and ISSI-2 (ß = -0.433, P = 0.008). Quetiapine reduced the insulin expression in isolated mouse islets suggesting a direct ß-cell effect. Our results suggest that quetiapine treatment in youth is associated with impaired ß-cell function, specifically lower insulin secretion. Prospective longitudinal studies are required to understand the progression of ß-cell dysfunction after quetiapine initiation.


Subject(s)
Antipsychotic Agents/adverse effects , Dibenzothiazepines/adverse effects , Insulin/metabolism , Risperidone/adverse effects , Adolescent , Animals , Blood Glucose/drug effects , Body Mass Index , Child , Cross-Sectional Studies , Dibenzothiazepines/therapeutic use , Female , Glucose Tolerance Test , Humans , Insulin Resistance , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/pathology , Male , Mental Disorders/drug therapy , Mice , Mice, Inbred C57BL , Quetiapine Fumarate , Risperidone/therapeutic use
4.
Endocrinology ; 151(11): 5226-36, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20881250

ABSTRACT

The low-density lipoprotein receptor (Ldlr) is a key molecule involved with lipid clearance. The Ldlr(-/-) mouse has been used extensively as a model for studying atherosclerosis. This study sought to characterize the energy balance phenotype of Ldlr(-/-) mice with respect to weight gain, body composition, energy expenditure (EE), glucose homeostasis, and leptin sensitivity. Adult Ldlr(-/-) mice and Ldlr(+/+) controls on a C57Bl/6J background were fed either a chow or a high-fat, high-sucrose Western-type diet (WTD) for eight wk. Physiological studies of food intake, EE, activity, insulin sensitivity, and leptin responsiveness were performed. The effect of these diet interventions on circulating leptin and on leptin gene expression was also examined. On the chow diet, Ldlr(-/-) mice had lower EE and higher activity levels relative to controls. On the WTD, Ldlr(-/-) mice gained less weight relative to Ldlr(+/+) mice, specifically gaining less fat mass. Increased thermogenesis in Ldlr(-/-) mice fed the WTD was detected. Additionally, leptin responsiveness was blunted in chow-fed Ldlr(-/-) mice, suggesting a novel role for the Ldlr pathway that extends to leptin's regulation of energy balance. In addition to its known role in lipid transport, these results demonstrate the importance of the Ldlr in energy homeostasis and suggest a direct physiological link between altered lipid transport and energy balance.


Subject(s)
Dietary Fats/metabolism , Disease Susceptibility/metabolism , Obesity/physiopathology , Receptors, LDL/metabolism , Thermogenesis/physiology , Analysis of Variance , Animals , Body Composition/physiology , Calorimetry , Diet , Eating/physiology , Energy Metabolism/physiology , Enzyme-Linked Immunosorbent Assay , Insulin/metabolism , Insulin Resistance/physiology , Leptin/metabolism , Leptin/pharmacology , Mice , Mice, Knockout , Obesity/genetics , Obesity/metabolism , Receptors, LDL/genetics , Reverse Transcriptase Polymerase Chain Reaction
5.
Am J Med Genet A ; 152A(11): 2784-90, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20979189

ABSTRACT

Pseudohypoparathyrodism (PHP) is a disorder caused by mutations in the guanine nucleotide-binding α-subunit (GNAS). We sought to determine the genetic origin of PHP1a in one affected family. We identified the previously reported Gsα R231H mutation in family members affected with PHP1a. DNA analysis found that the two clinically affected sons are heterozygous for the mutation. The sons have PHP1a, manifesting obesity, intellectual disability, hypogonadism, hypothyroidism and elevated PTH levels. Initial DNA sequencing did not detect the mutation in either parent. However, their mother displayed some features of PHP, including elevated PTH levels and asymmetrical metacarpal shortening. Using molecular cloning, we detected the mutation at low levels in the mother's leukocyte DNA, consistent with somatic mosaicism and her mildly affected status. Thus, we have identified additional cases of PHP1a caused by the Gsα R231H mutation. In this family, the mother has a milder phenotype due in part to somatic mosaicism, whereas the two affected sons have full PHP1a. Though somatic mosaicism for activating GNAS mutations is known to occur in McCune-Albright syndrome, this is the first report confirming somatic mosaicism for a hypofunctioning GNAS mutation in a PHP kindred.


Subject(s)
Amino Acid Substitution/genetics , GTP-Binding Protein alpha Subunits, Gs/genetics , Mosaicism , Mutation/genetics , Pseudohypoparathyroidism/genetics , Adolescent , Adult , Child , Child, Preschool , Chromogranins , Female , Heterozygote , Humans , Infant, Newborn , Male , Middle Aged , Pregnancy
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