Association between the insulin-induced gene 2 ( ) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?

• Published in: Molecular psychiatry Vol. 14; no. 3; pp. 308 - 317
• Main Authors: Le Hellard, S, Theisen, F M, Haberhausen, M, Raeder, M B, Fernø, J, Gebhardt, S, Hinney, A, Remschmidt, H, Krieg, J C, Mehler-Wex, C, Nöthen, M M, Hebebrand, J, Steen, V M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2009; Nature Publishing Group
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; Antipsychotic Agents - adverse effects; Antipsychotic Agents - therapeutic use; Antipsychotic drugs; Antipsychotics; Appetite; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Biosynthesis; Body mass index; Body weight gain; Chi-Square Distribution; Child; Child & adolescent psychiatry; Cholesterol; Clozapine - adverse effects; Clozapine - therapeutic use; Complications and side effects; Diabetes; Diabetes mellitus (non-insulin dependent); DNA binding proteins; Drug therapy; Drugs; Dyslipidemia; Energy expenditure; Fatty acids; Female; Genes; Genetic aspects; Genetic Linkage; Genetic Predisposition to Disease; Genomics; Haplotypes; Health aspects; Histamine; Humans; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins - genetics; Kinases; Lipogenesis; Lipogenesis - drug effects; Lipogenesis - genetics; Male; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Mental disorders; Metabolic diseases; Metabolic disorders; Metabolic syndrome; Metabolism; Middle Aged; Miscellaneous; Neuropharmacology; Neurosciences; Obesity; original-article; Other metabolic disorders; Patients; Pharmacology. Drug treatments; Pharmacotherapy; Polymorphism, Single Nucleotide; Proteins; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Psychosis; Psychotherapy; Psychotropic drugs; Retrospective Studies; Risk factors; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - genetics; Serotonin; Side effects; Single-nucleotide polymorphism; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Proteins - genetics; Sterol regulatory element-binding protein; Sterols; Transcription factors; Weight Gain - drug effects; Weight Gain - genetics; Young Adult; Europe; Germany; Norway; metabolic syndrome; cholesterol; antipsychotic; functional convergent genomics; gene; Endocrinopathy; Human; Pancreatic hormone; Neuroleptic; Psychotropic; Pharmacotherapy; Schizophrenia; Lipids; Metabolic diseases; Cardiovascular disease; German; Metabolic syndrome; Genetic determinism; Insulin; Weight gain; Cholesterol; Psychosis; Treatment; Gene; Genetics; Antipsychotic; Lipogenesis
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4002133

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (
SREBF1, SREBF2, SCAP, INSIG1
and
INSIG2
) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (
P
=0.0003–0.00007) between three markers localized within or near the
INSIG2
gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the
INSIG2
gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.