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Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications.

ABSTRACT: Second-generation antipsychotics can greatly improve symptoms of psychosis-spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient's risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical factors. In addition, genetic variations in pathways associated with satiety are increasingly recognized as potential contributors to antipsychotic-associated weight gain. Polymorphisms in the leptin gene, as well as the leptin receptor gene, are potential pharmacogenetic markers associated with these outcomes. This article summarizes evidence for the associations of the leptin gene and the leptin receptor gene polymorphisms with antipsychotic-induced weight gain, potential mechanisms underlying these relationships, and discusses areas for future pharmacogenetic investigation.

SUBMITTER: Lee AK

PROVIDER: S-EPMC3792568 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications.

Lee Amy K AK Bishop Jeffrey R JR

Pharmacogenomics 20110701 7

Second-generation antipsychotics can greatly improve symptoms of psychosis-spectrum disorders. Unfortunately, these drugs are associated with weight gain, which increases a patient's risk for developing chronic diseases including Type 2 diabetes, cardiovascular diseases or other obesity-related complications. There are interindividual differences in weight gain resulting from antipsychotic drug use that may be explained by pharmacodynamic characteristics of these agents as well as clinical facto ...[more]

PMID: 21787190

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Project description:Adiponectin exerts beneficial effects by reducing inflammation and improving lipid metabolism and insulin sensitivity. Although the adiponectin level is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans.Forty-four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8 weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8±1.2?kg resulted in increased adiponectin level (P=0.03), whereas weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (P=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, whereas a leptin antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal-weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in the adipose tissue from normal-weight participants, but did not do so in the adipose tissue from obese participants. Second, we noted that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin.Modest weight gain in healthy individuals is associated with increases in adiponectin levels, which correlate positively with changes in leptin. In vitro, leptin induces adiponectin expression, which is attenuated by increased caveolin-1 expression. In addition, the adipose tissue from obese subjects shows increased caveolin-1 expression and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin levels in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity.

Project description:Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (?7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

Dataset Information

Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications.

Publications

Pharmacogenetics of leptin in antipsychotic-associated weight gain and obesity-related complications.

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