The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C

Lord, Caleb C.; Wyler, Steven C.; Wan, Rong; Castorena, Carlos M.; Ahmed, Newaz; Mathew, Dias; Lee, Syann; Liu, Chen; Elmquist, Joel K.

doi:10.1172/jci93362

Cited by 135 publications

(124 citation statements)

References 22 publications

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“…Human gene HTR2C (5-hydroxytryptamine receptor 2C, synonym: serotonin receptor 2C) contains a known SNP marker (rs3813929) of overexpression of this gene causing obesity as a complication of antipsychotic treatment with olanzapine [15]. This SNP can therefore speed up atherogenesis, consistently with the above-mentioned review [120] and independent clinical data [125,126] (Table 5). Around rs3813929, we recognized five unannotated SNPs (e.g., rs1348095721), all of which seem to yield HTR2C overexpression too, thereby allowing us to recommend them as candidate SNP markers of an atherogenesis increase, as presented in Table 5.…”

Section: Human Genes Associated With Obesitymentioning

confidence: 67%

Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters Show Stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It

Пономаренко

Рассказов

Chadaeva

et al. 2020

IJMS

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(1) Background: The World Health Organization (WHO) regards atherosclerosis-related myocardial infarction and stroke as the main causes of death in humans. Susceptibility to atherogenesis-associated diseases is caused by single-nucleotide polymorphisms (SNPs). (2) Methods: Using our previously developed public web-service SNP_TATA_Comparator, we estimated statistical significance of the SNP-caused alterations in TATA-binding protein (TBP) binding affinity for 70 bp proximal promoter regions of the human genes clinically associated with diseases syntonic or dystonic with atherogenesis. Additionally, we did the same for several genes related to the maintenance of mitochondrial genome integrity, according to present-day active research aimed at retarding atherogenesis. (3) Results: In dbSNP, we found 1186 SNPs altering such affinity to the same extent as clinical SNP markers do (as estimated). Particularly, clinical SNP marker rs2276109 can prevent autoimmune diseases via reduced TBP affinity for the human MMP12 gene promoter and therefore macrophage elastase deficiency, which is a well-known physiological marker of accelerated atherogenesis that could be retarded nutritionally using dairy fermented by lactobacilli. (4) Conclusions: Our results uncovered SNPs near clinical SNP markers as the basis of neutral drift accelerating atherogenesis and SNPs of genes encoding proteins related to mitochondrial genome integrity and microRNA genes associated with instability of the atherosclerotic plaque as a basis of directional natural selection slowing atherogenesis. Their sum may be stabilizing the natural selection that sets the normal level of atherogenesis.

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Section: Human Genes Associated With Obesitymentioning

confidence: 67%

Candidate SNP Markers of Atherogenesis Significantly Shifting the Affinity of TATA-Binding Protein for Human Gene Promoters Show Stabilizing Natural Selection as a Sum of Neutral Drift Accelerating Atherogenesis and Directional Natural Selection Slowing It

Пономаренко

Рассказов

Chadaeva

et al. 2020

IJMS

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“…However, a recent study has reported that chronic clozapine treatment induced weight gain and fasting glucose levels in male rats (von Wilmsdorff et al, 2013 ). The most successfully established rodent model for APD-induced weight gain/obesity is by olanzapine (Weston-Green et al, 2011 ; van der Zwaal et al, 2014 ; Lord et al, 2017 ). Other APDs such as risperidone, sulpiride, haloperidol, and chlorpromazine have also been established to cause some degree of weight gain in rats and mice (Boyda et al, 2010a ; Lian et al, 2015 ).…”

Section: Mechanisms For Antipsychotic-induced Diabetesmentioning

confidence: 99%

Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

et al. 2017

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Antipsychotic drugs (APDs) are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1) APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2) APD-induced obesity can result in high levels of free fatty acids (FFA) and inflammation, which can also cause insulin resistance. (3) APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

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“…SGAs, such as olanzapine (OLZ), have numerous metabolic side effects (Newcomer, 2005). These include weight gain, dyslipidaemia, hyperglycaemia, insulin resistance, and an increased risk for the development of type 2 diabetes and cardiovascular disease (Bergman and Ader, 2005;Newcomer, 2005;Kessing et al, 2010;Lord et al, 2017;Reynolds and McGowan, 2017). Although impairments in glucose homeostasis often accompany weight gain itself, there is evidence that OLZ has direct diabetogenic effects independent of changes in body weight.…”

Section: Introductionmentioning

confidence: 99%