Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism

Sarsenbayeva, Assel; Marques-Santos, Cátia M.; Thombare, Ketan; Nunzio, Giada Di; Almby, Kristina E.; Lundqvist, Monalill; Eriksson, Jan W.; Pereira, Maria João

doi:10.1016/j.psyneuen.2019.104445

Cited by 28 publications

(29 citation statements)

References 53 publications

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“…Our findings also contrast with the short-term effects of olanzapine, which at 100 µM inhibited isoprenaline-induced lipolysis in rat adipocytes, whereas risperidone was inefficient at the same dose [11]. Moreover, these observations are in line with the very recent findings of Sarsenbayeva et al, who reported during the completion of our work that olanzapine can lower basal lipolysis after short-term incubation (30 min) with human adipocytes, but not after longer treatment (24 h) [37]. Therefore, the fattening side-effect of olanzapine found in psychotic patients under prolonged treatment (Zyprexa ® at >15 mg/day) did not appear to be mediated by an immediate modulation of lipolytic activity in adipocytes.…”

Section: In Vitro Evaluation Of the Direct Influence Of Antipsychoticsupporting

confidence: 92%

“…Indeed, testing the putative antilipolytic properties of any given agent in basal conditions is poorly relevant. This may explain some of the discrepancies found in the literature regarding the effects of antipsychotic and antidepressant drugs on basal lipolysis [10,11,37]. To further characterize any antilipolytic capacity, it is more discerning to work under prestimulated conditions.…”

Section: Influence Of Opipramol On Basal and Stimulated Lipolytic Actmentioning

confidence: 99%

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Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

et al. 2020

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Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

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Section: In Vitro Evaluation Of the Direct Influence Of Antipsychoticsupporting

confidence: 92%

Section: Influence Of Opipramol On Basal and Stimulated Lipolytic Actmentioning

confidence: 99%

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

et al. 2020

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“…Glucose uptake assessment was performed in adipocytes after incubating adipose tissue with simvastatin as described previously [ 57 ]. In short, following the incubation with the drugs, isolated adipocytes were washed with glucose-free KRH medium (4% BSA, 150 nM adenosine, pH = 7.4).…”

Section: Methodsmentioning

confidence: 99%

Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome

et al. 2021

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Inhibition of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase is associated with an increased risk of new-onset type 2 diabetes. We studied the association of genetic or pharmacological HMG-CoA reductase inhibition with plasma and adipose tissue (AT) metabolome and AT metabolic pathways. We also investigated the effects of statin-mediated pharmacological inhibition of HMG-CoA reductase on systemic insulin sensitivity by measuring the HOMA-IR index in subjects with or without statin therapy. The direct effects of simvastatin (20–250 nM) or its active metabolite simvastatin hydroxy acid (SA) (8–30 nM) were investigated on human adipocyte glucose uptake, lipolysis, and differentiation and pancreatic insulin secretion. We observed that the LDL-lowering HMGCR rs12916-T allele was negatively associated with plasma phosphatidylcholines and sphingomyelins, and HMGCR expression in AT was correlated with various metabolic and mitochondrial pathways. Clinical data showed that statin treatment was associated with HOMA-IR index after adjustment for age, sex, BMI, HbA1c, LDL-c levels, and diabetes status in the subjects. Supra-therapeutic concentrations of simvastatin reduced glucose uptake in adipocytes and normalized fatty acid-induced insulin hypersecretion from β-cells. Our data suggest that inhibition of HMG-CoA reductase is associated with insulin resistance. However, statins have a very mild direct effect on AT and pancreas, hence, other tissues as the liver or muscle appear to be of greater importance.

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“…An in-vitro study reported that aripiprazole increases blood adiponectin levels in the supernatants on mouse fibroblast cultures (120). Another in-vitro study revealed that aripiprazole does not change the mRNA expression of ADIPOQ gene on human subcutaneous adipose tissue (121). The study by Gao et al reported that patients with first episode schizophrenia receiving a 24-week aripiprazole treatment have lower blood adiponectin levels than those before treatment (122).…”

Section: Aripiprazolementioning

confidence: 99%

The Role of Adiponectin in the Pathogenesis of Metabolic Disturbances in Patients With Schizophrenia

et al. 2021

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Antipsychotic-induced metabolic disturbance is a common adverse event occurring in patients treated with antipsychotic drugs. The mechanisms underlying metabolic dysregulation are complex, involving various neurochemical and hormonal systems, the interaction of genetic and lifestyle risk factors, and the antipsychotic drug prescribed. Recently, there has been increasing interest in the relationship between antipsychotic-induced metabolic disturbances and body weight regulatory hormones such as adiponectin. Adiponectin, an adipocyte-derived protein related to insulin sensitivity, weight gain, and anti-inflammation, has attracted great attention because of its potential role of being a biomarker to predict cardiovascular and metabolic diseases. Previous studies regarding the effects of antipsychotics on blood adiponectin levels have shown controversial results. Several factors might contribute to those inconsistent results, including different antipsychotic drugs, duration of antipsychotic exposure, age, sex, and ethnicity. Here we summarize the existing evidence on the link between blood adiponectin levels and metabolic disturbances related to antipsychotic drugs in patients with schizophrenia. We further discuss the effects of individual antipsychotics, patients' gender, ethnicity, age, and treatment duration on those relationships. We propose that olanzapine and clozapine might have a time-dependent biphasic effect on blood adiponectin levels in patients with schizophrenia.

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Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism

Cited by 28 publications

References 53 publications

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control

Impaired HMG-CoA Reductase Activity Caused by Genetic Variants or Statin Exposure: Impact on Human Adipose Tissue, β-Cells and Metabolome

The Role of Adiponectin in the Pathogenesis of Metabolic Disturbances in Patients With Schizophrenia

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