A Murine Model of Atypical Antipsychotic‐Induced Weight Gain and Metabolic Dysregulation

Coccurello, Roberto; Moles, Anna

doi:10.1002/0471142301.ns0933s52

Cited by 9 publications

(5 citation statements)

References 47 publications

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“…Mice were housed in individually ventilated cages with an artificial 12-hour light/ dark cycle at room temperature (20-25°C) and fed with a medium fat diet (metabolizable energy, 17.5 kJ/g), which resembles a typical human diet consisting of 14% protein, 31% lipid, and 54% carbohydrate (46). Mice were treated with 3 mg/kg olanzapine (MilliporeSigma) or vehicle (DMSO) for 2, 4, and 8 weeks as previously described (20,47).…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Cui

Peng

Zhang

et al. 2018

Journal of Clinical Investigation

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Yale University holds rights to patents that describe the potential utility of MIF inhibition and MIF genotype determination. RB has applied for a patent related to MIF modulators (9540322). RB and LL have applied for a patent related to the method of inhibiting binding or activity of MIF by administering a MIF antagonist (9221903). RB has applied for a patent related to MIF promoter polymorphism in inflammatory disease (9139877).

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Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Cui

Peng

Zhang

et al. 2018

Journal of Clinical Investigation

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“…In this context, the present work shows novel aspects with respect to the existing literature in the field. First, very poor data are actually available on the possible impact of the psychotic disorder per se on adipose tissue amount, distribution and functioning, as most of preclinical data have been obtained by using pharmacological animal models of this disorder, such as the ketamine model ( Coccurello and Moles, 2010 ). Moreover, although some clinical studies have described weight elevation, adipose tissue dysfunctions, as well as other metabolic alterations, in drug-free and drug-naive psychotic patients ( Ryan et al, 2003 , 2004 ; Spelman et al, 2007 ), limited evidence still exist on this subject, mostly because some existing reports on the pre-medication era present some important biases in the methodological aspects and in the definition of the concept of “drug-free” and “drug-naïve” patients.…”

Section: Discussionmentioning

confidence: 99%

Visceral Fat Dysfunctions in the Rat Social Isolation Model of Psychosis

et al. 2017

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Medication with neuroleptics has been associated with adipose tissue dysfunctions and, in particular, with increased visceral fat amount. However, several studies suggested that antipsychotic treatment might not be the main responsible of fat mass accumulation, as this has been also described in not treated psychotic patients. One of the most used “drug-free” rodent models of psychosis is the social isolation rearing of young adult rats, which provides a non-pharmacologic method of inducing long-term alterations reminiscent of symptoms seen in psychotic patients. Recent data highlighted a crucial role of redox imbalance in adipose tissue dysfunctions, in terms of decreased antioxidant defense and increased reactive oxygen species (ROS). Here, we investigated possible oxidative stress-related biomolecular alterations associated with visceral fat increase in 7 week isolated rats. To this purpose, we quantified total and visceral fat amount by using dual-energy X-ray (DEXA) absorptiometry. On visceral fat, we analyzed the expression of specific ROS-producer genes (Nox1, Nox4, Hmox-1), antioxidant enzymes (Prdx1 and Ucp-1) and oxidative stress-induced damage markers (Cidea, Slc2a4, and Acacb). The impact of oxidative stress on beta3-adrenergic receptors (Adrb3), at both mRNA and protein level, was also assessed. We found that 7 weeks of social isolation induced an increase in total and visceral fat, associated with a decrease in Prdx1 (mRNA and protein) as well as Ucp-1 mRNA levels and an enhanced expression of Nox1 (mRNA and protein) and Hmox-1 mRNA. No differences were detected in Nox4 mRNA levels between grouped and isolated animals. Elevations in Cidea, Slc2a4, and Acacb expression in visceral fat of isolated animals accounted for oxidative stress-related damage in this tissue, further associated with a significant increase in Adrb3 mRNA and protein. Our results provide a novel understanding of the pathological link existing among psychosocial stress-induced psychosis, adipose tissue dysfunctions and redox imbalance, opening new therapeutic perspectives for the treatment of alterations in peripheral tissues associated with this mental disorder.

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“…Previously proposed mechanisms for the metabolic effects of antipsychotics are diverse 3, 5, 6, 8, 50 , but many postulate that their CNS effects resulted in increased appetite and hence weight gain 8, 50 . However, this could not be sufficient to account for all metabolic side effects, since a direct correlation between weight gain and diabetes in antipsychotic treated patients is often not seen 20, 51, 52 .…”

Section: Discussionmentioning

confidence: 99%

Antipsychotics activate the TGFβ pathway effector SMAD3

Cohen

Sundaresh²,

Levine

2012

Mol Psychiatry

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Although effective in treating an array of neurological disorders, antipsychotics are associated with deleterious metabolic side effects. Through high-throughput screening, we previously identified phenothiazine antipsychotics as modulators of the human insulin promoter. Here, we extended our initial finding to structurally diverse typical and atypical antipsychotics. We then identified the TGFβ pathway as being involved in the effect of antipsychotics on the insulin promoter, finding that antipsychotics activated SMAD3, a downstream effector of the TGFβ pathway, through a receptor distinct from the TGFβ receptor family and known neurotransmitter receptor targets of antipsychotics. Of note, antipsychotics that do not cause metabolic side effects did not activate SMAD3. In vivo relevance was demonstrated by reanalysis of gene expression data from human brains treated with antipsychotics, which showed altered expression of SMAD3 responsive genes. This work raises the possibility that antipsychotics could be designed that retain beneficial CNS activity while lacking deleterious metabolic side effects.

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A Murine Model of Atypical Antipsychotic‐Induced Weight Gain and Metabolic Dysregulation

Cited by 9 publications

References 47 publications

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Visceral Fat Dysfunctions in the Rat Social Isolation Model of Psychosis

Antipsychotics activate the TGFβ pathway effector SMAD3

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