Metabolic Signature of Antipsychotics Used in the Treatment of Autism
[Technical Report, Annual Report]
CINCINNATI UNIV OH
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Atypical antipsychotics AAP are prescribed to patients with autism spectrum disorders with symptoms of aggression or agitation, stereotypic behavior, temper tantrums and self-injury. Although AAP can ameliorate some mental or behavioral dysfunctions, they have serious metabolic side-effects that include weight gain, fat accretion, the metabolic syndrome, and increased risk of diabetes and cardiovascular disease. The current dogma is that the metabolic side effects of AAP are attributed to their action on neuronal circuits the brain, primarily via dopaminergic and serotonergic receptors. However, we discovered expression of such receptors in human and rodent adipocytes and demonstrated that administration of AAP to animal models caused significant weight gain and increased adiposity. This led us to propose that these receptors are directly targeted by AAP. Recent In vitro studies using human adipocytes and rat adipose tissue explants demonstrated multiple direct effects of AAP on adipose tissue. These include increase preadipocyte proliferation, augmentation of adipocyte size, suppression of basal lipolysis, and alterations in key lipogenic and lipolytic enzyme gene expression. We conclude that AAP induced metabolic dysregulation is caused, in part, by their direct action on adipose tissue, most likely via local dopamine and serotonin receptor subtypes.