Expression of dopamine signaling genes in the post-mortem brain of individuals with mental illnesses is moderated by body mass index and mediated by insulin signaling genes

Abstract

Preclinical studies implicate insulin signaling as a modulator of dopamine transmission, but human data is currently limited. We hypothesize that changes in the expression of insulin receptor-related genes in the post-mortem brain tissue of patients with mood and psychotic disorders mediate the expression of dopamine regulation-related genes. From a database containing microarray data from the post-mortem dorsolateral prefrontal cortex (dlPFC) (healthy controls [HC]: n = 209; patients: n = 321) and hippocampus (HC: n = 180; patients: n = 196), we conducted a hypothesis-driven analysis through the a priori selection of 12 dopamine- and 3 insulin-related genes. Mediation and moderated mediation models, accounting for the role of body mass index (BMI), were used. In the dlPFC, expressions of insulin receptor- and dopamine regulation-related genes were moderated by BMI, with significantly lower expression in high BMI patients. In the hippocampus, there were significantly lower expressions of these genes, which were not moderated by BMI. Illnesses by BMI effects on expression of dopamine genes were fully mediated by expression of insulin receptor gene (INSR). Analysis of conditional indirect effects showed interactions between INSR and BMI, indicating significantly stronger indirect effects at higher BMI values. In the hippocampus we observed that expression of insulin receptor substrate 1 and 2 fully mediated the effects of illnesses on expression of dopamine genes. In conclusion, differential expression of dopamine-related genes was related to altered expression of insulin signaling genes. BMI had region-specific effects, supporting the hypothesis that metabolic systems are critical mediators of dopaminergic function.

Trial registration: ClinicalTrials.gov NCT00001260.

Keywords: Dopamine; Gene expression; Insulin; Mood disorders; Schizophrenia.

Figure 1–

Gene Expression in the Dorsolateral Prefrontal Cortex. Mean standardized expression values of insulin and dopamine signaling genes in the dorsolateral prefrontal cortex, according to group (HC vs. MI) and BMI. For illustration purposes, BMI was dichotomized as obesity (BMI ≥ 30 kg/m2) and non-obesity (BMI< 30 kg/m2). HC: healthy controls; MI: mental illness.