Psychoneuroendocrinology | 2019
Antipsychotics differentially regulate insulin, energy sensing, and inflammation pathways in hypothalamic rat neurons
Abstract
INTRODUCTION\nSecond generation antipsychotic (AP)s remain the gold-standard treatment for schizophrenia and are widely used on- and off-label for other psychiatric illnesses. However, these agents cause serious metabolic side-effects. The hypothalamus is the primary brain region responsible for whole body energy regulation, and disruptions in energy sensing (e.g. insulin signaling) and inflammation in this brain region have been implicated in the development of insulin resistance and obesity. To elucidate mechanisms by which APs may be causing metabolic dysregulation, we explored whether these agents can directly impact energy sensing and inflammation in hypothalamic neurons.\n\n\nMETHODS\nThe rat hypothalamic neuronal cell line, rHypoE-19, was treated with olanzapine (0.25-100\u2009uM), clozapine (2.5-100\u2009uM) or aripiprazole (5-20\u2009uM). Western blots measured the energy sensing protein AMPK, components of the insulin signaling pathway (AKT, GSK3β), and components of the MAPK pathway (ERK1/2, JNK, p38). Quantitative real-time PCR was performed to determine changes in the mRNA expression of interleukin (IL)-6, IL-10 and brain derived neurotrophic factor (BDNF).\n\n\nRESULTS\nOlanzapine (100\u2009uM) and clozapine (100, 20\u2009uM) significantly increased pERK1/2 and pJNK protein expression, while aripiprazole (20\u2009uM) only increased pJNK. Clozapine (100\u2009uM) and aripiprazole (5 and 20\u2009uM) significantly increased AMPK phosphorylation (an orexigenic energy sensor), and inhibited insulin-induced phosphorylation of AKT. Olanzapine (100\u2009uM) treatment caused a significant increase in IL-6 while aripiprazole (20\u2009uM) significantly decreased IL-10. Olanzapine (100\u2009uM) and aripiprazole (20\u2009uM) increased BDNF expression.\n\n\nCONCLUSIONS\nWe demonstrate that antipsychotics can directly regulate insulin, energy sensing, and inflammatory pathways in hypothalamic neurons. Increased MAPK activation by all antipsychotics, alongside olanzapine-associated increases in IL-6, and aripiprazole-associated decreases in IL-10, suggests induction of pro-inflammatory pathways. Clozapine and aripiprazole inhibition of insulin-stimulated pAKT and increases in AMPK phosphorylation (an orexigenic energy sensor) suggests impaired insulin action and energy sensing. Conversely, olanzapine and aripiprazole increased BDNF, which would be expected to be metabolically beneficial. Overall, our findings suggest differential effects of antipsychotics on hypothalamic neuroinflammation and energy sensing.