Background: Clinical and animal data suggest that atypical antipsychotics such as olanzapine (OLZ) induce significant metabolic changes that are serious side effects of their primary use. Since controlled human studies are problematic and rodent data may be poorly translatable, we sought a macaque model of OLZ-induced metabolic disease. Normal monkey chow contains significantly lower calories from sugar and fat compared to a western style diet (WSD). Therefore, we examined metabolic endpoints in the presence and absence of OLZ with monkey chow or WSD. Methods: A female Japanese macaque was administered OLZ (5mg/kg/day) for 6 months, with dietary changes at 2-month intervals as follows: OLZ + restricted chow, OLZ + unrestricted chow, OLZ + WSD, and placebo + WSD. Weight was accessed weekly, with glucose tolerance tests (GTT) and Dexascans performed at baseline and every 2 months. To evaluate adipose-specific effects, visceral (V) and subcutaneous (SC) adipose tissue biopsies were obtained at baseline and after OLZ + unrestricted chow and OLZ +WSD to evaluate adipocyte size, lipolysis and insulin-stimulated fatty acid uptake. A separate trial was conducted on 2 monkeys with 5 days of OLZ- or no-treatment followed by RT-PCR on rostral and medial basal hypothalamus (MBH). Results: Weight increased on OLZ+restricted chow and stabilized on OLZ+ unrestricted chow. OLZ+WSD did not significantly change the plateau in 2 months.Weight declined upon withdrawal of OLZ with continued WSD. Body fat increased from 14% at baseline to 22%, 30%, 28% and 19% at 2, 4, 6 and 8 mo, respectively, indicating that body fat was elevated on OLZ regardless of diet and declined upon OLZ removal. Fasting glucose levels were normal; and glucose tolerance and the insulin response during GTT were normal with OLZ +restricted chow or OLZ +unrestricted chow. Addition of WSD with OLZ impaired glucose tolerance during GTT. Insulin remained in the normal range, but first phase insulin secretion was reduced. Hence, insulin did not respond to elevated glucose during GTT. After removal of OLZ but continued WSD, glucose clearance returned to normal. However, this was associated with hyperinsulinemia, perhaps triggered by early insulin resistance. Adipocyte diameter was increased in V and SQ fat by OLZ +chow and OLZ+WSD (p<0.01, 2-way ANOVA), but OLZ+WSD was not different from OLZ +chow. Isoproterenol-stimulated lipolysis was present in V and SQ fat. Lipolysis was similar between baseline and OLZ+chow, but it was significantly reduced by addition of WSD (ANOVA p<0.0001; posthoc p<0.05). Insulin increased FFA uptake at baseline. However, insulin-induced FFA uptake was blunted with OLZ administration + chow or +WSD in both V and SC fat (posthoc p<0.05), suggesting the early development of adipose insulin resistance. There was an increase in expression of AgRP and a decrease in expression of CART & ghrelin in MBH and rostral hypothalamus compared to untreated control tissue. 5HT2C mRNA increased and POMC mRNA decreased in the MBH with OLZ treatment. There was no apparent change in MCR4 in either region. Conclusions: We conclude that OLZ acts on peripheral tissues as well as in the CNS; that changes in hypothalamic gene expression precede increased fat accumulation; that adipose tissue exhibits insulin resistance prior to alterations in GTT/ITT; that addition of WSD to OLZ precipitates impaired glucose tolerance without an obvious insulin response; and that removal of OLZ and continued WSD resulted in normalized glucose tolerance and elevated insulin. These data suggest OLZ rapidly changes hypothalamic gene expression; decreases insulin sensitivity in adipose tissue, and may suppress insulin with high fat diet. These data suggest complex and early responses to OLZ that may be exacerbated by WSD. Further study is needed with more animals.
C.L., B., O., V., P., K., A.P., R., & C.T., R. (2013). Olanzapine and diet affect cns and peripheral metabolic outcomes in a non-human primate. Neuropsychopharmacology. C.L. Bethea, Oregon National Primate Research Center, Beaverton, OR, United States: Nature Publishing Group. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed12&NEWS=N&AN=71278106