Clinical 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 have initiated development of a macaque model of OLZ-induced metabolic disease. In this preliminary feasibility study, we examined some metabolic effects of OLZ in a female macaque in the context of a standard low-calorie/fat monkey chow diet followed by a high-fat/sugar Western-style diet (WSD). A female Japanese macaque was administered OLZ (1.25 mg/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 assessed weekly. Glucose tolerance tests (GTT) and Dexascans were performed at baseline and every 2 months. Omental (OM) and subcutaneous (SQ) adipose tissue biopsies were obtained at baseline, after OLZ+Unrestricted chow and after OLZ+WSD to evaluate adipocyte size, lipolysis and insulin-stimulated free fatty acid uptake (FFA). 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. Weight increased on OLZ+Restricted chow and stabilized on OLZ+Unrestricted chow. OLZ+WSD did not significantly change the weight plateau. 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. 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 clearance during GTT. Insulin remained in the normal range, but first phase insulin secretion was reduced. After removal of OLZ, but continued WSD, glucose clearance returned to normal, but this was associated with hyperinsulinemia. Adipocyte diameter was increased in OM and SQ fat by OLZ+chow and OLZ+WSD to a similar extent. (p<0.01, 2-way ANOVA). In OM, isoproterenol-stimulated lipolysis occurred at baseline. In both depots, isoproterenol-stimulated lipolysis occurred with OLZ+chow, but it was significantly blunted by addition of WSD (ANOVA p<0.0001; posthoc p<0.05). Insulin increased FFA uptake at baseline. OLZ +chow or OLZ+WSD increased basal FFA uptake and insulin-induced FFA uptake was blunted in both depots (posthoc p<0.05). There was a marked decrease in POMC gene expression, and increased AgRP and NPY expression in the hypothalamus. There was also a clear increase in serotonin (5HT) 2C, melanocortin (MCR4), and Leptin (LepR) receptor gene expression. These data support the hypotheses that OLZ acts on peripheral tissues as well as in the CNS; that changes in hypothalamic gene expression occur very rapidly and precede increased fat accumulation; that adipose tissue exhibits insulin resistance prior to alterations in GTT; that addition of WSD to OLZ precipitates hyperglycemia without an obvious insulin response; and that removal of OLZ and continued WSD resulted in normalized glucose clearance and elevated insulin. These data suggest complex and early responses to OLZ that may be exacerbated by WSD.
Keywords: AGRP; Olanzapine; POMC; diabetes; free fatty acid; insulin; lipolysis; macaque; western style diet.