Olanzapine and diet affect cns and peripheral metabolic outcomes in a non-human primate

Bethea C.L., Varlamov O., Kievit P., Reddy A.P., Roberts C.T.

Research output: Chapter in Book/Report/Conference proceedingChapter


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
Original languageEnglish (US)
Title of host publicationNeuropsychopharmacology
Place of PublicationC.L. Bethea, Oregon National Primate Research Center, Beaverton, OR, United States
PublisherNature Publishing Group
ISBN (Print)0893-133X
StatePublished - 2013
Externally publishedYes

Publication series



  • *atypical antipsychotic agent
  • *body fat
  • *college
  • *diet
  • *glucose
  • *hypothalamus
  • *insulin resistance
  • *nonhuman
  • *olanzapine
  • *primate
  • *psychopharmacology
  • *weight
  • Haplorhini
  • Macaca fuscata
  • adipocyte
  • adipose tissue
  • analysis of variance
  • anterior hypothalamus
  • biopsy
  • calorie
  • central nervous system
  • diet restriction
  • fatty acid
  • fatty acid transport
  • female
  • gene expression
  • ghrelin
  • glucose tolerance
  • glucose tolerance test
  • human
  • hyperinsulinemia
  • impaired glucose tolerance
  • insulin
  • insulin release
  • insulin response
  • insulin sensitivity
  • isoprenaline
  • lipid diet
  • lipid storage
  • lipolysis
  • macaque model
  • mediobasal hypothalamus
  • messenger RNA
  • metabolic disorder
  • placebo
  • rodent
  • side effect
  • subcutaneous fat
  • sugar
  • tissues


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