Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents

Abstract

Objective: To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.

Research methods and procedures: Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.

Results: Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.

Discussion: A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.

Figures

Figure 1

Chronic self-administration of olanzapine in mice. A/J (upper panel) and C57Bl/6J (lower panel) mice were provided olanzapine (4 mg/kg) daily in a small amount of cookie dough (Olanzapine) or cookie dough alone (Control), as indicated. On Day 10, the dosage was increased to 8 mg/kg. Body weight was monitored daily for the duration of the experiment. Data are represented as mean body weight ± SE (n = 10).

Figure 2

Effect of chronic olanzapine exposure on body weight and food intake in rats. Sprague-Dawley rats were matched for body weight and then trained to eat cookie dough as indicated in “Research Methods and Procedures” (Day 0 body weights not significantly different: control, 246.00 ± 2.8; olanzapine, 245.9 ± 3.0). Cookie dough ± olanzapine (4 mg/kg body weight) was then self-administered daily starting at Day 0. Dose of olanzapine was increased at days 7, 21, and 29 to 8, 12, or 20 mg/kg body weight, respectively. Body weight (upper panel) and food intake (lower panel) were monitored daily. Data are mean ± SE (n = 12). Change in body weight differed significantly (p < 0.05) between Days 3 to 29. * p < 0.05.

Figure 3

Clozapine lacks the body weight gain side effect in rats. Sprague-Dawley rats were matched for body weight and then trained to eat cookie dough as indicated in “Research Methods and Procedures” (Day 0 body weights not significantly different: control, 256.8 ± 3.5; clozapine →clozapine plus olanzapine, 259.3 ± 3.6). Animals began self-administration of clozapine-containing dough (4 mg/kg) or cookie dough alone, as indicated. The dose of clozapine was increased to 8 mg/kg on Day 8. Starting with Day 13 (indicated by arrow), animals receiving clozapine-containing dough were given dough supplemented with olanzapine (4 mg/kg). Body weights were monitored daily, and the change in weight from day zero is expressed as mean ± SE (n = 12). Change in body weight differed significantly between groups from Day 17 through the end of the study (p < 0.05).

Figure 4

Glucose tolerance after chronic olanzapine exposure. Rats were fasted overnight after chronic olanzapine administration and then challenged with an OGTT. A fasting blood glucose was taken at time zero, and glucose was administered by oral gavage immediately afterward. (Upper panel) Blood glucose measurements were taken at 30-minute intervals until 2 hours post-glucose gavage. Data are mean ± SE (n = 24). (Lower panel) Corresponding insulin concentrations were calculated for each time-point. Data are mean ± SE (n = 24). * Value significantly different from control (p < 0.05).

Figure 5

Effect of chronic olanzapine exposure on tissue weights in rats. Animals received olanzapine (4 mg/kg) through oral gavage (Olz) or saline (Con) for 20 days. Tissues were collected and weighed after an overnight fast on Day 20. Data represent mean weight ± SE (n = 8). Gastroc, gastrocnemius. * Results significantly different from control (p < 0.05).

Figure 6

Topiramate blunts the olanzapine-induced weight gain in rats. Animals received olanzapine (Olz), olanzapine + topiramate (Olz + Top), or cookie dough alone (Control), as indicated. (Upper panel) Change in body weight after 5 days of treatment was determined for each condition. Data represent mean weight ± SE. * Result significantly different from control (p < 0.05). (Lower panel) Effects of drugs on tissue weights. Data represent mean weight ± SE (n = 8 per group). (a) Significantly different from the control condition. (b) Significantly different from animals receiving only olanzapine. Gastroc, gastrocnemius.

Figure 7

Glucose tolerance after acute olanzapine exposure. Rats received four doses of olanzapine divided over a 29-hour period. An OGTT was performed after a 5-hour fast. Blood glucose (upper panel) and insulin (lower panel) measurements are shown. Data are mean ± SE (n = 19 or 22). * Values statistically different from control (p < 0.05).

Figure 8

Plasma leptin before and 90 minutes after an IP glucose injection. Rats received olanzapine (4 mg/kg IP) acutely. Plasma leptin was measured before and at 90 minutes post-glucose injection in animals receiving either olanzapine or saline (Control) through oral gavage, as indicated. Data are represented as mean ± SE (n = 21 to 23). (a) Significantly different compared with control animals at time zero. (b) Significantly different compared with olanzapine-receiving animals at time zero.

Figure 9

Plasma leptin concentrations after acute olanzapine, olanzapine and topiramate, or clozapine exposure. Rats received vehicle (Control), olanzapine (Olz), or olanzapine and topiramate (Olz + Top) through oral gavage (upper panel) or clozapine through oral gavage (lower panel), and plasma leptin concentration was determined after a 5-hour fast. Data are represented as mean ± SE. (a) Significantly different from the control group (p < 0.05).