Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents

Abstract

Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague-Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition. The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.

Fig. 1.

Circulating Nutrient Concentrations in Fed and Food-Restricted Rats. Blood samples were collected from different cohorts of animals in the fed state (time 0) or after 5 h or 14 h of food restriction. All animals received either olanzapine (10 mg/kg) or vehicle via oral gavage 2 h prior to blood sampling, as described in Experimental Procedures. (A) Glucose was measured in whole blood while (B) insulin, (C) lactate, (D) free fatty acids, (E) alanine, and (F) triglycerides were measured in plasma. Data represent the mean ± SE (n = 10–20); asterisks indicate significant differences (***P < .001, **P < .01, *P < .05) compared with time-matched control values.

Fig. 2.

Effect of Olanzapine on Triglyceride Metabolism. (A and B) Oral lipid tolerance tests were conducted in narrow-weight range rats after 14 h of food restriction. An oral gavage of olive oil was administered as a single bolus on the second day of olanzapine treatment (10 mg/kg). (A) Plasma triglyceride concentration before and following oral olive oil challenge. (B) AUC for plasma triglycerides (n = 20). (C) Hepatic triglyceride secretion in 14 h food-restricted male rats. Baseline blood samples were collected, and tyloxapol (600 mg/kg) was then administered intravenously to inhibit lipoprotein lipase and thus triglyceride clearance. Serial blood samples were collected to measure the rise in plasma triglycerides and calculate the (C) rate of hepatic VLDL-triglyceride secretion. Data represent the mean ± SE (n = 6–7); asterisks indicate significant differences (***P < .001). (D–F) Tissue uptake of free fatty acids following olanzapine administration. The nonmetabolizable fatty acid analog, [¹²⁵I]-BMIPP, was used to measure fatty acid uptake in fed animals with ad libitum access to food and water. On the second day of olanzapine (10 mg/kg) administration, animals received a bolus i.v. injection of BMIPP, and serial blood samples were drawn for calculation of plasma radioactivity and FFA concentration during a 40-min in vivo labeling period. Tissues sampled included (D) skeletal and cardiac muscle, (E) liver and kidney, and (F) proximal duodenum, terminal ileum, and skin. Data represent the mean ± SE (n = 8); asterisks indicate significant differences (*P < .05, **P < .01).

Fig. 3.

Effect of Olanzapine on Respiratory Exchange Ratio (RER). RER (A–C) was calculated based on expired CO₂ and O₂ consumed (RER = VCO₂/VO₂). Each cage was measured for 1 min every 15 min. All data represent the mean ± SE. Time intervals that are statistically different are described in “Results.” Gray background shading or lack thereof indicates the dark and light cycles, respectively. Arrows indicate the time of olanzapine (10 mg/kg) or vehicle gavage. (A) After acclimatization period, ad libitum fed animals were briefly removed from the metabolic chambers for olanzapine (10 mg/kg) or vehicle gavage and then were replaced into the chambers without food. Automated calorimetry measurements where then initiated for a 24-h period. Using this approach, the RER was already significantly different by the time of the first measurement. Therefore, in (B), calorimetry measurements were recorded during the acclimatization period, and olanzapine or vehicle gavage was staggered in order to provide treatment a few minutes before readings from each cage were automatically collected by the calorimeter. After gavage, rats were replaced in the metabolic chambers but in this case (B) they retained ad libitum access to food and water. A second gavage was provided after 12 h as indicated (n = 12/group). A subset of animals remained in the cages for up to 36 h for additional measurements. (C and D) After acclimatization to the chambers, rats were 14 h food restricted and then gavaged with olanzapine 45 min prior to the start of the dark cycle. Refeeding began approximately 30 min after drug dosing. (C) RER and (D) food intake (2 and 12 h) were measured during the experiment (n = 6/group).

Fig. 4.

Schematic Representation of Findings. Olanzapine lowered fasting plasma glycerol implicating impaired lipolysis; however, FFA was depressed lower. FFA lowering appears secondary not only to impaired lipolysis but also increased uptake FFA by most peripheral tissues and elevated lipid oxidation. The key regulator of fat oxidation was decreased along with muscle TCA cycle intermediates, and anapleurotic metabolites contributing to the first strip of the TCA cycle. Measured metabolites are indicated by black text. A color version of this figure is in the Supplementary data as figure S4.

Fig. 5.

Effect of Antipsychotic Drugs on Respiratory Exchange Ratio (RER) in ad libitum Fed Mice during the Dark Cycle. Male mice were given a single dose of antipsychotic drug or vehicle via oral gavage (indicated by arrows) during the dark cycle following adequate food intake and normal rise in RER. Mice retained ad libitum access to food and water, except for a separate time-matched control group that was food restricted following vehicle gavage (A–D). The effects of olanzapine (OLZ), sulpiride (SUL), risperidone (RIS), clozapine (CLO), ziprasidone (ZIP), aripiprazole (ARI), and haloperidol (HAL) in ad libitum fed mice were examined and compared with vehicle-treated mice that were either fed ad libitum or food restricted. Data represent the mean ± SE (n = 5–6). Some of the same data are shown in different panels for easier comparison of time courses.