Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: Relationship with stearoyl-CoA desaturase activity

Abstract

Recent preclinical and clinical evidence suggests that the stearoyl-CoA desaturase-1 (Scd1) enzyme plays a key role in the regulation of triglyceride (TG) biosynthesis and insulin sensitivity, and in vitro studies have found that antipsychotic medications up-regulate Scd1 mRNA expression. To investigate these effects in vivo, rats were treated with risperidone (1.5, 3, 6 mg/kg/d), paliperidone (1.5, 3, 6 mg/kg/d), olanzapine (2.5, 5, 10 mg/kg/d), quetiapine (5, 10, 20 mg/kg/d), haloperidol (1, 3 mg/kg/d) or vehicle through their drinking water for 40 d. Effects on liver Scd1 mRNA expression and an index of Scd1 activity (the plasma 18:1/18:0 ratio, ‘deaturation index’) were determined, as were postprandial plasma triglyceride (TG), glucose, insulin, and polyunsaturated fatty acid (PUFA) levels. All atypical antipsychotics increased the plasma 18:1/18:0 ratio, but not liver Scd1 mRNA expression, at doses found to also increase plasma TG levels. Among all rats (n=122), the plasma 18:1/18:0 ratio accounted for 56% of the variance in TG concentrations. The plasma 18:1/18:0 ratio was also positively associated with erythrocyte and heart membrane phospholipid 18:1n-9 composition. All antipsychotics except risperidone increased glucose levels at specific doses, and none of the antipsychotics significantly altered insulin levels. The plasma 18:1/18:0 ratio accounted for 20% of the variance in glucose levels. Plasma omega-3 and omega-6 PUFA levels were inversely correlated with the plasma 18:1/18:0 ratio and TG and glucose levels. These in vivo data demonstrate that different atypical antipsychotic medications increase the plasma 18:1/18:0 ratio in association with elevations in postprandial TG levels, and that concomitant elevations in PUFA biosynthesis oppose these effects.

Chronic Olanzapine Treatment Induces Disorders of Plasma Fatty Acid Profile in Balb/c Mice: A Potential Mechanism for Olanzapine-Induced Insulin Resistance

“…In agreement with our results, Karen L.Teff et al[10] reported that olanzapine causes significant elevations in postprandial insulin, glucagon-like peptide 1, and glucagon coincident with insulin resistance in the absence of weight gain in healthy subjects. Moreover, decreased body weight has previously been observed in rats following chronic olanzapine or paliperidone treatment at specific dose[34]. Furthermore, numerous reports have documented hyperglycemia and new-onset type 2 diabetes in the absence of substantial weight gain inSGA-treated patients[6].…”

“…olanzapine at 6 mg/kg body weight in rats produced a mean plasma concentration of 12.0±4.9 ng/ml at 3h after the last daily dose, which is comparable to the plasma concentration (above 9 ng/ml) that had a greater likelihood of clinical response[51]. Moreover, numerous reports showed that chronic daily treatment with olanzapine induced significant changes in adiposity and lipid metabolismin female rats[34,44,52]. Nevertheless, without the plasma olanzapine concentration data it remains possible that greater changes in FA profile may have been observed with a different mode of administration.…”

Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways

“…Although SCD1 is just a desaturase that catalyse the synthesis of monounsaturated fatty acids, previous studies have shown that the elevated SCD1 activity is implicated in a wide range of disorders, including obesity [41,42] and hepatic insulin resistance [43]. Moreover, evidence for up-regulation of Scd1 mRNA expression had been obtained in cultured human and rat cell lines following exposure to SGAs treatment [44,45], as well as in blood cells of patients treated with olanzapine [46]. Therefore, increased lipid accumulation caused by olanzapine was particularly likely due to the promotion of Scd1 mRNA expression.…”

Olanzapine depot formulation in rat: a step forward in modelling antipsychotic-induced metabolic adverse effects

“…Rodents are commonly used to model antipsychotic-induced metabolic adverse effects, with hyperphagia and weight gain consistently replicated after subchronic olanzapine administration to female rats, either orally or via injections (Albaugh et al, 2006;Baptista et al, 1993;Choi et al, 2007;Goudie et al, 2002;MinetRinguet et al, 2006;Skrede et al, 2012a). Still, certain metabolic disturbances, such as antipsychotic-induced dyslipidemia, have not been convincingly modelled in rat (Boyda et al, 2010;Coccurello and Moles, 2010;Davoodi et al, 2009;Fell et al, 2007), although in a few recent experiments, olanzapine exposure led to increased serum triglyceride levels both in female (Skrede et al, 2012b) and in male (McNamara et al, 2011) rats. Discrepant findings in human and rat are likely related to species-specific aspects of energy and drug metabolism, in particular the short half-life (t 1/2 ) of olanzapine in rats -2.5-3 h, compared to the average 30 h in humans (Aravagiri et al, 1999;Callaghan et al, 1999;Mattiuz et al, 1997).…”