Olanzapine-Induced Hyperphagia and Weight Gain Associate with Orexigenic Hypothalamic Neuropeptide Signaling without Concomitant AMPK Phosphorylation

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance

Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat

This study aims to investigate whether orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain. Methods In the current study, we examined whether a single intraperitoneal injection of clozapine or olanzapine induced metabolic disturbances in adult female outbred Sprague–Dawley rats. Serum glucose and lipid parameters were measured during time-course experiments up to 48 h. Real-time quantitative PCR was used to measure specific transcriptional alterations in lipid and carbohydrate metabolism in adipose tissue depots or in the liver. Results Our results demonstrated that acute administration of clozapine or olanzapine induced a rapid, robust elevation of free fatty acids and glucose in serum, followed by hepatic accumulation of lipids evident after 12–24 h. These metabolic disturbances were associated with biphasic patterns of gluconeogenic and lipid-related gene expression in the liver and in white adipose tissue depots. Conclusion Our results support that clozapine and olanzapine are associated with primary effects on carbohydrate and lipid metabolism associated with transcriptional changes in metabolically active peripheral tissues prior to the development of drug-induced weight gain

The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK—carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity

Glycemic control in critically ill surgical patients: risks and benefits

Kaushik Mukherjee,1 Vance L Albaugh,2 Justin E Richards,3 Kelli A Rumbaugh,4 Addison K May1 1Division of Trauma and Surgical Critical Care, 2Division of General Surgery, 3Department of Anesthesiology, 4Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: Glucose metabolism in humans is exceedingly complex. At baseline, it is controlled by elaborate signaling mechanisms, and these mechanisms are profoundly altered by the surge of catecholamines and cytokines associated with acute postsurgical and post-traumatic stress. These alterations in signaling mechanisms result in hyperglycemia; although this hyperglycemia can start very rapidly after the traumatic or surgical insult, it can persist during the entire period of critical illness and even afterward. Numerous randomized clinical trials have been conducted to determine if hyperglycemia is associated with increased mortality in surgical patients. These studies have had different conclusions that are difficult to interpret in light of differences in study methodology, but there is certainly ample evidence that inadequately controlled hyperglycemia causes harm due to increased infectious morbidity, and possibly increased mortality. As we have become more proficient in controlling hyperglycemia, the concept of insulin resistance, determined as the amount of insulin required to achieve hyperglycemia, has come to the fore. Insulin resistance is not a static concept, and may change before significant events such as infection. Patients with elevated and persistent insulin resistance have been demonstrated to suffer increased infectious morbidity and mortality, albeit in nonrandomized studies. Along with insulin resistance, the concept of glycemic variability, the amount of variation in serum blood glucose over time, has also become relevant; increased variability has been associated with hypoglycemia and mortality. Both of these risks can result from aggressive insulin therapy, and glycemic control protocols must be appropriately planned and implemented to avoid hypoglycemia and excessive externally induced variability. Computer-assisted protocols may be of significant benefit in optimizing glycemic control. The most recent recommendations available are to keep serum blood glucose levels below 150 mg/dL and to avoid hypoglycemia. Keywords: insulin resistance, hypoglycemia, insulin signaling, hyperglycemia, critical illness, glycemic variabilit

Lipid-Lowering Effects of Tetradecylthioacetic Acid in Antipsychotic-Exposed, Female Rats: Challenges with Long-Term Treatment

Background: Psychiatric patients often require chronic treatment with antipsychotic drugs, and while rats are frequently used to study antipsychotic-induced metabolic adverse effects, long-term exposure has only partially mimicked the appetite-stimulating and weight-inducing effects found in the clinical setting. Antipsychotic-induced effects on serum lipids are also inconsistent in rats, but in a recent study we demonstrated that subchronic treatment with the orexigenic antipsychotic olanzapine resulted in weight-independent increase in serum triglycerides and activation of lipogenic gene expression in female rats. In addition, a recent long-term study in male rats showed that chronic treatment with antipsychotic drugs induced dyslipidemic effects, despite the lack of weight gain. Aims: In the current study, we sought to examine long-term effects of antipsychotic drugs on weight gain, lipid levels and lipid composition after twice-daily administration of antipsychotics to female rats, and to investigate potential beneficial effects of the lipid-lowering agent tetradecylthioacetic acid (TTA), a modified fatty acid. Methods: Female rats were exposed to orexigenic antipsychotics (olanzapine or clozapine), metabolically neutral antipsychotics (aripiprazole or ziprasidone), or TTA for 8 weeks. Separate groups received a combination of clozapine and TTA or olanzapine and TTA. The effects of TTA and the combination of olanzapine and TTA after 2 weeks were also investigated. Results: The antipsychotic-induced weight gain and serum triglyceride increase observed in the subchronic setting was not present after 8 weeks of treatment with antipsychotics, while lipid-lowering effect of TTA was much more pronounced in the chronic than in the subchronic setting, with concomitant upregulation of key oxidative enzymes in the liver. Unexpectedly, TTA potentiated weight gain in rats treated with antipsychotics. Conclusion: TTA is a promising candidate for prophylactic treatment of antipsychotic-induced dyslipidemic effects, but a more valid long-term rat model for antipsychotic-induced metabolic adverse effects is required