The long-term goals of this proposal are to elucidate the mechanisms of the metabolic side effects of atypical antipsychotics (e.g., olanzapine) that are used to treat psychiatric disorders like schizophrenia and other psychiatric disorders. Over the last 15 years their use has grown sharply in adults and children. This is problematic because patients taking take these drugs are frequented by serious metabolic side effects including obesity, metabolic syndrome, diabetes and sudden cardiac death. We hypothesize that these effects are preceded by causal changes in intermediary and lipid metabolism that drive the insulin resistance, hunger, adiposity and obesity-comorbidities. Interesting preliminary data shows that atypical antipsychotics rapidly and robustly increase fat oxidation and impair metabolic flexibility in male and femal rats and mice. We propose that this inappropriate switching of peripheral fuel utilization to lipid is what leads to insulin resistance via a Randle cycle effect. This fuel switching may involve lowering of skeletal muscle malonyl-CoA and anaplerotic precursors needed to produce it, suggesting a mechanism and strategies for reversing these metabolic side effects. Notably the tissue specific expression of enzymes and pathways that synthesize or are affected by malonyl CoA could explain the tissue specific differences in insulin sensitivity caused by olanzapine. Finally we and others have shown that the weight gain and adiposity caused by atypical antipsychotics in rodent models is associated in part with either increased food intake or maintaining an inappropriate pretreatment food intake in the context of decreased physical/habitual activity. Questions raised these exciting findings will be addressed in the following specific aims.
Aim 1 : Elucidate the role of metabolic inflexibility in the side effects of atypical antipsychotics, test strategies to alleviate this side effect, develop a rapid non-invasive in vivo or in vitro assay to predict likelihood of metabolic side effects in emerging third generation compounds and determine the underlying mechanisms.
Aim 2 : Determine the mechanisms underlying trapping of energy in fat by olanzapine and other antipsychotics.
Aim 3 : Examine the role of ingestive behavior, hypothalamic malonyl- CoA and leptin in the orexigenic side effects of atypical antipsychotics. Physiological, molecular and pharmacological approaches will be used to reveal the mechanism(s) underlying the metabolic side effects of atypical antipsychotics and we will test novel strategies to reverse them. By the conclusion of this work, we will have developed an approach to rapidly predict the likelihood of obesity-related side effects in emerging compounds before they are tested in humans. This will aid in the design of next generation drugs with reduced side effects and may also reveal new therapeutic targets for the treatment of obesity and diabetes.

Public Health Relevance

Atypical antipsychotics are drugs used for psychiatric disorders like schizophrenia. While very effective in treating the psychiatric disorders, they inadvertently cause diabetes and obesity in the patients that have to take them. The number of adults and children using these drugs is increasing. So it is very important that we determine how these side effects occur so that we can alleviate them, so new drugs can be developed with reduced side effects. The studies we propose in animal models and cells will help identify factors underlying these effects. Another potential benefit of this research is that we may discover new targets for the treatment of obesity and diabetes. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084428-04
Application #
8474748
Study Section
Special Emphasis Panel (ZRG1-EMNR-Q (50))
Program Officer
Pawlyk, Aaron
Project Start
2010-09-30
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$306,273
Indirect Cost
$108,038
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
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Klingerman, Candice M; Stipanovic, Michelle E; Hajnal, Andras et al. (2015) Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site. Dose Response 13:1559325815618915
Lynch, Christopher J; Xu, Yuping; Hajnal, Andras et al. (2015) RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats. PLoS One 10:e0123966
Lynch, Christopher J; Adams, Sean H (2014) Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 10:723-36
Klingerman, Candice M; Stipanovic, Michelle E; Bader, Mohammad et al. (2014) Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice. Schizophr Bull 40:327-40
Albaugh, Vance L; Vary, Thomas C; Ilkayeva, Olga et al. (2012) Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents. Schizophr Bull 38:153-66
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