Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance
- Andrea R. Nawrocki1,
- Carlos G. Rodriguez1,
- Dawn M. Toolan2,
- Olga Price1,
- Melanie Henry1,
- Gail Forrest1,
- Daphne Szeto1,
- Carol Ann Keohane1,
- Yie Pan1,
- Karen M. Smith3,
- Izzat T. Raheem4,
- Christopher D. Cox4,
- Joyce Hwa1,
- John J. Renger2 and
- Sean M. Smith2⇑
- 1In Vivo Pharmacology, Merck Research Laboratories, Rahway, NJ
- 2Neuroscience, Merck Research Laboratories, West Point, PA
- 3In Vivo Pharmacology, Merck Research Laboratories, West Point, PA
- 4Medicinal Chemistry, Merck Research Laboratories, West Point, PA
- Corresponding author: Sean M. Smith, .
Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0247/-/DC1.
- Received February 12, 2013.
- Accepted September 29, 2013.
- © 2014 by the American Diabetes Association.
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