Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

Abstract

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.

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition

“…Selective PDE10A inhibitors, such as SEP-39, are unlikely to produce the metabolic side effects seen with current antipsychotics, which are due to, in part, H1 antagonism. Furthermore, data in the literature suggest that PDE10A inhibitors protect against the effects of a high fat diet (Nawrocki et al, 2014) and may be insulinogenic (Cantin et al, 2007).…”

Brown and Beige Adipose Tissues in Health and Disease

“…The cAMP/PKA pathway is negatively regulated by phosphodiesterases (PDEs) that degrade cAMP. Pharmacological inhibition of PDE10A or deletion of PDE10A increases beige adipogenesis and energy expenditure in mice (115, 218). Furthermore, activation of α2 adrenergic receptors, unlike β adrenergic receptors, inhibits brown adipocyte thermogenesis (367).…”

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

“…For example, cell-based studies (Walz et al, 2007), studies with PDE3B KO mice (Choi et al, 2006), and studies in transgenic mice overexpressing PDE3B in pancreatic b-cells (Harndahl et al, 2002) clearly establish a central role for PDE3B in regulation of insulin secretion. However, inhibition of PDE8B (Dov et al, 2008) and PDE10A (Nawrocki et al, 2014) also modulates insulin secretion. Recent studies in a murine model of diet-induced obesity have indicated that adiposity and weight gain was reduced and insulin sensitivity was improved in PDE10A KO mice or in WT mice treated with a PDE10 inhibitor (Nawrocki et al, 2014).…”