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.
Atypical antipsychotic medications constitute the frontline treatment for schizophrenia; however, they have a high rate of discontinuation resulting from dissatisfaction with efficacy and a general lack of tolerability (1). Several atypical antipsychotics induce weight gain and produce adverse metabolic effects that contribute to morbidity and drive patient noncompliance with prescribed medications (2). Increases in weight gain vary and range from modest changes with aripiprazole to significant increases with olanzapine (3,4). Metabolic risks associated with these medications include increased insulin resistance, hyperglycemia, dyslipidemia, and type 2 diabetes (3–5). Therefore, there is a pressing need to identify novel therapeutics to treat schizophrenia that do not induce weight gain or have an increased risk for producing metabolic adverse effects in patients.
Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that selectively degrade cyclic AMP (cAMP) and cyclic GMP (cGMP). There are 11 different families of PDEs that vary in their substrate specificity, kinetic properties, modes of regulation, intracellular localization, and tissue expression patterns (6–8). PDE 10A (PDE10A) is a dual-substrate PDE that degrades both cAMP and cGMP. PDE10A is encoded by a single gene that is highly expressed in the brain and has limited expression in the peripheral tissues (6,9). In the brain, PDE10A is highly concentrated in the striatum and is expressed at lower levels in other brain regions (10–12). In peripheral tissues, measurable levels of PDE10A expression are limited to the testis and pancreatic islet cells (9,10,13,14).
Substantial evidence has been generated supporting the hypothesis that PDE10A may be a novel therapeutic target for the treatment of schizophrenia. PDE10A-deficient mice show reduced exploratory behavior when placed in a novel environment and have a blunted response to the psychomotor activating effects of N-methyl-d-aspartate receptor (NMDA) receptor antagonists phencyclidine and MK-801 (15,16). Selective PDE10A inhibitors decrease psychomotor activity, reverse deficits in prepulse inhibition, and inhibit conditioned avoidance responding in rodents, models that are predictive of antipsychotic activity in the clinic (17–21). PDE10A inhibitors are also efficacious in preclinical assays that test cognitive domains impaired in schizophrenia (17,20,22,23) and models of negative symptoms (17).
Here we describe a novel role for PDE10A in the regulation of caloric intake and energy homeostasis. Using PDE10A knockout (PDE10A−/−) mice and a selective small molecule PDE10A inhibitor, we investigated the role of PDE10A in regulating body weight, feeding behavior, locomotor activity, and energy expenditure in mice fed a standard diet or a highly palatable diet rich in fats and carbohydrates. We show that pharmacological inhibition of PDE10A activity leads to a dose-dependent suppression of food intake and increased energy expenditure in obese mice with subsequent reduction of adiposity and improved insulin sensitivity. Thus, we describe a novel role for PDE10A in the homeostatic regulation of energy metabolism, possibly by integrating peripheral satiety and adiposity signals with central regulation of food intake.
Research Design and Methods
Experiments were performed in lean and diet-induced obese (DIO) C57Bl/6NTac mice (Taconic, Germantown, NY). PDE10A−/− mice were generated by replacing a fragment of 2,756 nucleotides (bp 1,947 to 2,000) with the Neo cassette between exons 16 and 17 of the PDE10A gene. After backcrossing into C57Bl/6Ntac, 99.6% of the C57Bl/6 genome was confirmed. Animals were individually housed under a 12-h light/dark cycle and fed ad libitum a standard diet (Teklad 7012; Harlan Teklad, Indianapolis, IN), a high-fat diet (HFD; D12492: 60% kcal from fat; Research Diets, New Brunswick, NJ), or a Western-style diet containing 32% kcal from milk fat and corn-oil (D12266B) with ad libitum water. All protocols for the use of these animals were approved by the Merck Research Laboratories Institutional Animal Care and Use Committee.
At 8 weeks of age, male PDE10A−/− and wild-type (WT) mice (n = 10–13 per group) were switched on HFD ad libitum for 10 weeks. Whole-body composition was quantified by magnetic resonance analysis (Echo Medical Systems, Houston, TX). Leptin and adiponectin (Meso Scale Discovery, Gaithersburg, MD), insulin (PerkinElmer, Waltham, MA), and glucose (OneTouch Ultra, LifeScan, Milpitas, CA), were measured using commercially available assays. Triglycerides, cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were measured using an automated analyzer (Roche, Indianapolis, IN).
THPP-6 [2-(6-chloropyridin-3-yl)-4-[(2S)-1-methoxypropan-2-yl]oxy-N-(6-methylpyridin-3-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide] was synthesized in-house (18) and was dosed by oral gavage in 5% Tween80/0.25% methylcellulose. AM251 [N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] was purchased from (Tocris, Ellisville, MO). For glucose tolerance tests (GTTs), 6-h fasted mice were given 1.5 g/kg glucose intraperitoneally (i.p.), and glucose was measured by glucometer (OneTouch Ultra) at 0, 20, 40, 60 and 120 min. Blood (2.5 μL) was collected into 1× PBS/EDTA (12.5 μL) for insulin determination.
Data were analyzed using repeated-measures ANOVA with Bonferroni post hoc analysis or unpaired Student t tests. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as [fasting insulin (mU/L) × fasting glucose (mmol/L)]/22.5.
Male PDE10A−/− mice and their littermates were analyzed at 10 weeks of age (n = 12 per group). They were acclimated to individual boxes within the OxyMax system (Columbus Instruments, Columbus, OH). Total and ambulatory locomotor activity, food intake, and Vo2 and Vco2 were measured in 30-min intervals, and the respiratory exchange ratio (RER) was calculated as Vco2/Vo2. Heat (energy expenditure) was calculated as CV × Vo2 subject × body weight0.75, with CV = 3.815 + 1.232 × RER (24). Total locomotor activity was expressed as one count per two consecutive x-axis infrared beam breaks, and fine movement was defined a single-beam break. Food intake and locomotor activity data were excluded 30 min before and after handling of the mice.
For pair-feeding studies, C57Bl/6 mice were fed an HFD (D12492) for 16 weeks and then switched to D12266B for 4 weeks before study. Mice were acclimated to pair-feeding for 1 week. The average feeding activity pattern of the group treated with 10 mg/kg THPP-6 was imposed on the pair-fed group in 10-min intervals, and pair-feeding was achieved by automatically controlling access to the food hopper.
Plasma concentration of THPP-6 was sampled from 2 to 24 h after oral administration and quantified using a SCIEX API5000 Q-Trap mass spectrometer (Applied Biosystems, Concord, ON, Canada). Plasma samples were separated on an Acquity UPLC HSS T3 C18 column (50 mm × 2.1 mm × 1.8 µm), with a mobile phase consisting of solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with 0.1% formic acid). THPP-6 and the internal standard were monitored in the positive ion mode at the transition from m/z 469.10 to 134.90 and m/z 309.2 to 205.1, respectively. The concentration of THPP-6 in the samples was determined using MultiQuant 2.1 based on standard curve and quality control samples.
In Vitro PDE Activity Assays
PDE activity was determined in duplicate at room temperature using an IMAP FP kit (Molecular Devices, Sunnyvale, CA) (20). Human PDE10A2 and rhesus monkey PDE2A3 enzymes were prepared from cytosolic fractions of transiently transfected AD293 cells, as described (20). All other PDEs (PDE1A, PDE3A, PDE4A1A, PDE5A1, PDE6C, PDE7A, PDE8A1, PDE9A2, and PDE11A4) were glutathione S-transferase–tagged human enzymes expressed in insect cells and were obtained from BPS Bioscience (San Diego, CA). The apparent inhibition constant (Ki) for THPP-1 against the 11 PDEs was determined using the apparent KM values for each enzyme, as described by Smith et al. (20).
Measurement of MK-801–Induced Psychomotor Activity
Male C57Bl/6 mice were used to examine the influence of THPP-6 on MK-801–induced locomotor activity. After habituation, animals were given vehicle (10% Tween 80/90% water) or THPP-6 (1, 3, 10, or 30 mg/kg orally), followed 120 min later by vehicle (saline) or MK-801 (0.25 mg/kg i.p.). Animals were placed in locomotor activity monitors (21 × 42 cm; Kinder Scientific, Julian, CA) 90 min after injection of THPP-6 and left in the activity monitors 90 min after being given MK-801. Total distance traveled was used to assess the influence of THPP-6 administration on activity during habituation and after MK-801 treatment. Locomotor activity was analyzed with one-way ANOVA (group as a between-subjects factor), and group differences were further examined using post hoc comparisons (Fisher least significant difference).
Data are expressed as means ± SEM. Statistical analysis was conducted using ANOVA or unpaired Student t test, as indicated. Statistical significance was defined as P < 0.05.
PDE10A−/− Mice Are Protected From HFD-Induced Weight Gain and Associated Metabolic Disturbances
To explore a functional role of PDE10A in energy metabolism and feeding behavior, we challenged PDE10A−/− mice and WT controls with an HFD, which was high in saturated fats (60% kcal from lard and soybean oil, 20% kcal carbohydrates). Diet-induced body weight gain was inhibited [ANOVA, F(1,21) = 41.26, P < 0.01] in PDE10A−/− mice and associated with a reduction in caloric intake (Fig. 1A, Table 1). Cumulative food intake was significantly reduced in PDE10A−/− compared with WT mice [ANOVA, F(1,21) = 28.30, P < 0.01; Fig. 1B]. DIO resistance correlated with reduced fat (t test, P < 0.01) and lean mass (t test, P < 0.01; Fig. 1C) and reduced leptin levels in PDE10A−/− mice (16.8 ± 3.4 ng/mL) versus WT controls (65.04 ± 4.1 ng/mL; Fig. 1D).
Feeding of an HFD leads to modest diet-induced insulin resistance and dyslipidemia in C57Bl/6 mice. After 10 weeks on the HFD, WT control mice developed hyperglycemia (286 ± 13 mg/dL) and mild hyperinsulinemia (6.5 ± 1.7 ng/mL; Table 1). Deletion of PDE10A was associated with a normalization of the metabolic profile evidenced by improved fed plasma glucose (232 ± 7 mg/dL; t test vs. WT, P < 0.01) and insulin levels (1.1 ± 0.3 ng/mL; t test vs. WT, P < 0.05; Table 1). Improved insulin sensitivity was indicated by a reduction in HbA1c (Table 1). PDE10A−/− mice showed lower total cholesterol levels in plasma and a trend toward reduced triglyceride levels in plasma compared with controls, indicative of improved lipid metabolism (Table 1). A significant reduction of AST levels (t test, P < 0.01) suggested overall improved liver function in PDE10A−/− mice.
Diet-Dependent Suppression of Food Intake in PDE10A−/− Mice
To investigate the involvement of PDE10A in the regulation of food intake and whole-body energy metabolism, we placed PDE10A−/− mice in metabolic rate chambers and determined feeding behavior, locomotor activity, energy expenditure, and RER in mice when fed a regular chow and after switching them to the HFD. No genotypic differences were found in cumulative food intake or daily food intake when mice were fed a regular chow diet (Fig. 2A–C). As observed previously, introduction of a highly palatable HFD suppressed food intake in PDE10A−/− mice [ANOVA, F(1,19) = 4.44; P < 0.05], resulting in resistance to diet-induced body weight gain [ANOVA, F(1,22) = 58.77; P < 0.001; Fig. 2A and B]. The suppression of food intake was not associated with a change in circadian behavior or meal patterns; however, 30-min food intake was significantly reduced [ANOVA, F(1,22) = 20.11; P < 0.01; Fig. 2D]. Total distance traveled and fine locomotor activity was unaffected by genotype or diet (Fig. 2E and F). Leptin levels (16.3 ± 1.74 vs. 4.3 ± 0.66 ng/mL, respectively; t test, P < 0.001) and insulin (6.5 ± 1.7 vs. 1.1 ± 0.3 ng/mL, respectively; t test, P < 0.05) were also reduced in PDE10A−/− mice compared with WT mice.
Using indirect calorimetry, we investigated the implication of a PDE10A deficiency on whole-body energy expenditure and nutrient utilization. Net metabolic rate was unchanged on the chow diet or after switching PDE10A−/− mice to an HFD (Supplementary Fig. 1A and B). We hypothesize that potential effects on energy expenditure may have been masked by compensatory decreases in energy expenditure due to reduced caloric intake. The RER ( CO2-to-O2 ratio) was similar mice fed the chow diet (Supplementary Fig. 1C) but was reduced in PDE10A−/− mice within 24 h after switching to the HFD [ANOVA, F(1,22) = 17.79, P < 0.001]. These findings suggest that a shift in nutrient partitioning toward increased fatty acid oxidation relative to glucose oxidation likely contributed to obesity resistance (Supplementary Fig. 1D).
Inhibition of PDE10A Causes Weight Loss and Metabolic Improvements in Obese Mice
A small molecule PDE10A inhibitor, THPP-6, was used to further characterize the effects of PDE10A inhibition on body weight, glucose, and lipid metabolism in DIO mice. THPP-6 (Fig. 3A) is a potent inhibitor of PDE10A (Ki = 0.92 ± 0.08 nmol/L) as determined by a fluorescence polarization assay measuring the ability of test compounds to inhibit hydrolysis of cAMP (25). THPP-6 is greater than 300-fold selective over the other 10 PDE families (Table 2) and did not have any significant activity when tested against a panel of more than 150 receptors, enzymes, and ion channels (Panlabs Screen, MDS Pharma). The antipsychotic potential of THPP-6 was evaluated in the psychostimulant-induced locomotor activity assay, and THPP-6 produced a full attenuation of MK-801 (NMDA receptor antagonist) activity in mice at a dose (10 mg/kg, orally) that yielded a total plasma concentration of 3.46 ± 0.91 μmol/L (Fig. 3B). DIO mice were dosed with THPP-6 daily before the feeding period began. Steady-state plasma concentrations of THPP-6 were 0.28 ± 0.03, 1.98 ± 0.18, and 13.12 ± 1.51 μmol/L after oral administration of 3, 10, and 30 mg/kg THPP-6, respectively.
THPP-6 treatment caused significant body weight loss within 3 days at all doses [ANOVA, F(4,35) = 60.92, P < 0.01; Fig. 4A] comparable to efficacy with a CB1 neutral antagonist, AM251, at full target engagement (Fig. 4A). THPP-6 treatment also decreased food intake [ANOVA, F(4,29) = 16.04, P < 0.01; Fig. 4B] and reduced fat mass (Fig. 4C and D). Reduced leptin [ANOVA, F(4,35) = 30.02, P < 0.01] and an increase in total adiponectin (Fig. 4E and F) was observed with THPP-6 but not AM251 treatment [ANOVA, F(4,35) = 12.59, P < 0.001]. Body weight loss was associated reduced fasting insulin [ANOVA, F(4,35) = 8.57, P < 0.001; Fig. 5A] and HOMA-IR [ANOVA, F(4,35) = 6.5, P < 0.001; Fig. 5B]. GTT results were not affected by THPP-6 in this study (Fig. 5C). However, glucose-stimulated insulin release was reduced during the GTT [ANOVA, F(4,35) = 9.48, P < 0.001; Fig. 5D]. In summary, PDE10A inhibition improved insulin sensitivity by mechanisms that are likely secondary to body weight loss.
In a separate experiment, we investigated the effect of feeding of a Western-style diet on PDE10A-mediated food intake in obese mice. We confirmed that equivalent doses of THPP-6 caused comparable suppression of food intake and body weight loss independently of the source or the amount of the fat in the diet, that is, when fed lard- (60% kcal from fat) or milk fat–based (32% kcal from fat) diets (Figs. 4 and 6). DIO mice (initial body weight, 43.9 ± 0.6 g) were treated with vehicle, 10 mg/kg THPP-6, or were vehicle pair-fed to the average food intake of the THPP-6–treated group for 13 days (n = 7 per group). Caloric intake was indistinguishable between THPP-6–treated and pair-fed groups (average −12% cumulative reductions compared with vehicle group; Fig. 6A). Despite equal food intake, body weight loss was significantly greater in the THPP-6–treated group, indicating a feeding-independent mechanism (Student t test; Fig. 6B). Notably, the first dose of THPP-6 caused a marked suppression of food intake (Supplementary Fig. 2) that was sustained for ∼8 h postdose, followed by a compensatory increase on days 2 and 3. Food intake then stabilized for the remainder of the study (85% of the control groups). Lean mass was not significantly different between the THPP-6–treated mice and their pair-fed group (Fig. 6C); however, loss in adipose tissue was greater in the THPP-6 group than in the pair-fed group, suggesting that PDE10A inhibition promotes utilization fat independent of food intake.
Pair-feeding allowed us to uncover a PDE10A-related increase in energy expenditure (Fig. 6D). Energy expenditure was decreased in the pair-fed group as result of reduced food intake but was reversed by THPP-6 treatment to normal levels. The differential drug effect was highly reproducible after 5 days of dosing and independent of food intake and body weight. THPP-6 treatment did not independently affect RER and tracked closely with food intake (Fig. 6E and Supplementary Fig. 2). Ambulatory activity was comparable to vehicle (Fig. 6F), with the exception of a transient reduction after the first dose that subsided quickly at steady-state concentrations of the drug. Our results indicate that PDE10A inhibition affects body weight and adiposity due to a combination of hypophagia and increased resting and active metabolic rate. In addition, the PDE10A inhibitor THPP-6 causes hypophagia and increases energy expenditure unrelated to the source of lipids and/or composition of the diets (Figs. 4 and 6).
Schizophrenia is a debilitating disorder estimated to effect up to 1% of the general population (26). In addition to the well-defined psychiatric symptoms, schizophrenic patients have an increased prevalence of obesity (27,28). A number of atypical antipsychotic medications have also been reported to induce significant weight gain and increase the likelihood of developing type 2 diabetes and cardiovascular disease (3,4,29). Therefore, developing novel antipsychotic medications that do not induce weight gain or that have the potential to reverse weight gain and metabolic effects produced by marketed antipsychotic drugs is of utmost importance.
In this study, we describe a novel role for PDE10A in the regulation of caloric intake and energy expenditure. We found that deletion of PDE10A in mice leads to a profound suppression of food intake after exposure to highly palatable Western-style diets containing an excess of fats and sugars. This significant reduction of food consumption conferred resistance to diet-induced weight gain in PDE10A−/− mice and protection against the development of comorbidities typically associated with obesity such as insulin resistance and dyslipidemia. PDE10A−/− mice had normalized lipid profiles and a significant reduction in fasting insulin and glucose-stimulated insulin secretion compared with obese DIO controls (Table 1). These changes correlated with improved HbA1c levels and demonstrate a protective effect against the development of insulin resistance associated with obesity.
Using indirect calorimetry, we show that PDE10A regulates feeding behavior and also influences overall metabolic rate. Under conditions of HFD feeding, PDE10A−/− mice exhibited a small but significant shift in RER toward increased lipid oxidation, whereas total heat was unchanged. The increase in lipid oxidation at the relative cost of glucose utilization is reflective of a state of reduced caloric intake when increased mobilization of lipids is necessary to maintain energy balance (24). Such an increase in lipid oxidation may have contributed to a preservation of lean mass and a reduction of fat mass in PDE10A−/− mice. From these findings we speculate that effects on total energy utilization in PDE10A−/− mice were masked by a compensatory decrease in energy expenditure associated with reduced caloric intake. The net balance therefore contributing to the obesity resistance in PDE10A−/− mice is likely a combination of reduced intake and increased metabolism.
Findings based on genetically deficient PDE10A mice were mirrored pharmacologically with a PDE10A inhibitor, THPP-6. Chronic THPP-6 treatment of DIO mice caused significant body weight loss and suppression of food intake at similar plasma exposures that produce antipsychotic-like activity in animal models. Body composition analysis indicated that body weight loss was driven by a reduction in body fat while lean mass was maintained. Inhibition of PDE10A activity produced body weight loss significantly greater than data from the pair-fed group, revealing a previously not appreciated role of PDE10A in the regulation of energy expenditure. Importantly, these effects were sustained after multiple doses and chronic THPP-6 treatment caused metabolic improvements in the absence of effects on locomotive behavior.
Our data also indicate that the type of substrates used by the body is not affected by PDE10A inhibition. Unlike the results from the PDE10A−/− mice, RER was overlapping with the pair-fed group, suggesting that the compound did not affect substrate preference. However, the lack of an effect may be attributable to food restriction and cannot be dissected in this particular paradigm. Our pair-feeding experiments unequivocally demonstrate a food-independent component of PDE10A inhibition leading to increased overall energy utilization. The mechanism for this increase in metabolic rate is yet to be dissected on a molecular level, and greater understanding of the link between PDE10A inhibition and peripheral oxidative capacity is needed to fully interpret the utility of this mechanism. In any case, enhanced nutrient combustion in the absence of cardiovascular effects (data not shown) and in combination with significant caloric restriction may be of great therapeutic interest.
Pharmacological inhibition of PDE10A was also associated with an improved metabolic profile in insulin-resistant DIO mice. Similar to PDE10A−/− mice, fasting insulin levels were reduced, and there was a trend toward improved glucose disposal with reduced glucose-stimulated insulin release during a GTT. It is noteworthy that fasting insulin was reduced to a greater extent upon inhibition of PDE10A than with similar body weight loss associated with AM251 treatment at full-target engagement, suggesting superior insulin-sensitizing efficacy. The CB1 receptor antagonist AM251 is thought to drive metabolic improvements predominantly through central regulation of appetite. Although CB1 receptors are expressed in peripheral tissue, in our hands, non–brain-penetrant antagonists do not have insulin-sensitizing properties independently of body weight loss (data not shown). To that effect, reductions in fasting insulin correlated with an increase in circulating total adiponectin levels after THPP-6 treatment that was absent in mice treated with our anorexic control compound AM251. Adiponectin levels inversely correlate with adipose tissue inflammation, hepatic glucose output and peripheral glucose uptake, and adiposity (30). Taken together, our data indicate a potential for additional body weight–independent benefits related to PDE10A inhibition on handling of glucose that should be further investigated. However, whether PDE10A activity directly impacts metabolic parameters independently of CNS-mediated effects remains to be examined.
PDE10A mRNA is expressed in pancreatic islet cells, and researchers have reported that small-molecule PDE10A inhibitors function as insulin secretagogues in vitro (31,32). Furthermore, Cantin et al. (31) demonstrated that PDE10A inhibitors improved glucose tolerance and reduced insulin secretion in Wistar rats after a glucose challenge, suggesting that the effects of THPP-6 in DIO and HFD studies may be partly related to altered insulin secretion. In this study, we examined the effects of THPP-6 on glucose-stimulated insulin release and showed that THPP-6 did not significantly affect glucose-stimulated insulin release in isolated mouse islets (data not shown). These data support the hypothesis that THPP-6–mediated effects on glucose metabolism and insulin levels are conferred predominantly by body weight loss and not through direct regulation of insulin secretion.
Preclinical data pointing to nutrient-dependent effects on feeding behavior suggest that PDE10A plays a role in central orexigenic pathways and/or with a reward mechanism related to the palatability of various types of nutrient and caloric content of food. This is supported by the abundant expression of PDE10A in the brain and limited distribution in peripheral tissue. Specifically, PDE10A is expressed at high levels in the mesolimbic and mesocortical dopamine systems, including the caudate, nucleus accumbens, hippocampus, and prefrontal cortex (10,11). Preclinical studies have linked cues from highly palatable foods to multiple aspects of dopaminergic signaling. Mesolimbic dopaminergic neurons that innervate the nucleus accumbens have been associated with motivation for highly palatable food and related reward behaviors (33–36). Furthermore, mesocortical dopaminergic neurons innervate brain regions that regulate the emotional response to eating, and dopaminergic neurons that innervate the caudate influence sensory-motor aspects of feeding (34,36,37). In addition to the direct effects of palatable foods on central dopaminergic systems, a number of peripheral metabolic signals, including leptin, insulin, and ghrelin, influence dopaminergic systems (34,38,39). Taken together, these studies suggest that PDE10A is positioned to play an important role in the central regulation of feeding behavior.
In summary we have described a novel role for PDE10A in the regulation of feeding behavior and the regulation of metabolic rate. We have demonstrated that genetic deletion and pharmacological inhibition of PDE10A both have significant effects on body weight and food intake in rodents and on improved insulin sensitivity. Furthermore, PDE10A inhibition increased energy expenditure, leading to reduced adiposity and greater weight loss than seen under conditions of equal caloric intake. These findings suggest that PDE10A inhibitors may be novel therapeutics for the treatment of schizophrenia with the potential to address weight gain and metabolic issues associated with this disorder.
Funding. All work in the manuscript was funded by Merck Research Laboratories.
Duality of Interest. All authors are employees of Merck Research Laboratories. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. A.R.N. and S.M.S. wrote and edited the manuscript. C.G.R., D.M.T., O.P., M.H., G.F., D.S., C.A.K., Y.P., K.M.S., I.T.R., and C.D.C. generated data for the manuscript and contributed to discussion. J.H. and J.J.R. contributed to discussion and edited the manuscript. S.M.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.