Abstract
The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS). Rats were fed either standard chow (SC) or a cafeteria (CAF) diet comprised of intermittent human snacks and a constant free choice between a HF/sweet (HF/S) diet and SC for 13 weeks. Thereafter the SC group was treated with vehicle (for 4 weeks) and the CAF group was divided into a vehicle and an ACT-335827 treatment group. Energy and water intake, food preference, and indicators of MetS (abdominal obesity, glucose homeostasis, plasma lipids, and blood pressure) were monitored. Hippocampus-dependent memory, which can be impaired by DIO, was assessed. CAF diet fed rats treated with ACT-335827 consumed less of the HF/S diet and more of the SC, but did not change their snack or total kcal intake compared to vehicle-treated rats. ACT-335827 increased water intake and the high-density lipoprotein associated cholesterol proportion of total circulating cholesterol. ACT-335827 slightly increased body weight gain (4% vs. controls) and feed efficiency in the absence of hyperphagia. These effects were not associated with significant changes in the elevated fasting glucose and triglyceride (TG) plasma levels, glucose intolerance, elevated blood pressure, and adiposity due to CAF diet consumption. Neither CAF diet consumption alone nor ACT-335827 affected memory. In conclusion, the main metabolic characteristics associated with DIO and MetS in rats remained unaffected by chronic ACT-335827 treatment, suggesting that pharmacological OXR-1 blockade has minimal impact in this model.
Highlights
Metabolic syndrome (MetS) represents a group of risk factors for diabetes and cardiovascular disease; it is characterized by abdominal obesity plus two of four factors including: elevated circulating triglyceride (TG) levels, reduced circulating high density lipoprotein-associated cholesterol (HDLc) levels, elevated blood pressure, and elevated fasting plasma glucose levels (International Diabetes Federation; http://www.idf.org)
This parameter was used to divide CAF diet fed rats in two subgroups with a similar mean and distribution of glucose to food choice, both of the CAF diet fed groups consumed significantly more of the HF/S diet (77.3% of total calories) than standard chow (SC) (22.7% of total calories) [Food: F(1, 18) = 53.11, p < 0.05], but they did not differ in their level of preference [CAF diet treatment Group × Food: F(1, 18) = 1.97, p = 0.18]
Under a CAF diet comprised of a choice between a HF/S diet and SC and an additional snack 4 times weekly, rats developed major signs of human metabolic syndrome (MetS), including abdominal adiposity, elevated TG and fasting blood glucose levels, glucose intolerance, and elevated blood pressure when compared to rats fed only SC
Summary
Metabolic syndrome (MetS) represents a group of risk factors for diabetes and cardiovascular disease; it is characterized by abdominal obesity plus two of four factors including: elevated circulating triglyceride (TG) levels, reduced circulating high density lipoprotein-associated cholesterol (HDLc) levels, elevated blood pressure, and elevated fasting plasma glucose levels (International Diabetes Federation; http://www.idf.org). Pharmacological treatments are expected to help patients to restrict over-eating by reducing systemic and brain signals responsible for driving high caloric palatable food intake (Adamo and Tesson, 2008). Orexin neuropeptides A and B modulate energy balance and metabolic homeostasis (Sakurai, 2006) and palatable food and sweet reward perception (Di Sebastiano and Coolen, 2012). OXRs are expressed widely in orexinergic projection areas throughout the brain including the mesolimbic system, implicated in reward/aversion, and including several mid- and hindbrain regions, implicated in regulating energy homeostasis and food intake (Trivedi et al, 1998; Marcus et al, 2001). Some orexin neurons project to the ventral tegmental area (VTA), where they synapse with www.frontiersin.org
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