Centrally administered urocortin 2 decreases gorging on high-fat diet in both diet-induced obesity-prone and -resistant rats

Abstract

ObjectiveObesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to play a role in obesity risk. The present study tested the hypothesis that i) the microstructure of chronic high-fat diet intake differs between genetically selected Diet-Induced Obesity (DIO) and Diet Resistant (DR) rats, and ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 (CRF2) agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats.DesignMale, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg).ResultsIrrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ~40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with 2/3rd less water.ConclusionsUnlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically-prone DIO rats, which otherwise show a “gorging” meal pattern. These results open new opportunities of investigation towards treating some forms of diet-induced obesity.

Analyses of meal patterns across dietary shifts

“…This dark-light difference was not observed for the HE animals except during the recovery period when the animals were switched to standard chow. In other studies, the size of meals taken in the dark or light were comparable for both chow-fed and high-fat diet fed rats (Furnes, et al, 2009; Melhorn, et al, 2010) or dark meal size was larger than light meal size for both chow-fed and high-fat fed rats (Cottone, et al, 2013; Cottone, Sabino, Nagy, Coscina, & Zorrilla, 2007). In contrast, consistent with the findings of the current study, average meal size of chow pellets taken during the dark cycles were larger than those taken in the light cycles for both Otsuka Long-Evans Tokushima Fatty (OLETF) rats that do not express CCK-A receptors and Long-Evans Tokushima (LETO) controls (Moran, Katz, Plata-Salaman, & Schwartz, 1998).…”

“…In contrast, the number of meals does not significantly change across the phases (Brooks, Lockwood, & Wiggins, 1946; Teitelbaum & Campbell, 1958). In general high-fat diet driven hyperphagia also appears to be influenced by an increase in meal size (Cottone, et al, 2013; Farley, Cook, Spar, Austin, & Kowalski, 2003; Furnes, Zhao, & Chen, 2009; Melhorn, et al, 2010). Collectively, evidence in the literature points to changes in meal pattern parameters across the development of DIO but there are some conflicting findings.…”

Diet-induced obesity and diet-resistant rats: differences in the rewarding and anorectic effects of d-amphetamine

“…Rats were housed in a 12h reverse light/dark cycle, AAALAC-approved vivarium. DIO and DR rats were fed either ad libitum fed chow (corn-based Harlan Teklad LM-485 Diet 7012 (Cottone et al 2013; Cottone et al 2007)) or ad libitum high-fat diet (D12266B Research Diets, New Brunswick, NJ) for 4 weeks, to allow DIO to develop obesity. (Ricci and Levin 2003) Procedures adhered to the NIH Guide for the Care and Use of Laboratory Animals and the Principles of Laboratory Animal Care and were approved by the Institutional Animal Care and Use Committee of Boston University.…”

“…DIO and DR rats, after prolonged ad libitum feeding with chow diet or high-fat diet, were euthanized and carcasses were transferred to the University of Alabama–Birmingham where the body composition analysis was carried out as previously described (Cottone et al 2013; Cottone et al 2007). Additional information is available in the online Supplementary Information file.…”

“…When fed a standard chow diet, DIO rats are lean; however, when exposed to high-fat diet, they disproportionally gain weight and become obese, while DR remain lean (Cottone et al 2013; Levin et al 1997). Therefore, the DIO/DR rodent model effectively mimics the polygenic, heritable differences in the vulnerability to diet-induced obesity observed in humans, allowing the study of pre-existing, predisposing factors leading to obesity (Cottone et al 2007).…”