Feeding microstructure in diet-induced obesity susceptible versus resistant rats: central effects of urocortin 2.

One billion people worldwide are now overweight or obese (Ogden et al. 2006). Genetic factors moderate susceptibility to obesity (Comuzzie & Allison, 1998), perhaps by altering the regulatory influence of neuropeptides (Adan, 2002) and peripheral feedback hormones (Drazen & Woods, 2003) on energy balance. Obese individuals are resistant to the weight-loss promoting properties of many molecules (Mann et al. 1988; Halaas et al. 1997; Niederau et al. 1997). While such resistance states can develop after obesity, central resistance to some anorexigens also is present before the onset of obesity in rats genetically prone to diet-induced obesity (Levin et al. 2003; Levin et al. 2004; Clegg et al. 2005; Irani et al. 2007). Such rats, and their counterpart diet resistant (DR) genotype, were selectively bred based on differential weight gain when fed a high-fat/high-energy diet and model the polygenic, heritable differences in vulnerability to diet-induced obesity seen in humans (Levin et al. 1997; Levin & Dunn-Meynell, 2002; Ricci & Levin, 2003). DIO rats fail to reduce intake adequately in response to high-energy diets, unlike DR rats, leading to obesity (Levin et al. 2003). However, when maintained on low-fat chow diets, DIO-prone rats do not become obese, showing normal feed efficiency, normal or marginally increased food intake (Ricci & Levin, 2003), and normal adiposity as compared to DR rats. Therefore, the preobese DIO rat may be a useful model for identifying preexisting, genetic differences in sensitivity to anorexigens, variations that may increase risk for hyperphagia and obesity. Conversely, anorectics that do retain efficacy in obesity-prone DIO rats might hold greater preventative/therapeutic potential than those that do not. In outbred rats, intracerebroventricular (i.c.v.) infusion of corticotropin-releasing factor (CRF)/urocortin (Ucn) family peptides suppresses food intake and promotes negative energy balance through two G-protein coupled receptor subtypes (CRF1 and CRF2) (Richard et al. 2002; Zorrilla et al. 2003; Fekete & Zorrilla, 2007). Whereas obese animals are resistant to central leptin or insulin anorexia, chronic central infusion of subtype non-selective CRF receptor agonists reduces food intake and promotes weight loss not only in lean animals (Bradbury et al. 2000; Cullen et al. 2001), but equally or more so in animals that are obese due to leptin receptor mutation (Arase et al. 1989a; Rohner-Jeanrenaud et al. 1989; Heinrichs et al. 1996; Heinrichs et al. 2001) or ventromedial hypothalamic (VMH) lesions (Arase et al. 1989b). However, the functional sensitivity of central CRF/Ucn receptors in genetically selected DIO and DR rats, a polygenic model of obesity-proneness, is unknown. The anorectic effectiveness of CRF2 receptors in obesity-prone rats is of particular interest. Central infusion of CRF1 agonists (CRF itself or Ucn 1) acutely suppresses feeding, but with accompanying anxiety-like and aversive states. In contrast, i.c.v. infusion of type 2 urocortins (Ucn 2, Ucn 3), preferential CRF2 agonists, can suppress intake with delayed onset (∼2–3 h) at doses that do not elicit malaise- or anxiety-like behaviour (Zorrilla et al. 2003). The codistribution of Ucns and CRF2 receptors in hypothalamic nuclei (e.g. VMH, arcuate) and the nucleus of the solitary tract (Fekete & Zorrilla, 2007), sites where local Ucn infusion suppresses food intake (Daniels et al. 2004; Fekete et al. 2007), suggests that Ucn–CRF2 systems control food intake. Perhaps accordingly, CRF2 knock-out (KO) mice eat more corn syrup-sweetened chow (Tabarin et al. submitted) and high-fat diet (Bale et al. 2003) than wild-type mice. Decreased CRF2 mRNA expression is present in the VMH of several animal models that display increased appetite and low central leptin or insulin signalling (Richard et al. 1996; Makino et al. 1998; Huang et al. 2006a), each of which is a characteristic of DIO rats. These results, in contrast to the reviewed efficacy of non-selective CRF receptor agonists in obesity models, suggest that DIO rats might show reduced potency or efficacy of central CRF2 anorectic action. The present studies aimed to (1) identify intrinsic differences in the quantity or microstructure of chow and water intake between genetically selected DR and DIO rats; (2) compare the potency, efficacy, time course and microstructure mechanism of anorectic action of central administration of Ucn 2 between chow-maintained, genetically selected DR and DIO rats, and (3) determine whether observed anorectic effects of Ucn 2 were mediated by CRF2 receptors. Though Ucn 2 is a preferential CRF2 agonist, it might also act as direct CRF1 agonist at pharmacological doses (Hoare et al. 2005) or as an indirect CRF1 agonist due to its nanomolar affinity for the rodent CRF-binding protein (Jahn et al. 2004). It was hypothesized that DIO rats would show similar or only subtly greater spontaneous chow intake than DR rats. It was further hypothesized that i.c.v. Ucn 2 would retain anorectic efficacy in DIO rats, making them eat smaller and briefer meals more slowly (Inoue et al. 2003), but with diminished dose-potency as compared to DR rats. Finally, the anorectic effects of Ucn 2 were predicted to be reversed by cotreatment with astressin2-B (A2-B), a selective CRF2 antagonist (Rivier et al. 2002).