Altered taste sensitivity in obese, prediabetic OLETF rats lacking CCK-1 receptors

Abstract

-Otsuka Long-Evans Tokushima fatty (OLETF) rats lack the CCK-1 receptor, are hyperphagic, progressively become obese, and develop type-2 diabetes. We recently demonstrated an increased preference for both real and sham feeding of sucrose in this strain, suggesting altered orosensory sensitivity. To investigate taste functions, we used an automated gustometer with 10-s access to different concentrations of various sapid stimuli. Tests were repeated at 10 and 18 wk of age to assess the early and advanced stages of prediabetes, respectively. Compared with age-matched, nonmutant controls, the OLETF rats showed higher avidity for sucrose at both ages. This difference increased as a function of age and tastant concentration. An exaggerated response also occurred for saccharin, alanine, and fructose, but not for Polycose. Similarly, OLETF rats consumed monosodiumglutamate more at the lower concentrations compared with controls, an effect that age also accentuated. In contrast, there was no statistical strain or age differences in responses to NaCl, MgCl2, citric acid, quinine-HCl, and the trigeminal stimulus capsaicin. These findings demonstrate that compared with controls, OLETF rats differ in their gustatory functions with an overall augmented sensitivity for sweet that progresses during prediabetes. This effect explains their overconsumption of sweet solutions and may contribute to the overall hyperphagia and obesity in this strain.overeating; dietary obesity; insulin resistance; sweet receptors; hedonic coding OBESITY IS A GLOBAL PANDEMIC that continues to accelerate and increases the risk of multiple medical conditions, such as noninsulin-dependent diabetes mellitus (NIDDM), hypertension, and coronary heart disease (34). Although the etiology of obesity is complex, overconsumption induced by the high palatability of the modern diet, in general, and individual differences in responsivity to palatability, in particular, may contribute to obesity (34,74,87). Meal size is controlled by orosensory stimulatory and postingestive inhibitory feedback (71). Thus increased appetite and overeating can be the result of either an enhanced responsiveness to orosensory stimulatory properties of a meal, a decreased sensitivity to postingestive inhibitory signals, or both. Importantly, the signaling systems that underlie appetite control appear to operate independently from the energy homeostatic regulation resulting in sustained overeating and body weight gain in some individuals and also in animal models of obesity.Despite the controversy about the particular contribution of different nutrients to the epidemic of obesity, there is agreement that an increased palatability of foods that taste sweet and contain fats, plays a critical role by increasing the overall calorie intake (40, 56). As with humans, high carbohydrate and high fat foods are strongly preferred by rats (59). Postingestive factors play an important role in this preference (63, 84), but rats also sham feed sugar and fat solutions (i.e., fatty acids and triglycerides...

Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism

“…On the other hand, the overall lack of major changes in operant behavior for sucrose, despite the dramatic change of glucose control in the OLETF rats, however, mitigates the possibility that the initial preference for sweet stimuli with bias for higher concentrations were critically dependent on insulin or other metabolic factors. Indeed, we observed increased sucrose preference in the OLETF rats as early as 8 wk of age, which is enhanced for higher concentrations, well before signs of impairments in glucose control can be detected (26). In this context, it is plausible that an increased motivation for palatable meals may, in part, contribute to overconsumption, and this increase in reward sensitivity may further progress with increasing metabolic derangement.…”

“…Thus, it is feasible that in OLETF rats the absence of CCK-1 receptors may result in altered dopamine receptor regulation of sucrose intake. In support of this notion, we have recently shown that compared with age-matched lean control Long-Evans Tokushima Otsuka (LETO) rats, OLETF rats have an increased dopamine release in the nucleus accumbens (1) and an accentuated preference for higher concentrations of sucrose (26). More direct evidence for a role of dopamine in the increased avidity for sucrose in this strain comes from findings demonstrating an increased sensitivity to dopamine antagonism in reducing two-bottle sucrose preference in both real and sham feeding conditions in prediabetic OLETF rats.…”

Altered dopamine D2 receptor function and binding in obese OLETF rat

“…For example, obesity as well as NIDDM can be greatly reduced by caloric restriction [36] or exercise [41] suggesting that obesity and NIDDM in OLETF rats are secondary to their hyperphagia. Relevant to this, we have demonstrated that in addition to diminished sensitivity to postingestive satiation signals, OLETF rats express increased sham intake of normally preferred sucrose solutions [18] and an increased avidity generalized to various agents that taste sweet to human including non caloric sweetener saccharin and the amino acid alanine [25]. This finding suggests that an increased sensitivity to sweet reward may be contributory to the development of obesity in this strain.…”

Interoceptive “satiety” signals produced by leptin and CCK

“…Similarly, OLEFT rats that lack CCK-A receptors overeat and exhibit heightened sweet sensitivity relative to nonmutant controls [30]. This finding suggests that CCK may function to decrease behavioral responsiveness to sweet taste in normal animals.…”

“…Leptin and CCK may suppress intake by participating in a variety of processes which are themselves complex. For example, either or both peptides could reduce food intake through their effects on (a) nonspecific behavioral deactivating mechanisms such as those involved with arousal or malaise [14,20,23,34]; (b) the hedonic properties of orosensory stimulation produced by eating [30,46]; and (c) the rewarding postingestive afteraffects of intake [26,32,43]; (d) the generation of interoceptive "satiety signals (e.g., feelings "fullness") that inform animals about their current state of energy balance [6,27] and may enable them to anticipate the orosensory or postingestive consequences of eating in advance of actual contact with food [19].…”