The vagal afferent pathway is important in short-term regulation of food intake, and decreased activation of this neural pathway with long-term ingestion of a high-fat diet may contribute to hyperphagic weight gain. We tested the hypothesis that expression of genes encoding receptors for orexigenic factors in vagal afferent neurons are increased by long-term ingestion of a high-fat diet, thus supporting orexigenic signals from the gut. Obesity-prone (DIO-P) rats fed a high-fat diet showed increased body weight and hyperleptinemia compared with low-fat diet-fed controls and high-fat diet-induced obesity-resistant (DIO-R) rats. Expression of the type I cannabinoid receptor and growth hormone secretagogue receptor 1a in the nodose ganglia was increased in DIO-P compared with low-fat diet-fed controls or DIO-R rats. Shifts in the balance between orexigenic and anorexigenic signals within the vagal afferent pathway may influence food intake and body weight gain induced by high fat diets.

Cholecystokinin (CCK), released by lipid in the intestine, initiates satiety by acting at cholecystokinin type 1 receptors (CCK 1 Rs) located on vagal afferent nerve terminals located in the wall of the gastrointestinal tract. In the present study, we determined the role of the CCK 1 R in the short term effects of a high fat diet on daily food intake and meal patterns using mice in which the CCK 1 R gene is deleted. CCK 1 R -/-and CCK 1 R +/+ mice were fed isocaloric high fat (HF) or low fat (LF) diets ad libitum for 18 hours each day and meal size, meal frequency, intermeal interval, and meal duration were determined. Daily food intake was unaltered by diet in the CCK 1 R -/-compared to CCK 1 R +/+ mice. However, meal size was larger in the CCK 1 R -/-mice compared to CCK 1 R +/+ mice when fed a HF diet, with a concomitant decrease in meal frequency. Meal duration was increased in mice fed HF diet regardless of phenotype. In addition, CCK 1 R -/-mice fed a HF diet had a 75% decrease in the time to 1 st meal compared to CCK 1 R +/+ mice following a 6 hr fast. These data suggest that lack of the CCK 1 R results in diminished satiation, causing altered meal patterns including larger, less frequent meals when fed a high fat diet. These results suggest that the CCK 1 R is involved in regulating caloric intake on a meal to meal basis, but that other factors are responsible for regulation of daily food intake.

It is accepted that there is a positive relationship between the level of fat in the diet and the body weight, possibly contributing in the long-term to obesity [11]. Recent evidence suggests that changes in lipid detection in the gut may contribute to diet-induced obesity. Recently Covasa M. et al. showed that dietary fat sensing within the small intestine was reduced in rats adapted to a high fat, high energy diet [12]. Persistently elevated plasma levels of CCK accompanying long-term HF diet consumption, leads to several adaptive changes such as increased food consumption due to reduced sensitivity to peripheral CCK [13]. Although there is evidence to show rats freely fed a high fat diet result in diet-induced obesity and diminished sensitivity to detection of lipid in the intestine, little is known about how the feeding behavior, in terms of meal patterns changes with adaptation to a high fat

Food intake is controlled by peripheral signals from the gastrointestinal tract and adipocytes, which are integrated within the central nervous system. There is evidence that signals from the GI tract are modulated by long term changes in diet, possibly leading to hyperphagia and increased body weight. We tested the hypothesis that diet-induced obese-prone (DIO-P) and obese-resistant (DIO-R) mice strains differ in the long term adaptive response of the gut-brain pathway to a high fat diet. Immunochemical detection of Fos protein was used as a measure of neuronal activation in the nucleus of the solitary tract (NTS) in response to intragastric administration of lipid in DIO-P (C57Bl6) and DIO-R (129sv) mouse strains maintained on chow or high fat, high energy diets (45% or 60% kcal from fat). Intragastric lipid administration activated neurons in the NTS in both DIO-P and DIO-R mice; the number of activated neurons was significantly greater in DIO-P than in DIO-R mice (P<0.001). However, lipid-induced activation of NTS neurons in DIO-P mice was attenuated by ≈ 30% after maintenance on either 45% or 60% HF diet, for 4 or 8 weeks, compared to chow fed controls (P<0.05). In contrast, in DIO-R mice, maintenance on a HF diet (45% or 60%) had no effect on lipid-induced activation of NTS neurons. These results demonstrate that DIO-P and DIO-R mice strains differ in the adaptation of the pathway to long term ingestion of high fat diets, which may contribute to decrease satiation and increased food intake.