Research ReportActivation of hindbrain neurons in response to gastrointestinal lipid is attenuated by high fat, high energy diets in mice prone to diet-induced obesity
Introduction
The gut–brain axis plays an important role in nutrient detection and in control of short term food intake (Schwartz, 2000). For example, lipid in the gastrointestinal tract is detected via release of CCK and activation of CCK1 receptors on vagal afferent nerve terminals in close apposition to endocrine cells (Raybould, 1999). The CCK1R dependent pathway, together with activation of vagal afferents in response to other gut peptides that can decrease food intake, seems to be important primarily in short-term control of food intake. However, evidence is accumulating to suggest that alteration in the function of this pathway maybe involved in long term control of food intake and body weight. Maintenance of rats on a high fat (HF) diet causes decreased hindbrain sensitivity to lipid (oleate) and to CCK (Covasa and Ritter, 1998, Covasa and Ritter, 1999); this occurs after ingesting the HF diet for only 2 weeks and even in the absence of obesity, when fed an isocaloric HF diet (Covasa and Ritter, 2000, Paulino et al., 2008). It has been suggested that the decrease in vagal afferent sensitivity in response to lipid may, in part, be responsible for increased food intake when rodents, or humans, ingest high fat diets (Savastano and Covasa, 2005).
Different strains of mice have been classified as “obesity prone” or “obesity resistant” (West et al., 1992), dependent on their propensity for weight gain when placed on high fat, high energy diets. However, it is not clear what factors are responsible for these phenotypic differences. Mice maintained on an HF diet can be grouped into two main categories according to their ability to gain weight; mouse strains such as AKR/J, C57BL/6J, DBA/2J, and A/J have been shown to rapidly gain weight on HF diet and have been termed diet-induced obesity prone (DIO-P); in contrast, strains 129sv, SWR/J, I/STN and SJL/J have been termed diet-induced obesity resistant (DIO-R) due to their relative resistance to weight gain when on HF diets (West et al., 1992). Whether there is any difference in the response of the gut–brain axis to lipid in different mice strains, either DIO-P or DIO-R, or adaptation to HF diets, has not been investigated.
We tested the hypothesis that adaptation of the lipid-induced activation of the vagal afferent pathway to long term maintenance on a HF diet differ in DIO-P and DIO-R mice strains. We determined the effect of intragastric gavage of lipid on activation of neurons in the NTS, the region where vagal afferents terminate, in two mouse strains; one classified as DIO-P (C57BL/6) and one classified as DIO-R (129sv) (Almind and Kahn, 2004, West and Boozer, 1992). We investigated the effect of long term consumption (4 and 8 weeks) of two diets with increased levels of fat (45% and 60% kcal/fat) which cause obesity in mice (Van Heek et al., 1997).
Section snippets
Effect of high fat diets on body weight and adiposity
There was no significant difference in body weight gain in DIO-P and DIO-R mice maintained on chow for either 4 or 8 weeks (NS, n = 5–14 in each group) (Fig. 1 A). Maintenance on a diet containing 45% kcal from fat (45% HF) caused a tendency for increased body weight gain in both strains after either 4 or 8 weeks on the diet, but this did not reach statistical significance (Fig. 1 A; NS, n = 3–6 in each group). However, maintenance on a 60% HF diet resulted in a significant increase in body weight
Discussion
Perfusion of the gastrointestinal tract with nutrients has been shown to terminate a meal by mechanisms involving both neural and humoral pathways (Schwartz, 2000). There is evidence that activation of the gut–brain pathway transmitting information on the macronutrient content of a meal can be modified by long term changes in the diet. Thus, maintenance of rats on a high fat diet decreases activation of neurons in the NTS in response to intestinal lipid (Covasa et al., 2000) and to exogenous
Animals and diets
All experiments were performed in accordance with protocols approved by the UC Davis Institutional Animal Use and Care Committee. Experiments were performed using male C57BL/6J (diet-induced obesity-prone; DIO-P) (JAX Labs, Sacramento, CA) or 129S6/SvEv (diet-induced obesity-resistant; DIO-R) (Taconic, Oxnard, CA) mice of initial weight 17–27 g (6–8 weeks of age) (West et al. 1992). Mice were fed standard Purina rodent chow for the first week and had ad libitum access to water. After one week
Acknowledgment
Work funded by NIH DK41004 to HER.
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