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GLUCOSE-DEPENDENT, GUT-BRAIN VAGAL SIGNALING IS DISRUPTED IN A MOUSE MODEL OF HIGH FAT DIET-INDUCED OBESITY
Florina Corpodean
*, R. Leigh Townsend, Yanlin He, Vance L. Albaugh
Louisiana State University Pennington Biomedical Research Center, Baton Rouge, LA
Introduction: While high-fat diet (HFD)-induced obesity leads to apparent nutrient-desensitization within the hypothalamus, nutrient-induced Vagal responses have largely been understudied. Thus, this study aimed to test the hypothesis that obesity is associated with impaired Vagal signaling in response to glucose that might drive weight gain through impaired nutrient signaling via the Vagal arm of the gut-brain axis.
Materials and Methods: C57BL6/K mice (n=6/group) were fed purified diets of either HFD or low-fat diet (LFD) for 6 weeks. Body weight and composition were assessed before and after dietary intervention. At the time of testing mice were anesthetized and a duodenal catheter was implanted for glucose infusion and the left cervical Vagus was exposed to record peak firing rate (PFR) during saline, glucose and glucose plus an SGLT1 transport inhibitor (Phloridzin). Follow-up studies were repeated to control for the effect of body weight, matching the body weight of a high-fat fed group to mice receiving LFD (n=6/group).
Results: HFD feeding significantly increased body weight and total body adiposity relative to LFD. Glucose-dependent, Vagal peak firing rate (PFR) was significantly decreased by HFD compared to LFD (p<0.05). Vagal firing was similarly attenuated by Phloridzin co-infusion in both HFD and LFD fed groups (p<0.0001). Lean body mass percentage was positively correlated with increased PFR (p=0.0249). To test the hypothesis that impaired PFR results from obesity per se, HFD-fed mice weight matched to a separate LFD group underwent Vagal measurements. While ad libitum fed HFD mice with obesity continued to have impaired PFR relative to LFD, body weight matching of HFD-fed mice without obesity did not increase Vagal PFR.
Conclusion: HFD consumption impairs glucose-dependent Vagal signaling independent of obesity. Weight loss through dietary restriction (i.e. weight matching) was unable to reverse the negative effect of high fat feeding on Vagal firing, suggesting that the high fat content or other inflammatory properties or downstream effects (e.g. microbial shifts) may underlie the mechanisms of desensitizing the Vagus to enteral glucose. Future studies examining different macronutrient responses and non-dietary obesity treatments (e.g. pharmacologic, surgical) are warranted.
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