Palatable “comfort” food intake reduces HPA axis stress reactivity via cannabinoid receptor 1 signaling and is prevented by diet-induced obesity

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2023-06-16

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Palatable food intake reduces physiological and emotional responses to stress – a phenomenon known as “comfort” feeding. However, the mechanisms by which palatable food blunts stress responses are not known and are important as overconsumption of palatable food contributes to the develop of obesity. To study these mechanisms, the Ulrich-Lai group previously developed a limited sucrose intake (LSI) feeding paradigm that reduces hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress in male rats, and in female rats specifically during the proestrus/estrus (p/e) stage of the estrous cycle. This dissertation uses the LSI paradigm to test the hypotheses that HPA-dampening by LSI is impaired in the context of diet-induced obesity (DIO; chapters 2 and 3), and that cannabinoid receptor 1 (CB1R) signaling mediates HPA-dampening by LSI (chapter 4). We examined the HPA axis response to an acute restraint stressor in LSI-fed (vs. water control) rats that were maintained on either ad libitum normal chow (thereby remaining lean) or a high-fat high-sugar Western diet (WD) (to produce diet-induced obesity, DIO) for 8 weeks prior to LSI (using 3% and 30% sucrose vs. water controls). Data from male and female rats are shown in chapters 3 and 4, respectively; the female data includes estrous cycle stage in the analysis. In both male and female rats, WD effectively increased body fat. Moreover, male chow-fed lean rats who received either 3% or 30% sucrose had a blunted plasma corticosterone response to restraint stress, but this effect was absent in male WD-fed DIO rats, indicating that WD-obesity prevents HPA-dampening by LSI. In contrast, LSI did not alter post-stress plasma corticosterone in either chow (lean) or WD-fed (DIO) female rats, regardless of estrous cycle. Notably, the positive control condition (lean females given LSI using 30% sucrose and tested during p/e) did not show HPA axis dampening as seen in prior experiments. However, the female results are difficult to interpret as there were construction disturbances in the animal facility during this experiment that may have confounded measurements of HPA axis reactivity. In chapter 4, we examined the possible neural mechanisms that mediate the stress relieving effect of palatable food intake. The endocannabinoid system is well-poised to mediate HPA-dampening effect by LSI due to its ability to promote feeding behavior and reduce stress responses. We examined the role of iii endocannabinoid system by using systemic vs. central pharmacological antagonism of the cannabinoid receptor 1 (CB1R) and tested the effect on the HPA axis stress response in LSI-fed male and female rats. The results suggest that blocking CB1R signaling impairs LSI’s HPA-dampening effect in male rats, and in female rats during p/e. Collectively, these experiments identify a novel neurobiological mechanism that contributes to the stress-dampening effects of palatable feeding and indicate that this stress-dampening is prevented during obesity. This has important implications, suggesting that obesity may impair LSI’s effects by disrupting endocannabinoid system function. Moreover, impaired stress relief during obesity may suggest that obese individuals require larger amounts of palatable foods to maintain effective stress relief in the face of escalating body weight.

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Reward, Stress, Obesity, Corticosterone, Endocannabinoid

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