β‐endorphin differentially contributes to food anticipatory activity in male and female mice undergoing activity‐based anorexia

Abstract

Anorexia nervosa (AN) has a lifetime prevalence of up to 4% and a high mortality rate (~5–10%), yet little is known regarding the etiology of this disease. In an attempt to fill the gaps in knowledge, activity‐based anorexia (ABA) in rodents has been a widely used model as it mimics several key features of AN including severely restricted food intake and excessive exercise. Using this model, a role for the hypothalamic proopiomelanocortin (POMC) system has been implicated in the development of ABA as Pomc mRNA is elevated in female rats undergoing the ABA paradigm. Since the Pomc gene product α‐MSH potently inhibits food intake, it could be that elevated α‐MSH might promote ABA. However, the α‐MSH receptor antagonist SHU9119 does not protect against the development of ABA. Interestingly, it has also been shown that female mice lacking the mu opioid receptor (MOR), the primary receptor activated by the Pomc‐gene‐derived opioid β‐endorphin, display blunted food anticipatory behavior (FAA), a key feature of ABA. Thus, we hypothesized that the elevation in Pomc mRNA observed during ABA may lead to increased β‐endorphin concentrations and MOR activation to promote ABA. Further, given the known sex differences in AN and ABA, we hypothesized that MORs may contribute differentially in male and female mice. Using wild‐type and MOR knockout mice of both sexes, a MOR antagonist and careful analysis of food anticipatory behavior and β‐endorphin levels, we found 1) increased Pomc mRNA levels in both female and male mice that underwent ABA, 2) increased β‐endorphin in female mice that underwent ABA, and 3) blunted FAA in both sexes in response to MOR genetic deletion yet blunted FAA only in males in response to MOR antagonism. The results presented provide support for both hypotheses and suggest that it may be the β‐endorphin resulting from increased Pomc transcription that supports the development of some features of ABA.

Fear and food: Anxiety‐like behavior and the susceptibility to weight loss in an activity‐based anorexia rat model

“…It has been suggested that the runner’s high results from the stimulation of endorphins via opioid signaling during exercise 33 . In female ABA mice, transiently increasing levels of proopiomelanocortin RNA and peripheral β‐endorphin levels have been detected 34 . These findings could partially explain the association between running and reduced anxiety‐related behavior observed in the present study.…”

Behavioral reinforcement of pathological exercise in anorexia nervosa

“…Future studies using knockout models (e.g., Daimon & Hentges, 2021) targeting opioid and catecholamine receptors will hopefully provide information regarding the role of these systems in reinforcing exercise under the ABA model. Additionally, animal models may inform the development of medications to treat pathological exercise, similar to research in alcohol and substance use disorders (Spanagel, 2017).…”

Glial cell changes in the corpus callosum in chronically-starved mice

“…Therefore, it appears that starvation increases the orexigenic signaling, consistent with previous literature that reports an increase in Npy expression [ 18 , 19 ]. Previous studies revealed conflicting results regarding the Pomc expression [ 18 , 21 , 22 ]. In ABA rats, there was an increase in the density of POMC + cells in the ARC [ 23 ].…”

“…Food intake-related pathways may be involved in starvation, as evidenced by the upregulation of Npy and Agrp mRNA expression in an activity-based anorexia (ABA) model which includes a limited time for feeding [ 18 – 20 ]. However, the results for Pomc mRNA expression have been conflicting, as two studies demonstrated an increase in Pomc expression in the arcuate nucleus (ARC) in ABA animals, whereas one study reported a decrease in Pomc expression [ 18 , 21 , 22 ]. In addition, the POMC + cell densities in the ARC in ABA animals were increased [ 23 ].…”