ABSTRACT
BACKGROUND & AIMS: Anorexia nervosa (AN) is a severe psychological and potentially life-threatening eating disorder. The activity-based anorexia (ABA) mouse model is commonly used to investigate physiological abnormalities associated with this disorder. Characterizing the holistic biochemical alterations induced by anorexia is essential to understanding AN pathophysiology as well as to define biomarkers for prognosis. METHODS: To unravel the adaptive biochemical mechanisms occurring in this model in response to self-starvation, the urinary, plasma and fecal metabolic phenotypes of mice under different experimental conditions were compared. This included control mice with and without physical activity (CT and CTPA mice), a group with limited food access (LFA), and a group with both limited food access and physical activity (ABA). Using 1H nuclear magnetic resonance (NMR) spectroscopy, several biochemical perturbations were observed. RESULTS: Physical activity altered the abundance of 14 fecal metabolites, including those involved in gut microbial metabolism and proteolysis. Food restriction disrupted a wide range of metabolic pathways including gut microbial metabolism, proteolysis and fatty acid breakdown (24 urinary and 6 plasma metabolites). The combined impact of food restriction and physical activity resulted in the same pattern of metabolic disruption (24 urine, 6 plasma). CONCLUSIONS: This work defined the metabolic signatures of ABA mice and provides novel insights into biological adaptations of mice in response to both food restriction and physical activity. These results should be further confirmed in AN patients.
Subject(s)
Anorexia Nervosa/physiopathology , Magnetic Resonance Spectroscopy/methods , Starvation/physiopathology , Adaptation, Physiological/physiology , Animals , Anorexia Nervosa/etiology , Caloric Restriction , Disease Models, Animal , Fatty Acids/metabolism , Feces/chemistry , Gastrointestinal Microbiome/physiology , Mice , Mice, Inbred C57BL , Physical Conditioning, Animal , Proteolysis , Starvation/etiologyABSTRACT
Anorexia nervosa is an eating disorder often associated with intestinal disorders. To explore the underlying mechanisms of these disorders, the colonic proteome was evaluated during activity-based anorexia. Female C57Bl/6 mice were randomized into three groups: Control, Limited Food Access (LFA) and Activity-Based Anorexia (ABA). LFA and ABA mice had a progressive limited access to food but only ABA mice had access to an activity wheel. On colonic mucosal protein extracts, a 2D PAGE-based comparative proteomic analysis was then performed and differentially expressed proteins were identified by LC-ESI-MS/MS. Twenty-seven nonredundant proteins that were differentially expressed between Control, LFA, and ABA groups were identified. ABA mice exhibited alteration of several mitochondrial proteins involved in energy metabolism such as dihydrolipoyl dehydrogenase and 3-mercaptopyruvate sulfurtransferase. In addition, a downregulation of mammalian target of rapamycin (mTOR) pathway was observed leading, on the one hand, to the inhibition of protein synthesis, evaluated by puromycin incorporation and mediated by the increased phosphorylation of eukaryotic elongation factor 2, and on the other hand, to the activation of autophagy, assessed by the increase of the marker of autophagy, form LC3-phosphatidylethanolamine conjugate/Cytosolic form of Microtubule-associated protein 1A/1B light chain 3 (LC3II/LC3I) ratio. Colonic mucosal proteome is altered during ABA suggesting a downregulation of energy metabolism. A decrease of protein synthesis and an activation of autophagy were also observed mediated by mTOR pathway.
Subject(s)
Anorexia/complications , Autophagy , Colon/metabolism , Energy Metabolism , Intestinal Mucosa/metabolism , Malnutrition/pathology , Protein Biosynthesis , Proteome/metabolism , Animals , Female , Malnutrition/etiology , Malnutrition/metabolism , Mice , Mice, Inbred C57BL , Tandem Mass SpectrometryABSTRACT
Restrictive anorexia nervosa is associated with reduced eating and severe body weight loss leading to a cachectic state. Hypothalamus plays a major role in the regulation of food intake and energy homeostasis. In the present study, alterations of hypothalamic proteome and particularly of proteins involved in energy and mitochondrial metabolism have been observed in female activity-based anorexia (ABA) mice that exhibited a reduced food intake and a severe weight loss. In the hypothalamus, mitochondrial dynamic was also modified during ABA with an increase of fission without modification of fusion. In addition, increased dynamin-1, and LC3II/LC3I ratio signed an activation of autophagy while protein synthesis was increased. In conclusion, proteomic analysis revealed an adaptive hypothalamic protein response in ABA female mice with both altered mitochondrial response and activated autophagy.
Subject(s)
Anorexia Nervosa/genetics , Dynamin I/genetics , Hypothalamus/metabolism , Microtubule-Associated Proteins/genetics , Mitochondrial Dynamics/genetics , Proteome/genetics , Aconitate Hydratase/genetics , Aconitate Hydratase/metabolism , Animals , Anorexia , Anorexia Nervosa/metabolism , Anorexia Nervosa/physiopathology , Autophagy/genetics , Disease Models, Animal , Dynamin I/metabolism , Eating/genetics , Female , Gene Expression Profiling , Gene Expression Regulation , Hypothalamus/physiopathology , Mice , Mice, Inbred C57BL , Microtubule-Associated Proteins/metabolism , Physical Conditioning, Animal , Protein Biosynthesis , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proteome/metabolism , Receptors, Enterotoxin/genetics , Receptors, Enterotoxin/metabolism , Signal Transduction , Weight Loss/geneticsABSTRACT
PURPOSE: The purposes of this study were to: (1) describe the sedation protocols of postgraduate pediatric dentistry programs (PPDPs) in the U.S.; (2) evaluate how consistent they were with current American Academy of Pediatric Dentistry sedation guidelines and Commission on Dental Accreditation (CODA) sedation curriculum requirements; (3) identify barriers to and tools for implementing these guidelines; and (4) determine the independent association between PPDPs' adherence to guidelines and the program setting. METHODS: In February 2015, a 40-item questionnaire was e-mailed to all postgraduate pediatric dentistry program directors (PPDPDs) of CODA-accredited programs in the U.S. (n equals 74). Data were analyzed using descriptive statistics and Kruskal-Wallis and pairwise Nemenyi tests. RESULTS: Fifty-two PPDPDs responded (70 percent). Since the 2013 change in CODA sedation requirements, only a limited number of PPDPs (36 percent) were found to be noncompliant with CODA standards. PPDPDs trained at hospital-based programs were found to direct programs that were more compliant with CODA sedation standards (P<.05). A major perceived barrier to increasing the number of sedation cases was the lack of a patient pool (37 percent). CONCLUSIONS: Further efforts should be made by teaching institutions for programs to be compliant with American Academy of Pediatric Dentistry and Commission on Dental Accreditation sedation standards.
