1.
Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake.
Rask-Andersen, M, Olszewski, PK, Levine, AS, Schiƶth, HB
Brain research reviews. 2010;(2):147-64
Abstract
Anorexia nervosa (AN) is a complex multi-factorial disease with high heritability. The psychological AN symptoms are poorly connected with specific molecular mechanisms. Here we review the molecular basis of AN with the focus on human genetic association studies; we put these in the experimental biological context with emphasis on molecular systems controlling food intake and body weight in a direct or indirect manner. We systematically searched for human genetic studies related to AN and grouped data into main categories/systems reflecting their major known roles: (1) Systems related to mental disorders (serotonin, brain-derived neurotrophic factor (BDNF), norepinephrine (NE), glutamate (NMDA) receptor and SK3 channel, KCCN3). (2) Hunger regulatory systems (leptin, AGRP, MSH, melanocortin 4 receptor (MC4R), NPY, ghrelin, cholecystokinin (CCK). (3) Feeding motivation- and reward-related systems (opioids, OPRD1, cannabinoids (anandamide (AEA), THC, CBR1), dopamine, DRD2, DRD3, DRD4, catecholamine-O-methyl transferase (COMT). (4) Systems regulating energy metabolism (uncoupling proteins 2 and 3 (UCP2 and UCP3). (5) Neuroendocrine systems with emphasis on sex hormones (estrogen receptor-beta (ESR2). (6) The immune system and inflammatory response (tumor necrosis factor-alpha (TNF-alpha)). Overall, we found that in total 175 association studies have been performed on AN cohorts on 128 different polymorphisms related to 43 genes. We review the strongest associations, identify some genes that have an important role in regulating BMI whose possible relationship to AN has not been investigated and discuss the potential targets for pharmacological interventions.
2.
Neural-immune gut-brain communication in the anorexia of disease.
Schwartz, GJ
Nutrition (Burbank, Los Angeles County, Calif.). 2002;(6):528-33
Abstract
Peripheral administration of toxic bacterial products and cytokines have been used to model the immunological, physiological, and behavioral responses to infection, including the anorexia of disease. The vagus nerve is the major neuroanatomic linkage between gut sites exposed to peripheral endotoxins and cytokines and the central nervous system regions that mediate the control of food intake, and thus has been a major research focus of the neurobiological approach to understanding cytokine-induced anorexia. Molecular biological and neurophysiologic evidence demonstrates that peripheral anorectic doses of cytokines and endotoxins elicit significant increases in neural activation at multiple peripheral and central levels of the gut-brain axis and in some cases may modify the neural processing of meal-related gastrointestinal signals that contribute to the negative feedback control of ingestion. However, behavioral studies of the anorectic effects of peripheral cytokines and endotoxins have shown that neither vagal nor splanchnic visceral afferent fibers supplying the gut are necessary for the reduction of food intake in these models. These data do not rule out 1) the potential contribution of supradiaphragmatic vagal afferents or 2) a modulatory role for immune-stimulated gut vagal afferent signals in the expression of cytokine and endotoxin-induced anorexia in the intact organism.