R. Legrand

Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide α-MSH, at the origin of eating disorders

The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies (auto-Abs) reactive with α-melanocyte-stimulating hormone (α-MSH) are involved in regulation of feeding and emotion; however, the origin of such auto-Abs is unknown. Here, using proteomics, we identified ClpB heat-shock disaggregation chaperone protein of commensal gut bacteria Escherichia coli as a conformational antigen mimetic of α-MSH. We show that ClpB-immunized mice produce anti-ClpB IgG crossreactive with α-MSH, influencing food intake, body weight, anxiety and melanocortin receptor 4 signaling. Furthermore, chronic intragastric delivery of E. coli in mice decreased food intake and stimulated formation of ClpB- and α-MSH-reactive antibodies, while ClpB-deficient E. coli did not affect food intake or antibody levels. Finally, we show that plasma levels of anti-ClpB IgG crossreactive with α-MSH are increased in patients with AN, bulimia and BED, and that the ED Inventory-2 scores in ED patients correlate with anti-ClpB IgG and IgM, which is similar to our previous findings for α-MSH auto-Abs. In conclusion, this work shows that the bacterial ClpB protein, which is present in several commensal and pathogenic microorganisms, can be responsible for the production of auto-Abs crossreactive with α-MSH, associated with altered feeding and emotion in humans with ED. Our data suggest that ClpB-expressing gut microorganisms might be involved in the etiology of EDs.

Delayed gastric emptying and altered antrum protein metabolism during activity-based anorexia.

Anorexia nervosa, a restrictive eating disorder, is often associated with gastrointestinal disorders, particularly a delayed gastric emptying. However, the mechanisms remained poorly documented. Thus, we aimed to evaluate gastric emptying and antrum protein metabolism in the Activity‐Based Anorexia model (ABA).

Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans

Significance The number of inmates imprisoned for violent aggression is increasing, as are the penitentiaries, but still our understanding of mechanisms underlying criminality is limited. Our analysis of violent aggressor inmates reveals unique properties of IgG reactive with adrenocorticotropic hormone (ACTH). We show that these IgGs can regulate ACTH-induced cortisol secretion in the adrenal gland, and they exhibit a clear-cut difference in ACTH epitope binding in violent aggressors vs. controls. Additionally, IgG from a subset of aggressive subjects selectively bind to hypothalamic vasopressin neurons. Thus, using several in vitro and in vivo approaches, the study reveals a molecular mechanism involved in the variability of stress response relevant to the neurobiology of aggression and possibly other stress-related conditions. Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11–24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1–13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident–intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors’ sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation.

MON-PP031: Development of a Plasma Assay for the Bacterial ClpB Protein as a Biomarker of Eating Disorders

compared with animal-derived proteins. However, there are few data to support this contention. We assessed postprandial plasma amino acid profiles and whole-body protein synthesis following the ingestion of 35 g wheat protein hydrolysate compared with casein and whey in healthy, older males. Methods: Healthy older males (73±1 y) received a primed continuous infusion of L-[C6]-phenylalanine and L-[H2]tyrosine and ingested 35 g wheat protein hydrolysate (WHEAT; n = 12), whey (WHEY; n = 12), or micellar casein (CAS; n = 12). Plasma and muscle samples were collected at regular intervals. Repeated measures ANOVA was used to identify differences between groups over time. Results: Plasma leucine concentrations increased following protein ingestion (P < 0.01), to a similar extent following WHEAT and CAS (P = 0.86) and to a greater extent following WHEY (P < 0.01). In agreement, peak leucine concentrations averaged 351±11, 316±24, and 580±18mM for WHEAT, CAS, and WHEY, respectively (WHEAT vs CAS P = 0.40; WHEY vs WHEAT and CAS P < 0.01). Whole-body protein synthesis increased following protein ingestion in all groups (P < 0.01), with no significant differences between groups (P = 0.13). Postprandial muscle protein synthesis rates will be assessed by determining the incorporation of L-[C6]-phenylalanine into myofibrillar protein. Conclusion: Ingesting wheat protein hydrolysate increases plasma amino acid availability and stimulates whole-body protein synthesis as effectively as casein in healthy, older males.