Circadian copeptin and oxytocin profiles in anorexia nervosa: Exploring the interplay with neurohypophysis opioid tone.

CONTEXT: Neurohypophysis (NH) function in eating disorders (ED) remains poorly elucidated. Studies on vasopressin and oxytocin display inconclusive findings regarding their levels and associations with psychological complications in ED. The profile of opioid tone, a crucial NH activity regulator, is also unknown. OBJECTIVE: To characterise the circadian profile of NH hormones and NH opioid tone using positron emission tomography/MRI (PET/MRI) imaging in patients with ED compared to healthy controls. METHODS: Twelve-point plasma circadian profiles of copeptin and oxytocin, alongside nutritional and psychological scores, were assessed in age-matched female participants: 13 patients with anorexia nervosa restrictive-type (ANR), 12 patients recovered from AN (ANrec), 14 patients with bulimia nervosa and 12 controls. Neurohypophysis PET/MRI [11C] diprenorphin binding potential (BPND) was evaluated in AN, ANrec and controls. RESULTS: Results revealed lower copeptin circadian levels in both ANR and ANrec compared to controls, with no oxytocin differences. Bulimia nervosa exhibited elevated copeptin and low oxytocin levels. [11C] diprenorphin pituitary binding was fully localised in NH. Anorexia nervosa restrictive-type displayed lower NH [11C] diprenorphin BPND (indicating higher opioid tone) and volume than controls. In ANR, copeptin inversely correlated with osmolarity. Neurohypophysis [11C] diprenorphin BPND did not correlated with copeptin or oxytocin. CONCLUSION: Copeptin demonstrated significant group differences, highlighting its potential diagnostic and prognostic value. Oxytocin levels exhibited conflicting results, questioning the reliability of peripheral blood assessment. Increased NH opioid tone in anorexia nervosa may influence the vasopressin or oxytocin release, suggesting potential therapeutic applications.

MRI atlas of the pituitary gland in young female adults.

The probabilistic topography and inter-individual variability of the pituitary gland (PG) remain undetermined. The absence of a standardized reference atlas hinders research on PG volumetrics. In this study, we aimed at creating maximum probability maps for the anterior and posterior PG in young female adults. We manually delineated the anterior and posterior parts of the pituitary glands in 26 healthy subjects using high-resolution MRI T1 images. A three-step procedure and a cost function-masking approach were employed to optimize spatial normalization for the PG. We generated probabilistic atlases and maximum probability maps, which were subsequently coregistered back to the subjects' space and compared to manual delineations. Manual measurements led to a total pituitary volume of 705 ± 88 mm³, with the anterior and posterior volumes measuring 614 ± 82 mm³ and 91 ± 20 mm³, respectively. The mean relative volume difference between manual and atlas-based estimations was 1.3%. The global pituitary atlas exhibited an 80% (± 9%) overlap for the DICE index and 67% (± 11%) for the Jaccard index. Similarly, these values were 77% (± 13%) and 64% (± 14%) for the anterior pituitary atlas and 62% (± 21%) and 47% (± 17%) for the posterior PG atlas, respectively. We observed a substantial concordance and a significant correlation between the volume estimations of the manual and atlas-based methods for the global pituitary and anterior volumes. The maximum probability maps of the anterior and posterior PG lay the groundwork for automatic atlas-based segmentation methods and the standardized analysis of large PG datasets.

Structure-function relationship of the pituitary gland in anorexia nervosa and intense physical activity.

Patients with Anorexia Nervosa (AN) and athletes share intense physical activity and pituitary hormonal disturbances related to absolute (AN) or relative (athletes) undernutrition. Pituitary gland (PG) structure evaluations in those conditions are scarce, and did not differentiate anterior from posterior lobe. We evaluated the structure-function relationship of anterior and posterior PG in AN and athletes, and potential reversibility of this alteration in a group of weight-recovered patients (AN_Rec). Manual delineation of anterior (AP) and posterior (PP) PG was performed on T1-weighted MR images in 17 women with AN, 15 women with AN_Rec, 18 athletes women and 25 female controls. Anthropometric, hormonal, and psychometric parameters were explored and correlated with PG volumes. AP volume (APV) was lower in AN (448 ± 82 mm3), AN_Rec (505 ± 59 mm3), and athletes (540 ± 101 mm3) vs. Controls (615 ± 61 mm3, p < 0.00001, p < 0.00001 and p = 0.02, respectively); and smaller in AN vs. AN_Rec (p = 0.007). PP volume did not show any differences between the groups. APV was positively correlated with weight (R = 0.36, p = 0.011) in AN, and luteinizing hormone (R = 0.35, p = 0.014) in total group. In AN, mean growth hormone (GH) was negatively correlated with global pituitary volume (R = 0.31, p = 0.031) and APV (R = 0.29, p = 0.037). Absolute and relative undernutrition led to a decreased anterior pituitary gland volume, which was reversible with weight gain, correlated with low bodyweight, and blockade of gonadal hypothalamic-pituitary axis. Intriguing inverse correlation between anterior pituitary gland volume and GH plasma level could suggests a low storage capacity of anterior pituitary gland and increased reactivity to low insulin-like growth factor type 1.

The value of a multidisciplinary consensus meeting in achieving agreement on eating disorders diagnosis at a specialized referral center.

OBJECTIVE: This study aimed to evaluate the concordance of eating disorders (EDs) diagnoses within a multidisciplinary team in a specialized hospital unit dedicated to the medical care of ED. METHODS: The study analyzed data from 608 female patients who sought consultation at the Eating Disorders Referral Center between 2017 and 2021. The diagnoses were established according to the DSM-5 criteria by endocrinologists, psychiatrists, and finally confirmed or discussed within a monthly multidisciplinary consensus meeting (MCM). Fleiss' Kappa tests were conducted to assess inter-raters' agreement. RESULTS: Overall, substantial agreement was observed between endocrinologists and psychiatrists and the MCM. A more detailed analysis revealed variations in agreement across different disorders. Certain EDs demonstrated substantial agreement (e.g., anorexia nervosa restrictive subtype), while others approached near-perfect agreement (e.g., binge-eating disorder). In contrast, agreement was fair to poor for anorexia nervosa binge-purge subtype (ANBP) and slight for other specified feeding and ED. A period of temporary disagreement was noted for ANBP, partially attributed to practitioner turnover. An improvement in interdisciplinary agreement was observed for all ED diagnoses by the end of the study period. DISCUSSION: Variations or lower levels of inter-rater agreement may stem from atypical cases that fall on the border between two diagnoses or complex cases, as well as fluctuating symptoms. The progress observed throughout the study can be attributed in part to interdisciplinary learning, particularly facilitated by the MCM. The findings underscore the significance of striving for optimal concordance among different medical specialties to enhance patient care in ED treatment. PUBLIC SIGNIFICANCE: This study scrutinizes the agreement levels of ED diagnoses among endocrinologists and psychiatrists within a multidisciplinary team at an Eating Disorders Referral Center. While substantial overall agreement was achieved, disparities or lower agreement levels were evident for certain diagnoses such as anorexia nervosa binge-purge subtype. However, collaborative meetings led to a progressive enhancement in agreement over time. This research underscores the crucial role of a multidisciplinary team working collectively to ensure precise diagnoses and improved care for patients with EDs.

Systematic review of prospective studies assessing risk factors to predict anorexia nervosa onset.

BACKGROUND: According to case‒control studies, a multitude of factors contribute to the emergence of anorexia nervosa (AN). The present systematic review examines prospective studies specifically designed to evaluate the prediction of AN onset. METHODS: According to the ARMSTAR 2 and PRISMA 2020 checklists, the PubMed, PsycINFO and Cochrane databases were searched. The methodological quality of the studies was assessed with the Downs and Black checklist. RESULTS: Three articles concerning prospective studies of the general population were ultimately included in the review. The methodological quality of these studies was not optimal. Bidirectional amplification effects were observed between risk factors, some of which could have a relative predictive force as low bodyweight or body dissatisfaction. Even if not included according to specified criteria for this systematic review 11 longitudinal studies, with retrospective analysis of AN onset' prediction, were also discussed. None of these studies asserted the predictive value of particular risk factors as low body weight, anxiety disorders or childhood aggression. CONCLUSIONS: To date there are insufficient established data to propose predictive markers of AN onset for predictive actions in pre-adolescent or adolescent populations. Future work should further evaluate potential risk factors previously identified in case‒control/retrospective studies within larger prospective investigations in preadolescent populations. It is important to clearly distinguish predisposing factors from precipitating factors in subjects at risk of developing AN.

Currently health care guidelines for eating disorders do not include proposal of markers to predict the onset of anorexia nervosa. The current work provides a systematic review of the scientific literature concerning this subject. To date only three published studies were designed in a prospective longitudinal way to evaluate potential predictors of anorexia nervosa onset. When taking into account these studies only low bodyweight and body dissatisfaction in early puberty were proposed as predicting elements for further anorexia nervosa development. Meanwhile the prediction precision was calculated for none of them. No other psychological elements were retained or studied. The age range of the population entering the follow up in these studies was too large covering the peak age of anorexia nervosa itself (13­16 years of age). Larger prospective studies including prepubescent individual and evaluating more psychological markers (perfectionism, negative affectivity or negative self-evaluation) or environmental ones are needed.

Mechanisms and predictors of menses resumption once normal weight is reached in anorexia nervosa.

BACKGROUND: In cases of Anorexia Nervosa (AN), achieving weight gain recovery beyond the lower limits set by the World Health Organization and normalizing classical nutritional markers appears to be essential for most patients. However, this is not always adequate to restore menstrual cycles. This discrepancy can cause concern for both patients and healthcare providers, and can impact the medical management of these individuals. Thus, the purpose of this study was to assess the ability of anthropometric and hormonal factors to predict the resumption of menstrual cycles in individuals with anorexia nervosa upon reaching a normal body weight. METHOD: Patients with AN who had achieved a normal Body Mass Index but had not yet resumed their menstrual cycles (referred to as ANRec) were evaluated on two occasions: first at visit 1 and then again 6 months later, provided their body weight remained stable over this period (visit 2). Among the 46 ANRec patients who reached visit 2, they were categorized into two groups: 20 with persistent amenorrhea (PA-ANRec) and 26 who had regained their menstrual cycles (RM-ANRec). Anthropometric measurements, several hormone levels, Luteinizing Hormone (LH) pulsatility over a 4-h period, and LH response to gonadotropin-releasing hormone injection (LH/GnRH) were then compared between the two groups at visit 1. RESULTS: Patients in the RM-ANRec group exhibited higher levels of follicular stimulating hormone, estradiol, inhibin B, LH/GnRH, and lower levels of ghrelin compared to those in the PA-ANRec group. Analysis of Receiver Operating Characteristic curves indicated that having ≥ 2 LH pulses over a 4-h period, LH/GnRH levels ≥ 33 IU/l, and inhibin B levels > 63 pg/ml predicted the resumption of menstrual cycles with a high degree of specificity (87%, 100%, and 100%, respectively) and sensitivity (82%, 80%, and 79%, respectively). CONCLUSIONS: These three hormonal tests, of which two are straightforward to perform, demonstrated a high predictive accuracy for the resumption of menstrual cycles. They could offer valuable support for the management of individuals with AN upon achieving normalized weight. Negative results from these tests could assist clinicians and patients in maintaining their efforts to attain individualized metabolic targets. TRIAL REGISTRATION: IORG0004981.

Once a minimally normal weight has been reached during eating disorder recovery for female patients with anorexia nervosa (AN), the persistence of amenorrhea can be a cause for concern both patient and practitioner. In our study, we have discovered that positive results in biological blood tests, which can be conveniently conducted in an ambulatory setting, offer valuable predictive insights. Specifically, parameters such as LH pulse numbers exceeding 2, LH response to GnRH injection surpassing 33 UI/L, or Inhibin B levels in the blood exceeding 63 pg/mL, can accurately predict the resumption of menstrual cycles in the upcoming months, provided that the patient does not experience weight loss or engage in intense exercise. Conversely, negative results from these tests at this critical juncture in the recovery process can serve as valuable tools to encourage and motivate both the healthcare provider and the patient. By maintaining their efforts and continuing to increase their weight, patients can work towards a more comprehensive restoration of their menstrual cycles.

Association of gut-specific non-inflammatory T lymphocytes with chronic anorexia nervosa and constitutional thinness.

OBJECTIVE: Previous studies of AN showed low-grade inflammation. Are low-grade inflammation and circulating lymphocytes associated with chronic conditions? METHOD: Peripheric blood cytokines were measured using Luminex™ technology in a chronic AN cohort (mean = 67.42 months), compared to Constitutional Thinness (CT), Constitutional Obesity (CO), and Healthy Controls (HC). Secondarily a prospective cohort of chronic AN (mean = 54.11 months) was recruited to compare the functional lymphocyte profile in blood by flow cytometry to CT and HC. RESULTS: In the AN group, most cytokine concentrations were lower than in CT and HC groups. The IL-23 (98.02 pg/ml) was elevated related to HC and CO, and the IL-10 (4.178 pg/ml) was elevated versus CO. In the CT group, IL-9 (0.06216 pg/ml) was elevated compared to AN. The AN group had high Treg (9.259% of CD4+ ) and CD8+ Integrinß7+ (9.552% of CD3+ ) versus HC for lymphocyte populations. In CT group, elevated Treg (9.7% of CD4+ ) elevated percentage of CD4+ CCR9+ (5.867% of CD3+ ) and CD8+ Integrinß7+ (10.21% of CD3+ ) were found versus HC. CONCLUSIONS: The chronic state of AN and CT is surprisingly non-inflammatory with elevated Treg cells. These results suggest that maintaining a dysregulated response to intestinal antigens may contribute to maintaining AN.

Continuous glucose monitoring assessment in patients suffering from anorexia nervosa reveals chronic prolonged mild hypoglycemia all over the nycthemeron.

OBJECTIVE: Anorexia nervosa (AN) is an eating disorder characterised by voluntary dietary restriction leading to severe undernutrition. Hypoglycaemia is mostly described through severe case reports and is always evaluated by fasting or post-meal blood glucose, showing nothing about hypoglycaemia's length or duration. The interest of continuous interstitial glucose monitoring (CGM), largely used in diabetes mellitus, has never been evaluated in AN patients. METHOD: Glycaemia cycles in AN patients were assessed using CGM over 5 days and then analysed according to food intake. RESULTS: Mean glycaemia was within normal range. 91% of the patients presented with at least one episode with glycaemia under 70 mg/dl. Within the 24 h, the percentage of time spent with a glycaemia under 70 mg/dl was of 20.82 ± 3.90% with a maximum of 52%. We found 2.52 ± 0.33 hypoglycaemia events per 24 h, including 21.11 ± 3.76% at night. CGM parameters correlated with cortisol and IGF1 plasma levels. Comparison with estimated carbohydrate intakes discriminated concordant and non-concordant estimations depending on patient. CONCLUSIONS: AN patients display chronic prolonged mild hypoglycaemia all over the nycthemeron despite normal fasting glycaemia. Associated adaptive increased counter-regulatory hormones might protect AN patients from deeper hypoglycaemia. CGM allowed testing food intake self-estimation reliability of AN patients and could be a very useful biofeedback tool.

New Insights on Bone Tissue and Structural Muscle-Bone Unit in Constitutional Thinness.

While few studies pointed out low bone mineral densities in constitutionally thin women, little is known about potential explanations. The objective was to further explore bone architecture in both women and men with constitutional thinness to investigate their mechanical muscle-bone coupling (or uncoupling). Thirty constitutionally thin people and 31 normal weight controls participated in the study. Body composition, hip structural analysis, and trabecular bone score were assessed by dual-energy X-ray absorptiometry, bone architecture using high-resolution peripheral quantitative computed tomography, and muscle explorations through histological staining on muscle biopsies. Thirty-two out of the 48 indexes relative to density, geometry, texture, and architecture of bones were found significantly lower (p < 0.05) in constitutionally thin individuals compared with controls. This observation was particularly pronounced in constitutionally thin men. Bone microarchitecture was more altered in weight-supporting bone (tibia) than in non-weight-supporting (radius) bone, which might refer to a normal physiological adaptation (Frost's mechanostat theory). Yet, the heat-maps of correlations analyses showed many alterations of body weight or muscle associations with bone parameters in constitutionally thin individuals contrary to controls. Present results might support the idea of intrinsic disturbances of bone cells independently to the small muscle structure, particularly in men.

Therapeutic Fasting: Are Patients Aged 65 and Over Ready?

While being the main potential beneficiaries of therapeutic fasting's health benefits, the elderly are frequently thought of as being too fragile to fast. The main objective of our survey was to review the knowledge, practices, and acceptability of therapeutic fasting in subjects aged 65 years and over. From September 2020 to March 2021, an online questionnaire was sent to subjects aged 65 and over, using the mailing list of local organizations working in the field of aging. The mean age of the 290 respondents was 73.8 ± 6.5 years, 75.2% were women and 54.1% had higher education. Among the respondents, 51.7% had already fasted and 80.7% deemed therapeutic fasting interesting, 83.1% would be willing to fast if it was proven beneficial for their health, and 77.2% if it was proven to decrease the burden of chronic diseases. Subjects aged 65 to 74 years considered themselves as having the greatest physical and motivational abilities to perform therapeutic fasting. People aged 65 years, or more, are interested in therapeutic fasting and a large majority would be ready to fast if such practice was proven beneficial. These results pave the way for future clinical trials evaluating therapeutic fasting in elderly subjects.

Proteomics reveals unique plasma signatures in constitutional thinness.

PURPOSE: Studying the plasma proteome of control versus constitutionally thin (CT) individuals, exposed to overfeeding, may give insights into weight-gain management, providing relevant information to the clinical entity of weight-gain resistant CT, and discovering new markers for the condition. EXPERIMENTAL DESIGN: Untargeted protein relative quantification of 63 CT and normal-weight individuals was obtained in blood plasma at baseline, during and after an overfeeding challenge using mass spectrometry-based proteomics. RESULTS: The plasma proteome of CT subjects presented limited specificity with respect to controls at baseline. Yet, CT showed lower levels of inflammatory C-reactive protein and larger levels of protective insulin-like growth factor-binding protein 2. Differences were more marked during and after overfeeding. CT plasma proteome showed larger magnitude and significance in response, suggesting enhanced "resilience" and more rapid adaptation to changes. Four proteins behaved similarly between CT and controls, while five were regulated in opposite fashion. Ten proteins were differential during overfeeding in CT only (including increased fatty acid-binding protein and glyceraldehyde-3-phosphate dehydrogenase, and decreased apolipoprotein C-II and transferrin receptor protein 1). CONCLUSIONS AND CLINICAL RELEVANCE: This first proteomic profiling of a CT cohort reveals different plasma proteomes between CT subjects and controls in a longitudinal clinical trial. Our molecular observations further support that the resistance to weight gain in CT subjects appears predominantly biological. CLINICALTRIALS: gov Identifier: NCT02004821.

Is constitutional thinness really different from anorexia nervosa? A systematic review and meta-analysis.

A growing interest in constitutional thinness has been observed in the last decades, but the publications however cover various fields of study and report equivocal results. The present work systematically reviewed any clinical trials enrolling participants with constitutional thinness and bibliographic researches were performed between December 2018 and June 2020. From a total of 1 212 records initially identified, 402 records were removed as duplicates, 381 articles were excluded based on titles or abstracts and 390 references were excluded against eligibility criteria. Thirty-nine articles were finally included in the systematic review. The results showed that constitutionally thin people seem to be underweight but not underfat and present a fat-free mass as blunted as anorexic patients, despite being a little less underweight. The meta-analysis confirmed that constitutionally thin people present normal energy intake and revealed a trend toward a higher resting metabolic rate to fat-free mass ratio which suggests a highly metabolic fat-free mass. Contrary to patients with anorexia nervosa, constitutionally thin people present normal levels of insulin-like growth factor 1, estradiol, growth hormone, follicle-stimulating hormone, and luteinizing hormone. An intermediate level of leptin between anorexic and control participants was however observed in constitutional thinness. While all the studies reported normal free triiodothyronine and cortisol levels in constitutionally thin individuals, a higher fasting free triiodothyronine level (p = 0.033) and a lower 24 h mean cortisol level (p = 0.005) were observed for the first time. Present results give robust evidence that constitutionally thin people present an atypical phenotype highly different from anorexia nervosa.

Underweight but not underfat: is fat-free mass a key factor in constitutionally thin women?

Constitutional thinness is defined as a state of severe underweight with a body mass index similar to anorectic patients (BMI < 17.5 kg/m2), in the absence of any eating disorders or other obvious disruptive factors impacting energy balance. The analysis of body composition is essential as a first approach to characterize constitutional thinness and might help identify new discriminating differences between constitutional thinness and anorexia nervosa. A meta-analytical approach was performed to compare body composition of constitutionally thin, anorectic, and normal-weight subjects from all available studies found in the literature. The statistical analysis was carried out on large sample sizes: n = 205 females with constitutional thinness, n = 228 normal-weight control females, and n = 258 females with anorexia nervosa. Despite being as underweight as anorectic patients, constitutionally thin participants paradoxically presented higher percentages of fat mass than anorectic patients (18.9% vs. 11.4%, respectively; SMD [95% CI]: 1.62 [1.16; 2.08]), even found in the normal healthy ranges. Constitutionally thin people, however, display as low fat-free mass as anorectic patients. These observations question the use of high-fat diets in this population and bring new insights for nutrition and/or training strategies directed toward muscle mass gain. The present results give new elements to further distinguish constitutional thinness from anorexia nervosa and reinforce the need to better investigate the atypical phenotype of constitutional thinness.

Skeletal muscle of females and males with constitutional thinness: a low intramuscular lipid content and oxidative profile.

Constitutional thinness (CT) is a nonpathological state of underweight. The current study aimed to explore skeletal muscle energy storage in individuals with CT and to further characterize muscle phenotype at baseline and in response to overfeeding. Thirty subjects with CT (15 females, 15 males) and 31 normal-weight control subjects (16 females, 15 males) participated in the study. Histological and enzymological analyses were performed on muscle biopsy specimens before and after overfeeding. In the skeletal muscle of CT participants compared with controls, we observed a lower content of intramuscular triglycerides for type I (-17%, p < 0.01) and type IIA (-14%, p < 0.05) muscle fibers, a lower glycogen content for type I (-6%, p < 0.01) and type IIA (-5%, p < 0.05) muscle fibers, a specific fiber-type distribution, a marked muscle hypotrophy (-20%, p < 0.001), a low capillary-to-fiber ratio (-19%, p < 0.001), and low citrate synthase activity (-18%, p < 0.05). In response to overfeeding, CT participants increased their intramuscular triglycerides content in type I (+10%, p < 0.01) and type IIA (+9%, p < 0.01) muscle fibers. CT individuals seem to present an unusual muscle phenotype and different adaptations to overfeeding compared with normal-weight individuals, suggesting a specific energy metabolism and muscle adaptations. ClinicalTrials.gov registration no. NCT02004821. Novelty Low intramuscular triglycerides and glycogen content in skeletal muscle of constitutionally thin individuals. Low oxidative capacity, low capillary supply, and fiber hypotrophy in skeletal muscle of constitutionally thin individuals. Increase in intramuscular triglycerides in constitutional thinness in response to overfeeding.

Two new reliable immunohistochemical methods for simultaneous identification of capillaries, the three types of fibers and basal lamina in human skeletal muscle.

Capillary network of skeletal muscle has a crucial role in oxygen supply and is strongly associated with the phenotype and metabolic profile of muscle fibers. Abundant literature has explored capillarization of skeletal muscle in different populations and in response to different interventions. Capillary and fiber type identification techniques have considerably evolved over the last decades, but to the best of our knowledge, no validated immunohistochemical method has yet been developed to simultaneously identify capillaries (using CD31), the three different muscle fiber types, and basal lamina. Nine human muscle biopsies of vastus lateralis were stained using 5 different methods to test: the reliability of different CD31 antibodies for capillary identification, the reliability between single-section or serial-section methods, and the intra-experimenter reproducibility in visual detection of capillaries. High reliability for the different antibodies directed against capillaries was observed for capillary contacts (CC) measurements (intra-class correlations (ICC) [ICC95%] of 0.89 [0.72; 0.96] for type I fibers, 0.93 [0.81; 0.97] for type IIA fibers, 0.88 [0.71; 0.96] for type IIX fibers, 0.95 [0.86; 0.98] for all fiber types) as well as a high level of similarity between single and serial sections methods. A strong similarity in capillary analysis between the different methods was obtained for each sample measurements. Analysis of Lin's concordance correlation coefficients and Bland and Altman's graphics showed a strong intra-experimenter reproducibility. This article proposes two time- and tissue-sparing immunohistochemical methods to accurately assess a complete fiber typing (type I, IIA, and IIX) along with muscle capillarization on a single muscle section.

Decreased cerebral opioid receptors availability related to hormonal and psychometric profile in restrictive-type anorexia nervosa.

PURPOSE: The opioid system role in anorexia nervosa (AN) pathophysiology is still unclear since conflicting results were reported on peripheral and cerebrospinal fluid opioids levels. The study main aim was to evaluate cerebral AN opiate receptor availability by using [11C] diprenorphine, a ligand with non-selective binding. METHODS: In vivo [11C]diprenorphine cerebral non-displaceable binding potential (BPND) evaluated by PET imaging was compared between three groups : 17 undernourished restrictive-type AN patients (LeanAN), 15 AN patients having regained normal weight (RecAN) and 15 controls. A lower BPND may account for an increased opioid tone and vice versa. Serum hormones and endogenous opioids levels, eating-related and unspecific psychological traits were also evaluated. RESULTS: Compared to controls, LeanAN and RecAN patients had decreased [11C]diprenorphine BPND in middle frontal gyrus, temporo-parietal cortices, anterior cingulate cortex and in left accumbens nucleus. Hypothalamo-pituitary (H-P), left amygdala and insula BPND was found decreased only in LeanAN and that of putamen only in RecAN. LeanAN presented higher dynorphin A and enkephalin serum levels than in controls or RecAN. Inverse correlations were found in total group between : 24 h mean serum cortisol levels and anterior cingulate gyrus or insula BPND; eating concern score and left amygdala BPND. Positive correlation were found between leptin and hypothamus BPND; LH and pituitary BPND. CONCLUSIONS: Low opiate receptor availability may be interpreted as an increased opioid tone in areas associated with both reward/aversive system in both AN groups. The relationship between the opioid receptors activity and hypercorticism or specific psychometric scores in some of these regions suggests adaptive mechanisms facing anxiety but also may play a role in the disease perpetuation.

Definition and diagnosis of constitutional thinness: a systematic review.

The existing literature about the definition and diagnostic criteria of constitutional thinness (CT) appears equivocal. The present work systematically reviewed the criteria used in the diagnosis of adult individuals with CT (PROSPERO registration number: CRD42019138236). Five electronic bibliographic databases were searched between December 2018 and November 2019: MEDLINE, Embase, CENTRAL (Cochrane Library), Google Scholar and Clinical Trials. Search terms were combined with Medical Subject Headings terms. The search strategy included any clinical trials that enrolled adults with CT. Studies were systematically excluded if the state of thinness was not due to a well-identified constitutional origin. From the 689 references after duplicate removal, 199 studies were excluded based on title and 164 based on abstract. According to the inclusion and exclusion criteria, 291 other studies were removed. Finally, thirty-five studies remained at the end of the process. The analysis of these studies showed high heterogeneity in the diagnostic criteria of CT. A real need emerged to adopt a common terminology and to systematically exclude potential non-constitutional origins of thinness such as eating disorders, associated pathology or over-exercising, with validated tools. Weight history, physiological menses and weight gain resistance are also important criteria to consider. The present systematic review revealed that our medical and scientific approaches of CT need to be harmonised in terms of terminology and diagnostic criteria. Although further studies are needed, we finally proposed recommendations and a decision tree to help in the recognition and diagnosis of CT.

Resistance to lean mass gain in constitutional thinness in free-living conditions is not overpassed by overfeeding.

BACKGROUND: Constitutional thinness (CT), a non-malnourished underweight state with no eating disorders, is characterized by weight gain resistance to high fat diet. Data issued from muscle biopsies suggested blunted anabolic mechanisms in free-living state. Weight and metabolic responses to protein caloric supplementation has not been yet explored in CT. METHODS: A 2 week overfeeding (additional 600 kcal, 30 g protein, 72 g carbohydrate, and 21 g fat) was performed to compare two groups of CTs (12 women and 11 men) to normal-weight controls (12 women and 10 men). Bodyweight, food intake, energy expenditure, body composition, nitrogen balance, appetite hormones profiles, and urine metabolome were monitored before and after overfeeding. RESULTS: Before overfeeding, positive energy gap was found in both CT genders (309 ± 370 kcal in CT-F and 332 ± 709 kcal in CT-M) associated with higher relative protein intake per kilo (1.74 ± 0.32 g/kg/day in CT-F vs. 1.16 ± 0.23 in C-F, P < 0.0001; 1.56 ± 0.36 in CT-M vs. 1.22 ± 0.32 in C-M, P = 0.03), lower nitrogen (7.26 ± 2.36 g/day in CT-F vs. 11.41 ± 3.64 in C-F, P = 0.003; 9.70 ± 3.85 in CT-M vs. 14.14 ± 4.19 in C-M, P = 0.02), but higher essential amino acids urinary excretion (CT/C fold change of 1.13 for leucine and 1.14 for arginine) in free-living conditions. After overfeeding, CTs presented an accentuated positive energy gap, still higher than in controls (675 ± 540 in CTs vs. 379 ± 427 in C, P = 0.04). Increase in lean mass was induced in both controls genders but not in CTs (a trend was noticed in CT women), despite a similar nitrogen balance after overfeeding (5.06 ± 4.33 g/day in CTs vs. 4.28 ± 3.15 in controls, P = 0.49). Higher anorectic gut hormones' tone, glucagon-like peptide 1 and peptide tyrosine tyrosine, during test meal and higher snacking frequency were noticed before and after overfeeding in CTs. CONCLUSIONS: The blunted muscle energy mechanism, previously described in CTs in free-living state, is associated with basal saturated protein turn over suggested by the concordance of positive nitrogen balance and an increased urine excretion of several essential amino acids. This saturation cannot be overpassed by increasing this spontaneous high-protein intake suggesting a resistance to lean mass gain in CT phenotype.

Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue.

BACKGROUND: Constitutional thinness (CT) is a state of low but stable body weight (BMI ≤18 kg/m2). CT subjects have normal-range hormonal profiles and food intake but exhibit resistance to weight gain despite living in the modern world's obesogenic environment. OBJECTIVE: The goal of this study is to identify molecular mechanisms underlying this protective phenotype against weight gain. METHODS: We conducted a clinical overfeeding study on 30 CT subjects and 30 controls (BMI 20-25 kg/m2) matched for age and sex. We performed clinical and integrative molecular and transcriptomic analyses on white adipose and muscle tissues. RESULTS: Our results demonstrate that adipocytes were markedly smaller in CT individuals (mean ± SEM: 2174 ± 142 µm 2) compared with controls (3586 ± 216 µm2) (P < 0.01). The mitochondrial respiratory capacity was higher in CT adipose tissue, particularly at the level of complex II of the electron transport chain (2.2-fold increase; P < 0.01). This higher activity was paralleled by an increase in mitochondrial number (CT compared with control: 784 ± 27 compared with 675 ± 30 mitochondrial DNA molecules per cell; P < 0.05). No evidence for uncoupled respiration or "browning" of the white adipose tissue was found. In accordance with the mitochondrial differences, CT subjects had a distinct adipose transcriptomic profile [62 differentially expressed genes (false discovery rate of 0.1 and log fold change >0.75)], with many differentially expressed genes associating with positive metabolic outcomes. Pathway analyses revealed an increase in fatty acid oxidation ( P = 3 × 10-04) but also triglyceride biosynthesis (P = 3.6 × 10-04). No differential response to the overfeeding was observed in the 2 groups. CONCLUSIONS: The distinct molecular signature of the adipose tissue in CT individuals suggests the presence of augm ented futile lipid cycling, rather than mitochondrial uncoupling, as a way to increase energy expenditure in CT individuals. We propose that increased mitochondrial function in adipose tissue is an important mediator in sustaining the low body weight in CT individuals. This knowledge could ultimately allow more targeted approaches for weight management treatment strategies. This trial was registered at clinicaltrials.gov as NCT02004821.