The Yucatan minipig model: A new preclinical model of malnutrition in obese patients with acute or chronic diseases.

BACKGROUND & AIMS: Malnutrition can develop in patients with obesity suffering from acute or chronic illness or after obesity surgery, promoting sarcopenic obesity. A better understanding of this pathophysiology and the development of new therapeutics for chronic diseases, that are often complicated with malnutrition and obesity, justify the development of new animal experimental models close to the human physiology. This study aims to characterize the effects of obesity and underfeeding on Yucatan obese minipigs, assessing its validity as a preclinical model for obesity-related malnutrition. METHODS: Sixteen 30-month-old Yucatan minipigs were divided into two groups for 8 weeks: a standard diet group (ST, n = 5) and an obesogenic diet group (OB, n = 11). After 8 weeks, the OB group was further divided into two sub-groups: a standard diet group (OB-ST, n = 5) and a low-calorie/low-protein diet group (OB-LC/LP, n = 6) for 8 weeks. Body composition by CT-Scan and blood parameters were monitored, and trapezius muscle biopsies were collected to analyse signaling pathways involved in protein turnover and energy metabolism. RESULTS: At W8, OB-ST animals exhibited significantly higher body weight (+37.7%, p = 0.03), muscle mass (+24.9%, p = 0.02), and visceral fat (+192.0%, p = 0.03) compared to ST. Trapezius cross sectional area (CSA) normalized to body weight was lower in OB-ST animals (-15.02%, p = 0.017). At W16, no significant changes were observed in protein turnover markers, although REDD1 increased in OB-ST (96.4%, p = 0.02). After 8 weeks of low-caloric/low protein diet, OB-LC/LP showed decreased body weight (-9.8%, p = 0.03), muscle mass (-6.5%, p = 0.03), and visceral fat (-41.5%, p = 0.03) compared to OB-ST animals. Trapezius fiber CSA significantly decreased in OB-LC/LP (-36.1%, p < 0.0001) and normalized to body weight (-25.4%, p < 0.0001), combined to higher ubiquitinated protein content (+38.3%, p = 0.02). CONCLUSION: Our data support that the Yucatan minipig model mimics nutritional and skeletal muscle phenotypes observed in obese patients, with or without protein-energy malnutrition. It also reproduces muscle atrophy observed in chronic diseases or post-obesity surgery, making it a promising preclinical model for obesity-related malnutrition.

Emotional overeating affected nine in ten female students during the COVID-19 university closure: A cross-sectional study in France.

OBJECTIVES: To estimate the proportion of female university students reporting overeating (EO) in response to emotions during the COVID-19 university closures, and to investigate social and psychological factors associated with this response to stress. DESIGN: Online survey gathered sociodemographic data, alcohol/drugs use disorders, boredom proneness and impulsivity using validated questionnaires, and EO using the Emotional Overeating Questionnaire (EOQ) assessing eating in response to six emotions (anxiety, sadness, loneliness, anger, fatigue, happiness), whose structure remains to be determined. PARTICIPANTS: Sample of 302 female students from Rennes University, France. MAIN OUTCOME MEASURE: Frequencies of emotional overeating. ANALYSIS: The frequency of emotional overeating was expressed for each emotion as percentages. Exploratory Factor analyses (EFA) were used to determine EOQ structure and provide an index of all EOQ items used for further analysis. Linear regression models were used to explore relationships between EO and others covariates. RESULTS: Nine in ten participants reported intermittent EO in the last 28 days, mostly during 6 to 12 days, in response to Anxiety (75.5%), Sadness (64.5%), Happiness (59.9%), Loneliness (57.9%), Tiredness (51.7%), and to a lesser extent to Anger (31.1%). EFA evidenced a one-factor latent variable reflecting "Distress-Induced Overeating" positively correlated with internal boredom proneness, tobacco use, attentional impulsivity, inability to resist emotional cues, and loss of control over food intake, and negatively with age and well-being. EO was unrelated to body mass index or substance abuse. CONCLUSION AND IMPLICATIONS: Nine in ten female students reported emotional overeating during the COVID-19 university closure. This response to stress was related to eating tendencies typical of young women, but also to personality/behavioral patterns such as boredom and impulsivity proneness. Better understanding of the mechanisms underlying EO in response to stress and lack of external/social stimulation would improve preventive interventions.

Exploration of fMRI brain responses to oral sucrose after Roux-en-Y gastric bypass in obese yucatan minipigs in relationship with microbiota and metabolomics profiles.

BACKGROUND & AIMS: In most cases, Roux-en-Y gastric bypass (RYGBP) is an efficient intervention to lose weight, change eating behavior and improve metabolic outcomes in obese patients. We hypothesized that weight loss induced by RYGBP in obese Yucatan minipigs would induce specific modifications of the gut-brain axis and neurocognitive responses to oral sucrose stimulation in relationship with food intake control. METHODS: An integrative study was performed after SHAM (n = 8) or RYGBP (n = 8) surgery to disentangle the physiological, metabolic and neurocognitive mechanisms of RYGBP. BOLD fMRI responses to sucrose stimulations at different concentrations, brain mRNA expression, cecal microbiota, and plasma metabolomics were explored 4 months after surgery and integrated with WGCNA analysis. RESULTS: We showed that weight loss induced by RYGBP or SHAM modulated differently the frontostriatal responses to oral sucrose stimulation, suggesting a different hedonic treatment and inhibitory control related to palatable food after RYGBP. The expression of brain genes involved in the serotoninergic and cannabinoid systems were impacted by RYGBP. Cecal microbiota was deeply modified and many metabolite features were differentially increased in RYGBP. Data integration with WGCNA identified interactions between key drivers of OTUs and metabolites features linked to RYGBP. CONCLUSION: This longitudinal study in the obese minipig model illustrates with a systemic and integrative analysis the mid-term consequences of RYGBP on brain mRNA expression, cecal microbiota and plasma metabolites. We confirmed the impact of RYGBP on functional brain responses related to food reward, hedonic evaluation and inhibitory control, which are key factors for the success of anti-obesity therapy and weight loss maintenance.

High Visceral Fat is Associated with a Worse Survival after Liver Resection for Intrahepatic Cholangiocarcinoma.

The impact of body composition (BC) on the prognosis of resected intrahepatic cholangiocarcinoma (ICC) has been poorly studied. Aims: i) to evaluate the prevalence of low muscle mass (MM) in patients; ii) to assess the impact of BC on patient overall survival (OS) and disease-free survival (DFS), and iii) on the incidence of postoperative complications. All consecutive patients who underwent liver resection for ICC between 2004 and 2016 and who had preoperative CT scans were included. Ninety-three patients were included. Sixty percent (55/91) had low total MM. On multivariable analysis, high visceral fat (HR 2.48, CI95% [1.63; 3.77], p < 0.0001), nodules >1 (HR 3.15 [1.67; 5.93], p = 0.0004), involvement adjacent organ (HR 6.67 [1.88; 23.69], p = 0.003), and postoperative sepsis (HR 3.04 [1.54; 5.99], p = 0.0013) were independently associated with OS. High visceral fat (HR 2.10 [1.31; 3.38], p = 0.002], nodules >1 (HR 3.01, [1.49; 6.10], p = 0.002), postoperative sepsis (HR 5.16 [2.24; 11.89], p = 0.0001), ASA score (p = 0.02) and perineural invasion (HR 3.30 [1.62; 6.76], p = 0.001) were independently associated with lower DFS. Conclusion: 60% of ICC patients had low MM before surgery. High visceral fat, but not muscle mass, was an independent prognostic factor for poor OS and DFS in European patients with resected ICC.

Food addiction among morbidly obese patients: prevalence and links with obesity complications.

Background: In the context of obesity, little is known about the prevalence of food addiction nor about the phenotype of obese patients with food addiction. Objectives: To assess: (i) the prevalence of food addiction among obese patients eligible for obesity surgery; (ii) the relationship between clinical features and the complications of obesity. Methods: Consecutive patients consulting for the first time were included. The Yale Food Addiction Scale (YFAS) 2.0 questionnaire was used to diagnose food addiction and its severity. Demographics, clinical features, and obesity complications were systematically collected. Statistics: Student's test was used for numerical variables and Chi-square test or Fisher's exact test for categorical variables. Results: A total of 292 patients were included: 79% female, age (mean ± SD) 42.6 ± 13.0 yrs., body mass index (BMI) 43.2 ± 6.8 kg/m2. One hundred and eight patients (37%) had food addiction: 58% severe, 33% moderate, 9% mild. Food addiction prevalence was 39% (n = 61/156) among patients eligible for obesity surgery. Food addiction was more frequent among the unemployed, compared to professionally active patients (41.0% vs. 33.5%, p = 0.046). Clinical and metabolic phenotypes and obesity complications were similar between patients with and without food addiction. Conclusion: Food addiction was present in 37% of obese patients, but was not associated with clinical features or obesity complications. Therefore, it should be systemically assessed for appropriate management.

Single bilateral ovarian venous return in uterine transplant: Validation in an orthotopic auto-transplant model in the Yucatan minipig.

BACKGROUND: Uterine transplant (UT) represents an opportunity to treat absolute uterine infertility. However, the use of uterine veins for venous return, in addition to ovarian veins, significantly increases the risk of ureteral wounds in the living donor and UT time for the recipient. Our aim was to demonstrate that dual ovarian venous return is sufficient for graft viability and survival. METHODS: Uterine orthotopic auto-transplant was performed under general anaesthesia in six Yucatan minipig sows. The uterus graft was implanted with termino-lateral anastomoses between the ovarian and external iliac veins, and between the uterine and external iliac arteries, respectively. RESULTS: The macroscopic physical aspect of the graft was adequate in 83 % of the sows (5/6) 30 min after reperfusion with a surgical time of 439±54 min (mean anastomosis time: 153±49 min). Two sows died the day after surgery. In the four remaining sows, two uteri were necrotic and two were adequately vascularized on Day 7. CONCLUSIONS: the learning curve was relatively fast, the sole use of bilateral ovarian venous return is possible and might reduce post-surgery morbidity in human living donors as well as UT time for the recipient.

Western diet, obesity and bariatric surgery sequentially modulated anxiety, eating patterns and brain responses to sucrose in adult Yucatan minipigs.

Palatable sweet/fatty foods overconsumption is a major risk factor for obesity and eating disorders, also having an impact on neuro-behavioural hedonic and cognitive components comparable to what is described for substance abuse. We hypothesized that Yucatan minipigs would show hedonic, cognitive, and affective neuro-behavioral shifts when subjected to western diet (WD) exposure without weight gain, after the onset of obesity, and finally after weight loss induced by caloric restriction with (RYGB) or without (Sham) gastric bypass. Eating behavior, cognitive and affective abilities were assessed with a spatial discrimination task (holeboard test) and two-choice feed tests. Brain responses to oral sucrose were mapped using 18F-FDG positron emission tomography. WD exposure impaired working memory and led to an "addiction-type" neuronal pattern involving hippocampal and cortical brain areas. Obesity induced anxiety-like behavior, loss of motivation, and snacking-type eating behavior. Weight loss interventions normalized the motivational and affective states but not eating behavior patterns. Brain glucose metabolism increased in gustatory (insula) and executive control (aPFC) areas after weight loss, but RYGB showed higher responses in inhibition-related areas (dorsal striatum). These results showed that diet quality, weight loss, and the type of weight loss intervention differently impacted brain responses to sucrose in the Yucatan minipig model.

Meeting of Minds around Food Addiction: Insights from Addiction Medicine, Nutrition, Psychology, and Neurosciences.

This review, focused on food addiction (FA), considers opinions from specialists with different expertise in addiction medicine, nutrition, health psychology, and behavioral neurosciences. The concept of FA is a recurring issue in the clinical description of abnormal eating. Even though some tools have been developed to diagnose FA, such as the Yale Food Addiction Scale (YFAS) questionnaire, the FA concept is not recognized as an eating disorder (ED) so far and is even not mentioned in the Diagnostic and Statistical Manuel of Mental Disorders version 5 (DSM-5) or the International Classification of Disease (ICD-11). Its triggering mechanisms and relationships with other substance use disorders (SUD) need to be further explored. Food addiction (FA) is frequent in the overweight or obese population, but it remains unclear whether it could articulate with obesity-related comorbidities. As there is currently no validated therapy against FA in obese patients, FA is often underdiagnosed and untreated, so that FA may partly explain failure of obesity treatment, addiction transfer, and weight regain after obesity surgery. Future studies should assess whether a dedicated management of FA is associated with better outcomes, especially after obesity surgery. For prevention and treatment purposes, it is necessary to promote a comprehensive psychological approach to FA. Understanding the developmental process of FA and identifying precociously some high-risk profiles can be achieved via the exploration of the environmental, emotional, and cognitive components of eating, as well as their relationships with emotion management, some personality traits, and internalized weight stigma. Under the light of behavioral neurosciences and neuroimaging, FA reveals a specific brain phenotype that is characterized by anomalies in the reward and inhibitory control processes. These anomalies are likely to disrupt the emotional, cognitive, and attentional spheres, but further research is needed to disentangle their complex relationship and overlap with obesity and other forms of SUD. Prevention, diagnosis, and treatment must rely on a multidisciplinary coherence to adapt existing strategies to FA management and to provide social and emotional support to these patients suffering from highly stigmatized medical conditions, namely overweight and addiction. Multi-level interventions could combine motivational interviews, cognitive behavioral therapies, and self-help groups, while benefiting from modern exploratory and interventional tools to target specific neurocognitive processes.

Adding the oxygen carrier M101 to a cold-storage solution could be an alternative to HOPE for liver graft preservation.

BACKGROUND & AIMS: Hypothermic oxygenated machine perfusion (HOPE) is a promising technique for providing oxygen to the liver during graft preservation; however, because of associated logistical constraints, addition of an oxygen transporter to static cold-storage solutions (SCS) might be easier. M101 is marine worm haemoglobin that has been shown to improve kidney preservation in the clinic when added to SCS. This study evaluated the effects of the addition of M101 to SCS on the quality of pig liver graft preservation. METHODS: Pig liver grafts were preserved using SCS, HOPE, or SCS+M101, and the liver functions were compared during cold preservation and after orthotopic allotransplantation (OLT) in pigs. RESULTS: During preservation of the liver grafts, mitochondrial function, ATP synthesis, antioxidant capacities, and hepatocyte architecture were better preserved, and free radical production, antioxidant activities, and inflammatory mediators were lower, with HOPE or SCS+M101 than with SCS alone. However, after 1 h of preservation, liver functions with HOPE were superior to those with SCS+M101. After 6 h of preservation and OLT, blood levels of aspartate and alanine aminotransferases and lactate dehydrogenase increased with a peak effect at Day 1 post-transplant; values were similar with HOPE and SCS+M101, and were significantly lower than those in the SCS group. At Days 1 and 3, tumor necrosis factor α levels remained lower with HOPE and SCS+M101 vs. SCS. At Day 7, liver cell necrosis and inflammation were less marked in both oxygenated groups. CONCLUSIONS: When added to SCS, M101 effectively oxygenates liver grafts during preservation, preventing post-transplant injury; although graft performances are below those achieved with HOPE. LAY SUMMARY: When transported between donors and recipients, even cold-stored liver grafts need oxygen to maintain their viability. To provide them with oxygen, we added a marine worm super haemoglobin (M101) to the cold-storage solution UWCS. Using a pig liver transplant model, we revealed that livers cold stored with UWCS+M101 showed improved oxygenation compared with simple cold-storage solutions, but did not reach the oxygenation level achieved with machine perfusion.

Locomotion and eating behavior changes in Yucatan minipigs after unilateral radio-induced ablation of the caudate nucleus.

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

Ethanolamine Produced from Oleoylethanolamide Degradation Contributes to Acetylcholine/Dopamine Balance Modulating Eating Behavior.

Oleoylethanolamide is a well-recognized anorectic compound which also has noteworthy effects on food-reward, influencing the acetylcholine (ACh)/dopamine (DA) balance in the cholinergic system. After its administration, oleoylethanolamide is quickly degraded into oleic acid and ethanolamine. The effect of oleic acid on the gut-brain axis has been extensively investigated, whereas ethanolamine has received scarce attention. However, there is scattered evidence from old and recent research that has underlined the influence of ethanolamine on the cholinergic system. In the present article, we propose a model by which the released ethanolamine contributes to the overall balance between DA and ACh after oleoylethanolamide administration.

Emotional overeating is common and negatively associated with alcohol use in normal-weight female university students.

INTRODUCTION: Eating in response to specific emotional cues was hitherto investigated in relation to weight gain, eating disorders, and psychiatric and addictive disorders. Given the difficulties in treating established obesity, preventive interventions towards normal-weight subjects could be more appropriate and cost effective. In order to design such interventions, it is important to characterize emotional overeating in normal-weight subjects, especially young women. METHODS: Female university students aged 18-24 years with healthy Body Mass Index (comprised between 18.5 and 24.9) were asked to complete questionnaires while attending a medical consultation. Emotional Eating frequency in the last 28 days was assessed together with data on habitual physical activity, drinking patterns, substance abuse, suspected eating disorders and cognitive/behavioural components of eating. Sociodemographic data and tobacco use were also collected. RESULTS: Half of participants reported intermittent Emotional Overeating in the last 28 days, mostly during one to five days in the last 28 days, in response to Anxiety (51.3%), Loneliness (45.1%), Sadness (44.8%), and Happiness (43.6%), and to a lesser extent in response to Tiredness (27.4%) and Anger (14.6%). In multivariate analysis, Distress-Induced Overeating (DIO) correlated positively with inability to resist emotional cues, disordered eating symptoms, and loss of control over food intake. It correlated negatively with moderate and excessive drinking. CONCLUSION: A large proportion of normal-weight female students used intermittent overeating episodes as a time-limited response to emotional states, especially anxiety. DIO was negatively correlated with alcohol use, which suggests two distinct and somewhat exclusive ways of coping with negative emotions. It was higher in the minority of students with disordered eating symptoms and loss of control over food intake, highlighting the need for a systematic screening in all female students entering college.

Dietary sugars: their detection by the gut-brain axis and their peripheral and central effects in health and diseases.

BACKGROUND: Substantial increases in dietary sugar intake together with the increasing prevalence of obesity worldwide, as well as the parallels found between sugar overconsumption and drug abuse, have motivated research on the adverse effects of sugars on health and eating behaviour. Given that the gut-brain axis depends on multiple interactions between peripheral and central signals, and because these signals are interdependent, it is crucial to have a holistic view about dietary sugar effects on health. METHODS: Recent data on the effects of dietary sugars (i.e. sucrose, glucose, and fructose) at both peripheral and central levels and their interactions will be critically discussed in order to improve our understanding of the effects of sugars on health and diseases. This will contribute to the development of more efficient strategies for the prevention and treatment for obesity and associated co-morbidities. RESULTS: This review highlights opposing effects of glucose and fructose on metabolism and eating behaviour. Peripheral glucose and fructose sensing may influence eating behaviour by sweet-tasting mechanisms in the mouth and gut, and by glucose-sensing mechanisms in the gut. Glucose may impact brain reward regions and eating behaviour directly by crossing the blood-brain barrier, and indirectly by peripheral neural input and by oral and intestinal sweet taste/sugar-sensing mechanisms, whereas those promoted by fructose orally ingested seem to rely only on these indirect mechanisms. CONCLUSIONS: Given the discrepancies between studies regarding the metabolic effects of sugars, more studies using physiological experimental conditions and in animal models closer to humans are needed. Additional studies directly comparing the effects of sucrose, glucose, and fructose should be performed to elucidate possible differences between these sugars on the reward circuitry.

Behavioural and neurobiological effects of colostrum ingestion in the newborn lamb associated with filial bonding.

In sheep, the onset of filial bonding relies on early intake of colostrum. The aim of our work was to describe in the newborn lamb housed with its mother the immediate post-ingestive effects of colostrum intake, in terms of behaviour and brain activity. In Experiment 1, lambs received five nasogastric infusions of colostrum, or saline, or sham intubations during the first 6 h after birth. Mother-young interactions were recorded before and after the first, third and fifth infusions. The activity of the dam and of the young, which diminished over time in all groups, was temporarily increased in both partners just after each intubation procedure. The number of high-pitched bleats was significantly lower in lambs that received colostrum than in the sham group, suggesting soothing or satiating properties of colostrum. In Experiment 2, newborn lambs received a single nasogastric infusion of colostrum or saline 4.5 h after birth, or were sham intubated. Neuronal activation was investigated 1.5 h later for maximum c-Fos activity. Infusion of colostrum and saline induced different patterns of c-Fos-like immunoreactivity in the paraventricular and supraoptic nuclei of the hypothalamus as compared with the sham group. A specific oxytocinergic/vasopressinergic (OT/VSP) cell population in the paraventricular nucleus was activated following colostrum and saline infusion, but not sham intubation. Only colostrum induced the activation of the cortical amygdala and insular cortex, two structures involved in learning, associative processes, reward and emotion. We hypothesize that filial bonding may be triggered through colostrum-rewarded learning/calming processes and that the OT/VSP system may play a role.

Differential c-Fos expression in the newborn lamb nucleus tractus solitarius and area postrema following ingestion of colostrum or saline.

Visceral stimuli and the gut-brain axis play a crucial role in the control of ingestion even in the neonate. The aim of this study was to assess the neuronal activation in the nucleus tractus solitarius (NTS) and the area postrema (AP) following nutritional and non-nutritional stimulations. Lambs received a single gastric infusion of colostrum or saline at 5% birth weight or were sham infused. Infusion of either liquid led to c-Fos-like immunoreactivity (c-FLI) in the NTS and AP. Differences were observed along the sections of the NTS rostro-caudal axis according to the nature of the stimulation, suggesting a specificity of certain afferents and/or NTS areas for nutritional or non-nutritional signals. In the AP, the neuronal activation induced by colostrum was much higher than that induced by saline. A higher number of TH-immunoreactive cells were activated following colostrum infusion, suggesting a specific involvement of the catecholaminergic pathway in the treatment of meal-related stimuli. In spite of functional convergence, the two medullary structures observed responded differently according to the stimulation, indicating a complementary role in the integration of visceral signals.