Brain PET imaging in obesity and food addiction: current evidence and hypothesis.

The ongoing epidemics of obesity is one main health concern of the present time. Overeating in some obese individuals shares similarities with the loss of control and compulsive behavior observed in drug-addicted subjects, suggesting that obesity may involve food addiction. Here, we review the contributions provided by the use of positron emission tomography to the current understanding of the cerebral control of obesity and food intake in humans. The available studies have shown that multiple areas in the brain are involved with the reward properties of food, such as prefrontal, orbitofrontal, somatosensory cortices, insula, thalamus, hypothalamus, amygdala, and others. This review summarizes the current evidence, supporting the concepts that i) regions involved in the somatosensory response to food sight, taste, and smell are activated by palatable foods and may be hyperresponsive in obese individuals, ii) areas controlling executive drive seem to overreact to the anticipation of pleasure during cue exposure, and iii) those involved in cognitive control and inhibitory behavior may be resistant to the perception of reward after food exposure in obese subjects. All of these features may stimulate, for different reasons, ingestion of highly palatable and energy-rich foods. Though these same regions are similarly involved in drug abusers and game-addicted individuals, any direct resemblance may be an oversimplification, especially as the heterogeneities between studies and the prevalent exclusion of sensitive groups still limit a coherent interpretation of the findings. Further work is required to comprehensively tackle the multifaceted phenotype of obesity and identify the role of food dependency in its pathophysiology

Gut-derived metabolites mediating cognitive development in 5-year-old children: Early-life transplant in mice has lasting effects throughout adulthood

The gut microbiota has been causally linked to cognitive development. We aimed to identify metabolites mediating its effect on cognitive development, and foods or nutrients related to most promising metabolites. Faeces from 5-year-old children (DORIAN-PISAC cohort, including 90 general population families with infants, 42/48 females/males, born in 2011-2014) were transplanted (FMT) into C57BL/6 germ-free mice. Children and recipient mice were stratified by cognitive phenotype, or based on protective metabolites. Food frequency questionnaires were obtained in children. Cognitive measurements in mice included five Y-maze tests until 23 weeks post-FMT, and (at 23 weeks) PET-CT for brain metabolism and radiodensity, and ultrasound-based carotid vascular indices. Children (faeces, urine) and mice (faeces, plasma) metabolome was measured by 1H NMR spectroscopy, and the faecal microbiota was profiled in mice by 16S rRNA amplicon sequencing. Cognitive scores of children and recipient mice were correlated. FMT-dependent modifications of brain metabolism were observed. Mice receiving FMT from high-cognitive or protective metabolite-enriched children developed superior cognitive-behavioural performance. A panel of metabolites, namely xanthine, hypoxanthine, formate, mannose, tyrosine, phenylalanine, glutamine, was found to mediate the gut-cognitive axis in donor children and recipient mice. Vascular indices partially explained the metabolite-to-phenotype relationships. Children's consumption of legumes, whole-milk yogurt and eggs, and intake of iron, zinc and vitamin D appeared to support protective gut metabolites. Overall, metabolites involved in inflammation, purine metabolism and neurotransmitter synthesis mediate the gut-cognitive axis, and holds promise for screening. The related dietary and nutritional findings offer leads to microbiota-targeted interventions for cognitive protection, with long-lasting effects

Combined Effect of Fatty Diet and Cognitive Decline on Brain Metabolism, Food Intake, Body Weight, and Counteraction by Intranasal Insulin Therapy in 3×Tg Mice

Obesity and cognitive decline can occur in association. Brain dysmetabolism and insulin resistance might be common underlying traits. We aimed to examine the effect of high-fat diet (HFD) on cognitive decline, and of cognitive impairment on food intake and body-weight, and explore efficacy of chronic intranasal insulin (INI) therapy. We used control (C) and triple transgenic mice (3×Tg, a model of Alzheimer’s pathology) to measure cerebral mass, glucose metabolism, and the metabolic response to acute INI administration (cerebral insulin sensitivity). Y-Maze, positron emission-computed tomography, and histology were employed in 8 and 14-month-old mice, receiving normal diet (ND) or HFD. Chronic INI therapy was tested in an additional 3×Tg-HFD group. The 3×Tg groups overate, and had lower body-weight, but similar BMI, than diet-matched controls. Cognitive decline was progressive from HFD to 3×Tg-ND to 3×Tg-HFD. At 8 months, brain fasting glucose uptake (GU) was increased by C-HFD, and this effect was blunted in 3×Tg-HFD mice, also showing brain insulin resistance. Brain mass was reduced in 3×Tg mice at 14 months. Dentate gyrus dimensions paralleled cognitive findings. Chronic INI preserved cognition, dentate gyrus and metabolism, reducing food intake, and body weight in 3×Tg-HFD mice. Peripherally, leptin was suppressed and PAI-1 elevated in 3×Tg mice, correlating inversely with cerebral GU. In conclusion, 3×Tg background and HFD exert additive (genes*lifestyle) detriment to the brain, and cognitive dysfunction is accompanied by increased food intake in 3×Tg mice. PAI-1 levels and leptin deficiency were identified as potential peripheral contributors. Chronic INI improved peripheral and central outcomes

Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer's Disease Mouse Model

Metabolic impairments and liver and adipose depots alterations were reported in subjects with Alzheimer's disease (AD), highlighting the role of the liver-adipose-tissue-brain axis in AD pathophysiology. The gut microbiota might play a modulating role. We investigated the alterations to the liver and white/brown adipose tissues (W/BAT) and their relationships with serum and gut metabolites and gut bacteria in a 3xTg mouse model during AD onset (adulthood) and progression (aging) and the impact of high-fat diet (HFD) and intranasal insulin (INI). Glucose metabolism (18FDG-PET), tissue radiodensity (CT), liver and W/BAT histology, BAT-thermogenic markers were analyzed. 16S-RNA sequencing and mass-spectrometry were performed in adult (8 months) and aged (14 months) 3xTg-AD mice with a high-fat or control diet. Generalized and HFD resistant deficiency of lipid accumulation in both liver and W/BAT, hypermetabolism in WAT (adulthood) and BAT (aging), abnormal cytokine-hormone profiles, and liver inflammation were observed in 3xTg mice; INI could antagonize all these alterations. Specific gut microbiota-metabolome profiles correlated with a significant disruption of the gut-microbiota-liver-adipose axis in AD mice. In conclusion, fat dystrophy in liver and adipose depots contributes to AD progression, and associates with altered profiles of the gut microbiota, which candidates as an appealing early target for preventive intervention.This study was conducted within the JPI-HDHL-INTIMIC Knowledge Platform of Food, Diet, Intestinal Microbiomics, and Human Health (sub-project no. KP-778 MISVILUPPO, Italian Ministry of Agricultural, Food and Forestry Policies, Ministry Decree 23092/7303/19), and the JPI-HDHL-INTIMIC Joint Transnational Research program (project no. INTIMIC-085 GUTMOM, Italian Ministry of Education, University and Research, Ministry Decree no. 946/2019). The funders had no role in study design, data collection and analysis, or preparation of the manuscript. Projects supported by the Joint Action “European Joint Programming Initiative: A Healthy Diet for a Healthy Life (JPI HDHL)” are funded by the respective national/regional funding organisations: Fund for Scientific Research (FRS—FNRS, Belgium); Research Foundation—Flanders (FWO, Belgium); INSERM Institut National de la Santé et de la Recherche Médicale (France); Federal Ministry of Food and Agriculture (BMEL) represented by Federal Office for Agriculture and Food (BLE, Germany); Ministry of Education, University and Research (MIUR), Ministry of agricultural, food, and forestry policies (MiPAAF), National Institute of Health (ISS) on behalf of the Ministry of Health (Italy); the National Institute of Health Carlos III (Spain); The Netherlands Organisation for Health Research and Development (ZonMw, The Netherlands), Austrian Research Promotion Agency (FFG) on behalf of the Austrian Federal Ministry for Education, Science, and Research (BMBWF), Ministry of Science and Technology (Israel), Formas (Sweden). DM gratefully acknowledges funding from the Ministry of Science and Innovation of Spain (ACPIN2017-117 and PID2019-108973RB-C22).Peer reviewe

Developmental ORIgins of Healthy and Unhealthy AgeiNg : The Role of Maternal Obesity - Introduction to DORIAN

Peer reviewe

Identification and Characterization of Human Observational Studies in Nutritional Epidemiology on Gut Microbiomics for Joint Data Analysis

In any research field, data access and data integration are major challenges that even large, well-established consortia face. Although data sharing initiatives are increasing, joint data analyses on nutrition and microbiomics in health and disease are still scarce. We aimed to identify observational studies with data on nutrition and gut microbiome composition from the Intestinal Microbiomics (INTIMIC) Knowledge Platform following the findable, accessible, interoperable, and reusable (FAIR) principles. An adapted template from the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) consortium was used to collect microbiome-specific information and other related factors. In total, 23 studies (17 longitudinal and 6 cross-sectional) were identified from Italy (7), Germany (6), Netherlands (3), Spain (2), Belgium (1), and France (1) or multiple countries (3). Of these, 21 studies collected information on both dietary intake (24 h dietary recall, food frequency questionnaire (FFQ), or Food Records) and gut microbiome. All studies collected stool samples. The most often used sequencing platform was Illumina MiSeq, and the preferred hypervariable regions of the 16S rRNA gene were V3-V4 or V4. The combination of datasets will allow for sufficiently powered investigations to increase the knowledge and understanding of the relationship between food and gut microbiome in health and disease

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.We thank FPLD2 patients for donating biological samples. We thank the Italian Network for Laminopathies and the European Consortium of Lipodystrophies (ECLip) for support and helpful discussion. We thank Aurelio Valmori for the technical support. The studies were supported by Rizzoli Orthopedic Institute “5 per mille” 2014 project to MC, AIProSaB project 2016 and Fondazione Del Monte di Bologna e Ravenna grant 2015–2016 “New pharmacological approaches in bone laminopathies based on the use of antibodies neutralizing TGF beta 2” to GL. GL is also supported by PRIN MIUR project 2015FBNB5Y.S

Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer’s Disease Mouse Model

Metabolic impairments and liver and adipose depots alterations were reported in subjects with Alzheimer’s disease (AD), highlighting the role of the liver–adipose–tissue–brain axis in AD pathophysiology. The gut microbiota might play a modulating role. We investigated the alterations to the liver and white/brown adipose tissues (W/BAT) and their relationships with serum and gut metabolites and gut bacteria in a 3xTg mouse model during AD onset (adulthood) and progression (aging) and the impact of high-fat diet (HFD) and intranasal insulin (INI). Glucose metabolism (18FDG-PET), tissue radiodensity (CT), liver and W/BAT histology, BAT-thermogenic markers were analyzed. 16S-RNA sequencing and mass-spectrometry were performed in adult (8 months) and aged (14 months) 3xTg-AD mice with a high-fat or control diet. Generalized and HFD resistant deficiency of lipid accumulation in both liver and W/BAT, hypermetabolism in WAT (adulthood) and BAT (aging), abnormal cytokine–hormone profiles, and liver inflammation were observed in 3xTg mice; INI could antagonize all these alterations. Specific gut microbiota–metabolome profiles correlated with a significant disruption of the gut–microbiota–liver–adipose axis in AD mice. In conclusion, fat dystrophy in liver and adipose depots contributes to AD progression, and associates with altered profiles of the gut microbiota, which candidates as an appealing early target for preventive intervention

Exclusive Breastfeeding Predicts Higher Hearing-Language Development in Girls of Preschool Age

Cognitive disorders are increasing in prevalence. Nutritional or metabolic stressors during early life, and female sex, are predisposing conditions towards the development of cognitive diseases, including Alzheimer’s disease. Though there is evidence that breastfeeding may play a beneficial role in children’s neurocognitive development, the literature remains controversial. In this study we aimed at assessing the association between exclusive breastfeeding and children’s cognitive development from six months to five years of age, addressing sex differences. In 80 mother-child pairs from the Pisa birth cohort (PISAC), we measured cognitive development in groups of children of 6, 12, 18, 24, 36, and 60 months by Griffiths Mental Development Scales, parents’ intelligence quotient (IQ) by Raven’s progressive matrices, and maternal and infants’ anthropometric parameters. We found that exclusive breastfeeding was associated with higher hearing-language development in five years old girls, independent of maternal IQ, age and BMI (body mass index). Exclusive breastfeeding in the first three months of life seemed sufficient to establish this positive relationship. In conclusion, our data indicate that exclusive breastfeeding is a positive predictor of cognitive development in preschool-age girls, paving the way for the implementation of sex-specific cognitive disease risk detection and prevention strategies from early life. Further studies are warranted to explore causality and longer term effects