Search

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.

Maternal obesity causes metabolic dysfunction in the offspring, including dysbiosis, overeating, obesity, and type 2 diabetes. Early-life phases are fundamental for developing subcutaneous (SAT) and brown adipose tissues (BAT), handling energy excesses. Imaging of 18F-fluorodeoxyglucose by positron emission tomography (PET) and radiodensity by computerized tomography (CT) allows assessing adipose tissue (AT) whitening and browning in vivo and the underlying metabolic efficiency. Our aim was to examine these in vivo traits in SAT and BAT concerning gut microbiota composition in 1- and 6-month-old mice born to normal (NDoff) and high-fat diet-fed dams (HFDoff), accounting for body weight responses. We found low radiodensity (high lipids) in HFDoff SAT at 1 month, relating to an increased abundance of Dorea genus in the caecum and activation of the fatty acid biosynthetic pathway. Instead, low BAT radiodensity and glucose uptake were seen in adult HFDoff. Glucose was shifted in favor of BAT at 1 month and SAT at 6 months. In adults, unclassified Enterococcaceae and Rikenellaceae, and Bacillus genera were negatively related to BAT, whereas unclassified Clostridiales genera were related to SAT metabolism. Stratification of HFDoff based on weight-response, namely maternal induced obesity (MIO-HFDoff) or obesity-resistant (MIOR-HFDoff), showed sex dimorphism. Both subgroups were hyperphagic, but only obese mice had hyper-leptinemia and hyper-resistinemia, together with BAT dysfunction, whereas non-obese HFDoff had hyperglycemia and SAT hypermetabolism. In the caecum, unclassified Rikenellaceae (10-fold enrichment in MIO-HFDoff) and Clostridiales genera (4-fold deficiency in MIOR-HFDoff) were important discriminators of these two phenotypes. In conclusion, SAT whitening is an early abnormality in the offspring of HFD dams. In adult life, maternal HFD and the induced excessive food intake translates into a dimorphic phenotype involving SAT, BAT, and microbiota distinctively

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.

Metabolic-associated fatty liver disease is a major cause of chronic pathologies, of which maternal obesity is a frequent risk factor. Gut wall and microbiota, visceral fat, and liver form a pre-systemic network for substrates and pro-inflammatory factors entering the body, undergoing accelerated maturation in early-life when the weaning reaction, i.e., a transitory inflammatory condition, affects lifelong health. We aimed to characterize organ metabolism in the above network, in relation to weaning reaction and maternal obesity. Weaning or 6-months-old offspring of high-fat-diet and normal-diet fed dams underwent in vivo imaging of pre-/post-systemic glucose uptake and tissue radiodensity in the liver, visceral fat, and intestine, a liver histology, and microbiota and metabolic pathway analyses. Weaning mice showed the dominance of gut Clostridia and Bacteroidia members, overexpressing pathways of tissue replication and inflammation; adulthood increased proneness to steatohepatitis, and Desulfovibrio and RF39 bacteria, and lipopolysaccharide, bile acid, glycosaminoglycan, and sphingolipid metabolic pathways. In vivo imaging could track organ maturation, liver inflammation, and protective responses. A maternal high-fat diet amplified the weaning reaction, elevating liver glucose uptake, triglyceride levels, and steatohepatitis susceptibility along the lifespan. The visceral network establishes a balance between metabolism and inflammation, with clear imaging biomarkers, and crucial modulation in the weaning time window.

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.

An elevated number of women of reproductive age are overweight, predisposing their offspring to metabolic and neuropsychiatric disorders. Gut microbiota is influenced by maternal factors, and has been implicated in the pathogenesis of neurodegenerative diseases. Our aim was to explore the effects of maternal high-fat feeding on the relationship linking gut microbiota and cognitive development in the offspring. Murine offspring born to dams undergoing normal diet (NDm) and high-fat diet (HFDm) were studied at 1 or 6 months of age to assess cognitive function by Y-maze test, cerebral glucose metabolism and insulin sensitivity by Positron Emission Tomography, brain density by Computed Tomography, microbiota profile (colon, caecum) and inferred metabolic pathways (KEGG analysis) by 16S ribosomal RNA sequencing. From 3 weeks post-weaning, mice born to HFDm developed hyperphagia and overweight, showing reduction in memory and exploratory behaviour, and brain insulin resistance in adulthood. We identified a panel of bacteria characterizing offspring born to HFD dams from early life, and correlating with dysfunction in memory and exploratory behaviour in adults (including Proteobacteria phylum, Parabacteroides and unclassified Rikenellaceae genera). Microbiota-derived metabolic pathways involved in fatty acid, essential aminoacid and vitamin processing, sulphur metabolism, glutaminergic activation and Alzheimer’s disease were differently present in the HFDm and NDm offspring groups. Our results document tight relationships between gut dysbiosis and memory and behavioural impairment in relation to maternal HFD. Persistent bacterial signatures induced by maternal HFD during infancy can influence cognition during adulthood, opening the possibility of microbiota-targeted strategies to contrast cognitive decline.

An altered prenatal environment during maternal obesity predisposes offspring to insulin resistance, obesity, and their consequent comorbidities, type 2 diabetes and cardiovascular disease. Telomere shortening and frailty are additional risk factors for these conditions. The aim of this study was to evaluate the effects of resistance training on hepatic metabolism and ectopic fat accumulation. Thirty-five frail elderly women, whose mothers' body mass index (BMI) was known, participated in a 4-mo resistance training program. Endogenous glucose production (EGP) and hepatic and visceral fat glucose uptake were measured during euglycemic hyperinsulinemia with [F-18] fluorodeoxyglucose and positron emission tomography. Ectopic fat was measured using magnetic resonance spectroscopy and imaging. We found that the training intervention reduced EGP during insulin stimulation [ from 5.4 (interquartile range 3.0, 7.0) to 3.9 (-0.4, 6.1) mu mol.kg body wt(-1).min(-1), P = 0.042] in the whole study group. Importantly, the reduction was higher among those whose EGP was more insulin resistant at baseline (higher than the median) [-5.6 (7.1) vs. 0.1 (5.4) mu mol.kg body wt(-1).min(-1), P = 0.015]. Furthermore, the decrease in EGP was associated with telomere elongation (r = -0.620, P = 0.001). The resistance training intervention did not change either hepatic or visceral fat glucose uptake or the amounts of ectopic fat. Maternal obesity did not influence the studied measures. In conclusion, resistance training improves suppression of EGP in elderly women. The finding of improved insulin sensitivity of EGP with associated telomere lengthening implies that elderly women can reduce their risk for type 2 diabetes and cardiovascular disease with resistance training.