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Mavilio M.,University of Rome Tor Vergata | Marchetti V.,University of Rome Tor Vergata | Fabrizi M.,University of Rome Tor Vergata | Fabrizi M.,Research Unit for Multi Factorial Diseases | And 16 more authors.
Cell Reports | Year: 2016

The effect of gut microbiota on obesity and insulin resistance is now recognized, but the underlying host-dependent mechanisms remain poorly undefined. We find that tissue inhibitor of metalloproteinase 3 knockout (Timp3-/-) mice fed a high-fat diet exhibit gut microbiota dysbiosis, an increase in branched chain and aromatic (BCAA) metabolites, liver steatosis, and an increase in circulating soluble IL-6 receptors (sIL6Rs). sIL6Rs can then activate inflammatory cells, such as CD11c+ cells, which drive metabolic inflammation. Depleting the microbiota through antibiotic treatment significantly improves glucose tolerance, hepatic steatosis, and systemic inflammation, and neutralizing sIL6R signaling reduces inflammation, but only mildly impacts glucose tolerance. Collectively, our results suggest that gut microbiota is the primary driver of the observed metabolic dysfunction, which is mediated, in part, through IL-6 signaling. Our findings also identify an important role for Timp3 in mediating the effect of the microbiota in metabolic diseases. Mavilio et al. show that Timp3 impacts gut-microbiome-related liver steatosis and glucose intolerance. Loss of Timp3 potentiates gut microbiota dysbiosis, leading to an increase in the development of inflammatory and metabolic abnormalities, which are mediated, in part, through IL-6 signaling. Antibiotic-mediated depletion of the microbiota improved these metabolic and inflammatory phenotypes. © 2016 The Author(s). Source

Barraco G.M.,Research Unit for Multi Factorial Diseases | Semeraro M.,Research Unit for Multi Factorial Diseases | Prieto-Hontoria P.L.,University of Santiago de Chile | Manco M.,Research Unit for Multi Factorial Diseases
International Journal of Molecular Sciences | Year: 2014

White adipose tissue (WAT) asset, in terms of cell number, fat storage capacity and endocrine function, is largely determined in early stages of life and is pivotal for shaping the WAT pro-inflammatory behavior. WAT derived adipokines have been shown to play a main role in several cardio-metabolic abnormalities of obesity. This review focuses on the most recently identified adipokines, namely adipocyte-fatty acid-binding protein, chemerin, fibroblast growth factor-21, lipocalin-2, omentin-1 and vaspin; their role in the pathogenesis of obesity and associated cardio-metabolic abnormalities; and on their adaptive response to body weight change. Evidence consistently suggests a pathogenic role for A-FABP, chemerin and FGF-21. Nevertheless, large population studies are needed to verify whether they can be useful to predict the risk of cardio-metabolic abnormalities in adulthood and/or monitor the clinical response to therapeutic interventions. © 2014 by the authors; licensee MDPI, Basel, Switzerland. Source

Barraco G.M.,Research Unit for Multi Factorial Diseases | Spreghini M.R.,Unit for Clinical Nutrition | Sforza R.W.,Unit for Clinical Nutrition | Rustico C.,Unit for Clinical Nutrition | And 2 more authors.
Pediatrics | Year: 2015

OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid β-protein 42 (Aβ42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI. METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent β-cell function (HOMA-β) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS: Obese adolescents had values of Aβ42 higher than overweight and normal-weight peers (190.2 ± 9.16 vs 125.9 ± 7.38 vs 129.5 ± 7.65 pg/mL; P < .0001) as well as higher levels of PSEN1 (2.34 ± 0.20 vs 1.95 ± 0.20 vs 1.65 ± 0.26 ng/mL; P < .0001). Concentrations of Aβ42 were significantly correlated with BMI (ρ = 0.262; P < .0001), HOMA-IR (ρ = 0.261; P < .0001) and QUICKI (ρ = -0.220; P < .0001). PSEN1 levels were correlated with BMI (ρ = 0.248; P < .0001), HOMA-IR (ρ = 0.242; P < .0001), and QUICKI (ρ = -0.256; P < .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein. CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD. Copyright © 2015 by the American Academy of Pediatrics. Source

Manco M.,Research Unit for Multi Factorial Diseases | Castagneto-Gissey L.,Catholic University | Arrighi E.,Catholic University | Carnicelli A.,Catholic University | And 3 more authors.
PLoS ONE | Year: 2014

Background: Evidence favours insulin resistance and compensatory hyperinsulinemia as the predominant, perhaps primary, defects in polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate insulin metabolism in young women with PCOS but normal glucose tolerance as compared with age, body mass index and insulin resistance-matched controls to answer the question whether women with PCOS hypersecrete insulin in comparison to appropriately insulin resistance-matched controls. Research Design and Methods: Sixty-nine cases were divided according to their body mass index (BMI) in normal-weight (N = 29), overweight (N = 24) and obese patients (N = 16). Controls were 479 healthy women (age 16-49 y). Whole body Insulin Sensitivity (WBISI), fasting, and total insulin secretion were estimated following an oral glucose tolerance test (C-peptide deconvolution method). Results: Across classes of BMI, PCOS patients had greater insulin resistance than matched controls (p<0.0001 for all the comparisons), but they showed higher fasting and total insulin secretion than their age, BMI and insulin resistance-matched peers (p<0.0001 for all the comparisons). Conclusion: Women with PCOS show higher insulin resistance but also larger insulin secretion to maintain normal glucose homeostasis than age-, BMI- and insulin resistance-matched controls. © 2014 Manco et al. Source

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