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Positron emission tomography (PET) and computed tomography (CT) are among the most employed diagnostic imaging techniques, and both serve in understanding cardiac function and metabolism. In preclinical research, dedicated scanners with high sensitivity and high spatio-temporal resolution are employed, designed to cope with the demanding technological requirements posed by the small heart size and very high heart rates of mice and rats. In this paper, a bimodal cardiac PET/CT imaging protocol for experimental mouse and/or rat models of cardiac diseases is described, from animal preparation and image acquisition and reconstruction to image processing and visualization. In particular, the

To examine the effect of pioglitazone on epicardial (EAT) and paracardial adipose tissue (PAT) and measures of diastolic function and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM).Twelve patients with T2DM without clinically manifest cardiovascular disease and 12 subjects with normal glucose tolerance (NGT) underwent cardiac magnetic resonance imaging to quantitate EAT and PAT and diastolic function before and after pioglitazone treatment for 24 weeks. Whole-body insulin sensitivity was measured with a euglycaemic insulin clamp and the Matsuda Index (oral glucose tolerance test).Pioglitazone reduced glycated haemoglobin by 0.9% (P 0.05), increased HDL cholesterol by 7% (P 0.05), reduced triacylglycerol by 42% (P 0.01) and increased whole-body insulin-stimulated glucose uptake by 71% (P 0.01) and Matsuda Index by 100% (P 0.01). In patients with T2DM, EAT (P 0.01) and PAT (P 0.01) areas were greater compared with subjects with NGT, and decreased by 9% (P = 0.03) and 9% (P = 0.09), respectively, after pioglitazone treatment. Transmitral E/A flow rate and peak left ventricular flow rate (PLVFR) were reduced in T2DM versus NGT (P 0.01) and increased following pioglitazone treatment (P 0.01-0.05). At baseline normalized PLVFR inversely correlated with EAT (r = -0.45, P = 0.03) but not PAT (r = -0.29, P = 0.16). E/A was significantly and inversely correlated with EAT (r = -0.55, P = 0.006) and PAT (r = -0.40, P = 0.05). EAT and PAT were inversely correlated with whole-body insulin-stimulated glucose uptake (r = -0.68, P 0.001) and with Matsuda Index (r = 0.99, P 0.002).Pioglitazone reduced EAT and PAT areas and improved left ventricular (LV) diastolic function in T2DM. EAT and PAT are inversely correlated (PAT less strongly) with LV diastolic function and both EAT and PAT are inversely correlated with measures of insulin sensitivity.

We successfully radiolabelled a novel prospective cannabinoid type 2 receptor ligand with 18F and tested its biodistribution in animal models by positron emission tomography (PET)/computed tomography (CT) imaging. The radiolabelling process was conducted on an alkyl mesylate fragment of the main naphthyridine core, using highly efficient microfluidic technology. No preliminary protection was needed, and the product was purified by semi-prep HPLC and SPE formulation, allowing the desired diastereomeric mixture to be obtained in 29 % radiochemical yield and > 95 % radiochemically pure. SOD1G93A mice were used as model of overexpression of CB2 receptors; PET imaging revealed a significant increase of the tracer distribution volume in the brain of symptomatic subjects compared with the asymptomatic ones.

We aimed to investigate the effects of maternal obesity on brain structure and metabolism in frail women, and their reversibility in response to exercise. We recruited 37 frail elderly women (20 offspring of lean/normal-weight mothers (OLM) and 17 offspring of obese/overweight mothers (OOM)) and nine non-frail controls to undergo magnetic resonance and diffusion tensor imaging (DTI), positron emission tomography with Fluorine-18-fluorodeoxyglucose (PET), and cognitive function tests (CERAD). Frail women were studied before and after a 4-month resistance training, and controls were studied once. White matter (WM) density (voxel-based morphometry) was higher in OLM than in OOM subjects. Exercise increased WM density in both OLM and OOM in the cerebellum in superior parietal regions in OLM and in cuneal and precuneal regions in OOM. OLM gained more WM density than OOM in response to intervention. No significant results were found from the Freesurfer analysis, nor from PET or DTI images. Exercise has an impact on brain morphology and cognition in elderly frail women.

Interventions affecting gastrointestinal (GI) physiology suggest that the GI tract plays an important role in modulating the uptake of ingested glucose by body tissues. We aimed at validating the use of positron emission tomography (PET) with oral

Maternal gestational obesity is a risk factor for offspring's neurodevelopment and later neuro-cognitive disorders. Altered gut microbiota composition has been found in patients with neurocognitive disorders, and in relation to maternal metabolic health. We explored the associations between gut microbiota and cognitive development during infancy, and their link with maternal obesity. In groups of children from the Pisa birth Cohort (PISAC), we analysed faecal microbiota composition by 16S rRNA marker gene sequencing of first-pass meconium samples and of faecal samples collected at age 3, 6, 12, 24, 36 months, and its relationship with maternal gestational obesity or diabetes, and with cognitive development, as measured from 6 to 60 months of age by the Griffith's Mental Development Scales. Gut microbiota composition in the first phases of life is dominated by Bifidobacteria (Actinobacteria phylum), with contribution of Escherichia/Shigella and Klebsiella genera (Proteobacteria phylum), whereas Firmicutes become more dominant at 36 months of age. Maternal overweight leads to lower abundance of Bifidobacterium, Blautia and Ruminococcus, and lower practical reasoning scores in the offspring at the age of 36 months. In the whole population, microbiota in the first-pass meconium samples shows much higher alpha diversity compared to later samples, and its composition, particularly Bifidobacterium and Veillonella abundances, correlates with practical reasoning scores at 60 months of age. Maternal overweight correlates with bacterial colonization and with the development of reasoning skills at pre-school age. Associations between neonatal gut colonization and later cognitive function provide new perspectives of primary (antenatal) prevention of neurodevelopmental disorders.

Maternal high-fat diet (HFD) affects metabolic and immune development. We aimed to characterize the effects of maternal HFD, and the subsequent diet-normalization of the mothers during a second pregnancy, on the liver and thymus metabolism in their offspring, in minipigs. Offspring born to high-fat (HFD) and normal diet (ND) fed mothers were studied at week 1 and months 1, 6, 12 of life. Liver and thymus glucose uptake (GU) was measured with positron emission tomography during hyperinsulinemic-isoglycemia. Histological analyses were performed to quantify liver steatosis, inflammation, and hepatic hematopoietic niches (HHN), and thymocyte size and density in a subset. The protocol was repeated after maternal-diet-normalization in the HFD group. At one week, HFDoff were characterized by hyperglycemia, hyperinsulinemia, severe insulin resistance (IR), and high liver and thymus GU, associating with thymocyte size and density, with elevated weight-gain, liver IR, and steatosis in the first 6 months of life. Maternal diet normalization reversed thymus and liver hypermetabolism, and increased HHN at one week. It also normalized systemic insulin-sensitivity and liver fat content at all ages. Instead, weight-gain excess, hyperglycemia, and hepatic IR were still observed at 1 month, i.e., end-lactation. We conclude that intra-uterine HFD exposure leads to time-changing metabolic and immune-correlated abnormalities. Maternal diet-normalization reversed most of the effects in the offspring.

Cognitive dysfunctions are a global health concern. Early-life diet and weight status may contribute to children’s cognitive development. For this reason, we explored the associations between habitual food consumption, body mass index (BMI) and cognitive outcomes in 54 preschool children belonging to the Pisa birth Cohort (PISAC). We estimated groups of foods, nutrients and calorie intakes through a food frequency questionnaire (FFQ) and Italian national databases. Then, we adopted the Mediterranean diet (MD) score to assess relative MD adherence. Cognition was examined using the Griffiths Mental Development Scales-Extended Revised (GMDS-ER). We found that higher, compared to low and moderate, adherence to MD was associated with higher performance scores. Furthermore, white meat consumption was positively related to BMI, and BMI (age–gender specific, z-scores) categories were negatively related to practical reasoning scores. All associations were independent of maternal IQ estimates, parents’ socioeconomic status, exclusive/non-exclusive breastfeeding, actual age at cognitive assessment and gender. In conclusion, in preschool children, very high adherence to MD seemed protective, whereas BMI (reinforced by the intake of white meat) was negatively associated with cognition.

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., 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), 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), and the CNR Flagship Project InterOmics (Italian Ministry of Education, University and Research). 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 organizations: 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 the 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 Ministry of Health (Italy); 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). MCC would like to acknowledge the support of the H2020-ERC starting grant MAMI (ref. 639226).

Background:Telomeres are crucial parts of chromosomes that protect the genome. They shorten every time the cell replicates, and shorter telomeres have been associated with increasing age and with many health behaviours. There is inconclusive evidence on the association between physical activity (PA) and telomere length. Objectives: To examine how leisure-time PA (LTPA) is associated with telomere length and telomere attrition during 10 years of follow-up in elderly people. Design: This study is a 10-year prospective follow-up study. Method: For this prospective study, we examined 1,014 subjects (mean age at baseline 60.8 years) from the Helsinki Birth Cohort Study (HBCS). Relative leukocyte telomere length (LTL) was measured with a quantitative real-time PCR and LTPA with a validated questionnaire. Multiple linear regression analyses were used to assess the association between sex-specific LTPA quartiles and LTL at baseline and change in LTL over 10 years. The analyses were adjusted for age, educational attainment, smoking, body fat percentage, oestrogen exposure in women and for follow-up time when applicable. Results: At baseline, volume of LTPA was not associated with LTL in men (p = 0.66) or in women (p = 0.33). Among women, however, higher volume of LTPA at baseline was associated with greater shortening of LTL (p for linearity 0.040) during the 10-year follow-up. No association was found among men (p for linearity 0.75). Conclusions: Our findings suggest that PA has a sex-specific role in regulation of telomere length in the aging process as in our study a high volume of LTPA in elderly women, but not in men, was associated with more rapid telomere attrition.

Human studies of renal hemodynamics and metabolism in obesity are insufficient. We hypothesized that renal perfusion and renal free fatty acid (FFA) uptake are higher in subjects with morbid obesity compared with lean subjects and that they both decrease after bariatric surgery. Cortical and medullary hemodynamics and metabolism were measured in 23 morbidly obese women and 15 age- and sex-matched nonobese controls by PET scanning of [15O]-H2O (perfusion) and 14( R,S)-[18F]fluoro-6-thia-heptadecanoate (FFA uptake). Kidney volume and radiodensity were measured by computed tomography, cardiac output by MRI. Obese subjects were re-studied 6 mo after bariatric surgery. Obese subjects had higher renal volume but lower radiodensity, suggesting accumulation of water and/or lipid. Both cardiac output and estimated glomerular filtration rate (eGFR) were increased by ~25% in the obese. Total renal blood flow was higher in the obese [885 (317) (expressed as median and interquartile range) vs. 749 (300) (expressed as means and SD) ml/min of controls, P = 0.049]. In both groups, regional blood perfusion was higher in the cortex than medulla; in either region, FFA uptake was ~50% higher in the obese as a consequence of higher circulating FFA levels. Following weight loss (26 ± 8 kg), total renal blood flow was reduced ( P = 0.006). Renal volume, eGFR, cortical and medullary FFA uptake were decreased but not fully normalized. Obesity is associated with renal structural, hemodynamic, and metabolic changes. Six months after bariatric surgery, the hemodynamic changes are reversed and the structural changes are improved. On the contrary, renal FFA uptake remains increased, driven by high substrate availability.

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., This work was supported by the EU-FP7-HEALTH project entitled ‘Developmental origin of healthy and unhealthy ageing: the role of maternal obesity (DORIAN)’ (Grant No. 278603), and by the H2020-ERC Starting grant entitled ‘The power of maternal microbes on infant health (MAMI)’ (Grant No. 639226).

OBJECTIVE The aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA1c 6.5–10.5% (48–91 mmol/mol) and ≥3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [18F]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTS After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA1c −0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (−3.74%, P < 0.01), liver volume (−0.10 L, P < 0.05), visceral adipose tissue volume (−0.35 L, P < 0.01), interleukin-6 (−1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (−96 ng/L, P = 0.03). CONCLUSIONS In this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.

Background and aims Intra-uterine metabolic environment predicts newborns’ cardiac morphology, metabolism and future health. In adults, gut microbiota composition relates to altered cardiac structure and metabolism. We investigated the relationship between gut microbiota colonization and fetal cardiac growth. Methods and results Bacterial composition in meconium samples of 26 healthy, full-term newborns was assessed by 16S rDNA gene sequencing. Its relationship with birth echocardiographic parameters, and the interaction with cord blood levels of inflammatory markers were investigated. Correlative and cluster analysis, linear discriminant analysis effect size and predictive functional analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied. Fetal left ventricle growth was related to gut microbiota composition at birth. Specifically, left ventricle posterior wall thickness (LVPW) greater than 4 mm was associated with lower microbiota beta and alpha diversity, depletion (LDA score > 3) of several bacteria at each taxonomic level, including Lactobacillales, and enrichment (LDA score > 5) in Enterobacteriales and Enterobacteriaceae. The latter was significantly related to cord blood gamma-glutamyltransferase levels (r = 0.58, p = 0.0057). Functionally, a thicker LVPW was related to up-regulation of pathways involved in lipopolysaccharide biosynthesis (+50%, p = 0.045 in correlative analysis) and energy metabolism (+12%, p = 0.028), and down-regulation of pathways involved in xenobiotic biodegradation (−21 to −53%, p = 0.0063–0.039), PPAR signaling (−24%, p = 0.021) and cardiac muscle contraction (−100%, p = 0.049). Conclusion Fetal cardiac growth and gut colonization are associated. Greater neonatal LVPW thickness is related to lower diversity of the gut microbiota community, depletion of bacteria having anti-remodeling effects, and enrichment in bacteria functionally linked to inflammation.

Background and purpose The analysis of human faecal metabolites can provide an insight into metabolic interactions between gut microbiota and the host organism. The creation of metabolic profiles in faeces has received little attention until now, and reference values, especially in the context of dietary and therapeutic interventions, are missing. Exposure to xenobiotics significantly affects the physiology of the microbiome, and microbiota manipulation and short-chain fatty acid administration have been proposed as treatment targets for several diseases. The aim of the present study is to give concomitant concentration ranges of faecal sterol species, bile acids and short-chain fatty acids, based on a large cohort. Experimental approach Sterol species, bile acids and short-chain fatty acids in human faeces from 165 study participants were quantified by LC-MS/MS. For standardization, we refer all values to dry weight of faeces. Based on the individual intestinal sterol conversion, we classified participants into low and high converters according to their coprostanol/cholesterol ratio. Key results Low converters excrete more straight-chain fatty acids and bile acids than high converters; 5th and 95th percentile and median of bile acids and short-chain fatty acids were calculated for both groups. Conclusion and implications We give concentration ranges for 16 faecal metabolites that can serve as reference values. Patient stratification into high or low sterol converter groups is associated with significant differences in faecal metabolites with biological activities. Such stratification should then allow better assessment of faecal metabolites before therapeutic interventions. Linked articles This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Metabolic associated fatty liver disease (MAFLD), formerly named "nonalcoholic fatty liver disease" occurs in about one-third of the general population of developed countries worldwide and behaves as a major morbidity and mortality risk factor for major causes of death, such as cardiovascular, digestive, metabolic, neoplastic and neuro-degenerative diseases. However, progression of MAFLD and its associated systemic complications occur almost invariably in patients who experience the additional burden of intrahepatic and/or systemic inflammation, which acts as disease accelerator. Our review is focused on the new knowledge about the brain-gut-liver axis in the context of metabolic dysregulations associated with fatty liver, where insulin resistance has been assumed to play an important role. Special emphasis has been given to digital imaging studies and in particular to positron emission tomography, as it represents a unique opportunity for the noninvasive in vivo study of tissue metabolism. An exhaustive revision of targeted animal models is also provided in order to clarify what the available preclinical evidence suggests for the causal interactions between fatty liver, dysregulated endogenous glucose production and insulin resistance.

Leptin resistance occurs in obese patients, but its independent contribution to adiposity and the accompanying metabolic diseases, i.e., diabetes, liver steatosis, and steatohepatitis, remains to be established. This study was conducted in an extreme model of leptin resistance to investigate mechanisms initiating diabetes, fat expansion, liver steatosis, and inflammatory disease, focusing on the involvement of glucose intolerance and organ-specific glucose uptake in brown and subcutaneous adipose tissues (BAT, SAT) and in the liver. We studied preobese and adult Zucker rats (fa/fa, fa/+ ) during fasting or glucose loading to assess glucose tolerance. Relevant pancreatic and intestinal hormonal levels were measured by Milliplex. Imaging of 18F-fluorodeoxyglucose by positron emission tomography was used to quantify glucose uptake in SAT, BAT, and liver, and evaluate its relationship with adipocyte size and biopsy-proven nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Preobese fa/fa pups showed impaired glucose tolerance, adipocyte enlargement, hepatic microsteatosis, and lobular inflammation, with elevated hepatic post-glucose load glucose uptake and production. Adult fa/fa rats had more severe glucose intolerance, fasting hyperglycemia, hormonal abnormalities, elevated glucose uptake in SAT and BAT, and more markedly in the liver, together with macrosteatosis, and highly prevalent hepatic inflammation. Organ glucose uptake was proportional to the degree of fat accumulation and tissue inflammation and was able to dissect healthy from NAFLD and NAFLD/NASH livers. Most severe NASH livers showed a decline in glucose uptake and liver enzymes. In fa/fa Zucker rats, leptin resistance leads to glucose intolerance, mainly due to hepatic glucose overproduction, preceding obesity, and explaining pancreatic and intestinal hormonal changes and fat accumulation in adipocytes and hepatocytes. Our data support the involvement of liver glucose uptake in the pathogenesis of liver inflammatory disease. Its potential as more generalized biomarker or diagnostic approach remains to be established outside of our leptin-receptor-deficient rat model.

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&rsquo, s disease. Though there is evidence that breastfeeding may play a beneficial role in children&rsquo, s neurocognitive development, the literature remains controversial. In this study we aimed at assessing the association between exclusive breastfeeding and children&rsquo, 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&rsquo, intelligence quotient (IQ) by Raven&rsquo, s progressive matrices, and maternal and infants&rsquo, 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.

Objectives The aim of this study was to investigate the consequences of maternal overweight on cardiac development in offspring in infants (short term) and minipigs (short and longer term). Background The epidemic of overweight involves pregnant women. The uterine environment affects organ development, modulating disease susceptibility. Offspring of obese mothers have higher rates of cardiovascular events and mortality. Methods Echocardiography was performed in infants born to lean and overweight mothers at birth and at 3, 6, and 12 months of age. In minipigs born to mothers fed a high-fat diet or a normal diet, cardiac development (echocardiography, histology), glucose metabolism and perfusion (positron emission tomography), triglyceride and glycogen content, and myocardial enzymes regulating metabolism (mass spectrometry) were determined from birth to adulthood. Results In neonates, maternal overweight, especially in the last trimester, predicted a thicker left ventricular posterior wall at birth (4.1 ± 0.3 vs. 3.3 ± 0.2 mm; p Conclusions Neonatal changes in cardiac morphology were explained by late-trimester maternal body mass index; myocardial glucose overexposure seen in minipigs can justify early human findings. Longer term effects in minipigs consisted of myocardial insulin resistance, enzymatic alterations, and hyperdynamic systolic function.

OBJECTIVE We aimed to investigate the effect of bariatric surgery on lipid metabolism in supraclavicular brown adipose tissue in morbidly obese women. We hypothesized that lipid metabolism improves after surgery-induced weight loss. MATERIALS AND METHODS A total of 23 morbidly obese women (BMI, 42.1 ± 4.2 kg/m2 ; age, 43.8 ± 9.8 years) were assessed before and 6 months after bariatric surgery and 15 age- and sex-matched controls (22.6 ± 2.8 kg/m2 ) were assessed once. In the supraclavicular fat depot, fractional (FUR) and NEFA uptake rates were measured with 18 F-FTHA-PET. We assessed tissue morphology (triglyceride content) using computed tomography (CT)-radiodensity (in Hounsfield Units[HU]) and the proportion of fat with high density (sBAT [%]) in the entire supraclavicular fat depot. RESULTS The supraclavicular fractional uptake rate was lower in obese women compared to controls (0.0055 ± 0.0035 vs 0.0161 ± 0.0177 1/min, P = .001). Both FUR (to 0.0074 ± 0.0035 1/min, P = .01) and NEFA uptake rates (to 0.50 ± 0.50 μmol/100 g/min, P = .001) increased after surgery. Compared to controls, obese women had lower CT-radiodensity (-101.2 ± 10.1 vs -82.5 ± 5.8 HU, P < .001) and sBAT (43.4 ± 8.4% vs 64.5 ± 12.4%, P < .001). After surgery, CT-radiodensity increased (to -82.5 ± 9.6 HU, P < .001), signifying decreased triglyceride content and sBAT improved (to 58.0 ± 10.7%, P < .001), indicating an increased proportion of brown fat. The change in tissue morphology, reflected as increase in CT-radiodensity and sBAT (%), was associated with a decrease in adiposity indices and an increase in whole-body insulin sensitivity. CONCLUSIONS A decrease in triglyceride content, coupled with the increased proportion of brown adipose tissue in the supraclavicular fat depot, may play a role in the improvement of whole-body insulin sensitivity observed in morbidly obese women after surgery-induced weight loss.

Aims To study myocardial substrate uptake, structure and function, before and after bariatric surgery, to clarify the interaction between myocardial metabolism and cardiac remodelling in morbid obesity. Methods We studied 46 obese patients (age 44 ± 10 years, body mass index [BMI] 42 ± 4 kg/m2 ), including 18 with type 2 diabetes (T2D) before and 6 months after bariatric surgery and 25 healthy age-matched control group subjects. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated myocardial glucose uptake (MGU) were measured using positron-emission tomography. Myocardial structure and function, and myocardial triglyceride content (MTGC) and intrathoracic fat were measured using magnetic resonance imaging and magnetic resonance spectroscopy. Results The morbidly obese study participants, with or without T2D, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared with the control group. Surgery led to marked weight reduction and remission of T2D in most of the participants. Postoperatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with left ventricular hypertrophy, and BMI, age and intrathoracic fat mass were the main variables associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU. Conclusions In the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodelling in morbidly obese patients with or without T2D. Cardiac remodelling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of T2D.

Background Adipose tissue glucose uptake is impaired in insulin-resistant states, but ex vivo studies of human adipose tissue have yielded heterogeneous results. This discrepancy may be due to different regulation of blood supply. Objective The aim of this study was to test the flow dependency of in vivo insulin-mediated glucose uptake in fat tissues, and to contrast it with that of skeletal muscle. Design We reanalyzed data from 159 individuals in which adipose tissue depots-subcutaneous abdominal and femoral, and intraperitoneal-and femoral skeletal muscle were identified by MRI, and insulin-stimulated glucose uptake ([18F]-fluoro-2-deoxyglucose) and blood flow ([15O]-H2O) were measured simultaneously by positron emission tomography scanning. Results Individuals in the bottom tertile of whole-body glucose uptake [median (IQR) 36 (17) µmol. kg fat-free mass (kgFFM)-1 . min-1 .nM-1] displayed all features of insulin resistance compared with the rest of the group [median (IQR) 97 (71) µmol . kgFFM-1 .min-1 . nM-1]. Rates of glucose uptake were directly related to the degree of insulin resistance in all fat depots as well as in skeletal muscle. However, blood flow was inversely related to insulin sensitivity in each fat depot (all P ≤ 0.03), whereas femoral muscle blood flow was not significantly different between insulin-resistant and insulin-sensitive subjects, and was not related to insulin sensitivity. Furthermore, in subjects performing one-leg exercise, blood flow increased 5- to 6-fold in femoral muscle but not in the overlying adipose tissue. The presence of diabetes was associated with a modest increase in fat and muscle glucose uptake independent of insulin resistance. Conclusions Reduced blood supply is an important factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect. Diabetes provides a modest compensatory increase in fat and muscle glucose uptake that is independent of insulin resistance.

OBJECTIVE Changes in liver fatty acid metabolism are important in understanding the mechanisms of diabetes remission and metabolic changes after bariatric surgery. RESEARCH DESIGN AND METHODS Liver fatty acid uptake (LFU), blood flow, and fat content (LFC) were measured in 25 obese subjects before bariatric surgery and 6 months after using positron emission tomography/computed tomography and MRS; 14 lean individuals served as the control subjects. RESULTS The increased LFU in obese subjects was associated with body adiposity. LFU was reduced postoperatively but was still high compared with the control subjects. LFC was normalized. Liver blood flow (per unit volume) was higher in obese subjects than in the control subjects at baseline and was further increased postoperatively; however, the total organ blood flow was unchanged as the liver volume decreased. CONCLUSIONS The findings suggest that in a postoperative state, intrahepatic fatty acids are not stored in the liver but are used for oxidation to provide energy. Changes in perfusion may contribute to improved liver metabolism postoperatively.

OBJECTIVE To examine the effect of pioglitazone on myocardial insulin sensitivity and left ventricular (LV) function in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Twelve subjects with T2D and 12 with normal glucose tolerance received a euglycemic insulin clamp. Myocardial glucose uptake (MGU) and myocardial perfusion were measured with [18F]fluoro-2-deoxy-d-glucose and [15O]H2O positron emission tomography before and after 24 weeks of pioglitazone treatment. Myocardial function and transmitral early diastolic relation/atrial contraction (E/A) flow ratio were measured with magnetic resonance imaging. RESULTS Pioglitazone reduced HbA1c by 0.9%; decreased systolic and diastolic blood pressure by 7 ± 2 and 7 ± 2 mmHg, respectively (P < 0.05); and increased whole-body insulin-stimulated glucose uptake by 71% (3.4 ± 1.3 to 5.8 ± 2.1 mg/kg · min; P < 0.01) in subjects with T2D. Pioglitazone enhanced MGU by 75% (0.24 ± 0.14 to 0.42 ± 0.13 μmol/min · g; P < 0.01) and myocardial perfusion by 16% (0.95 ± 0.16 to 1.10 ± 0.25 mL/min · g; P < 0.05). Measures of diastolic function, E/A ratio (1.04 ± 0.3 to 1.25 ± 0.4) and peak LV filling rate (349 ± 107 to 433 ± 99 mL/min), both increased (P < 0.01). End-systolic volume, end-diastolic volume, peak LV ejection rate, and cardiac output trended to increase (P not significant), whereas the ejection fraction (61 ± 6 to 66 ± 7%) and stroke volume increased significantly (71 ± 20 to 80 ± 20 L/min; both P < 0.05). CONCLUSIONS Pioglitazone improves whole-body and myocardial insulin sensitivity, LV diastolic function, and systolic function in T2D. Improved myocardial insulin sensitivity and diastolic function are strongly correlated.

In a recent study, we showed that lymphocytes of obese Italian children/adolescents displayed levels of double strand breaks (DSB), assayed as serine 139-phosphorylated histone H2AX (γ-H2AX), about eightfold higher than normal weight controls, and that 30% of this damage-generated micronuclei. These findings suggested that obese children could be at increased risk of obesity-mediated cancer later in life. We therefore aimed to assess the level of γ-H2AX in a genetic animal model of obesity (Zucker rat) to identify a genotoxic/carcinogenic risk in some organs. The DSB marker was studied in 3- to 4-week-old rats and in 9- to 13-week-old rats. Paraffin-embedded sections of heart, thyroid, liver, pancreas, lung, kidney, esophagus, and gut from the fa-/fa- (obese) and the fa+/fa- (lean) control animals were processed for immunohistochemistry detection of γ-H2AX. Pancreas (0.0624 ± 0.0195), lung (0.1197 ± 0.0217), esophagus (0.1230 ± 0.0351), kidney (0.1546 ± 0.0149), and gut (0.1724 ± 0.0352) of 9- to 13-week-old obese rats showed a higher proportion of γ-H2AX-positive nuclei, than their lean counterparts (0.0092 ± 0.0033, 0.0416 ± 0.0185, 0.0368 ± 0.0088, 0.0686 ± 0.0318, and 0.0703 ± 0.0239, respectively). No difference was seen in the 3- to 4-week-old age group with regard to obesity, indicating that the DNA damage increased with older age of the rats. We hypothesize that the organs of the obese animals showing high levels of DSB could represent target tissues for the development of obesity-related cancers. Environ. Mol. Mutagen. 58:477-484, 2017. © 2017 Wiley Periodicals, Inc.

Computed tomography (CT)-derived adipose tissue radiodensity represents a potential noninvasive surrogate marker for lipid deposition and obesity-related metabolic disease risk. We studied the effects of bariatric surgery on CT-derived adipose radiodensities in abdominal and femoral areas and their relationships to circulating metabolites in morbidly obese patients.We examined 23 morbidly obese women who underwent CT imaging before and 6 months after bariatric surgery. Fifteen healthy non-obese women served as controls. Radiodensities of the abdominal subcutaneous (SAT) and visceral adipose tissue (VAT), and the femoral SAT, adipose tissue masses were measured in all participants. Circulating metabolites were measured by NMR. At baseline, radiodensities of abdominal fat depots were lower in the obese patients as compared to the controls. Surprisingly, radiodensity of femoral SAT was higher in the obese as compared to the controls. In the abdominal SAT depot, radiodensity strongly correlated with SAT mass (r = -0.72, p 0.001). After surgery, the radiodensities of abdominal fat increased significantly (both p 0.01), while femoral SAT radiodensity remained unchanged. Circulating ApoB/ApoA-I, leucine, valine, and GlycA decreased, while glycine levels significantly increased as compared to pre-surgical values (all p 0.05). The increase in abdominal fat radiodensity correlated negatively with the decreased levels of ApoB/ApoA-I ratio, leucine and GlycA (all p 0.05). The increase in abdominal SAT density was significantly correlated with the decrease in the fat depot mass (r = -0.66, p = 0.002).Higher lipid content in abdominal fat depots, and lower content in femoral subcutaneous fat, constitute prominent pathophysiological features in morbid obesity. Further studies are needed to clarify the role of non-abdominal subcutaneous fat in the pathogenesis of obesity.NCT01373892.