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Characterisation of epicardial adipose tissue and myocardial fat infiltration in humans
Get PDFL’obesità ed il diabete mellito di tipo 2 sono caratterizzati da un basso grado di infiammazione sistemica, aumento di dimensione del tessuto adiposo (TA), rilascio incontrollato di acidi grassi liberi nella circolazione; sono entrambi fortemente correlati con patologie metaboliche e cardiovascolari, come la dislipidemia, la patologia coronarica, l’ipertensione e l’infarto miocardico.
Il TA bianco è stato accettato come essere molto più di un semplice deposito statico di energia. Le sue capacità di regolare meccanismi omeostatici e metabolici dell’intero organismo sono stati evidenziati negli ultimi 20 anni; molti studi hanno proposto il TA come un organo endocrino, secernente ormoni, adipochine ed altre sostanze biologicamente attive localmente o a livello sistemico.
I depositi di TA non sono uniformi; le loro caratteristiche cambiano in diverse aree corporee, partecipando in modo diverso alla possibile patogenesi delle diverse patologie.
Il TA epicardico (EAT) è un particolare deposito di TA, che è stato recentemente al centro di molti studi. Si trova localizzato principalmente sulla parete destra libera del cuore e circonda le coronarie, entrando a diretto contatto con il miocardio. Si è visto che EAT secerne molte differenti adipochine e si suppone quindi abbia un ruolo nella generazione e progressione della patologia coronarica.
Lo scopo di questa tesi è quello di meglio caratterizzare EAT e lo strato di miocardio ad esso sottostante.
Nell’articolo 1 abbiamo analizzato le dimensioni cellulari adipocitarie e la secrezione di adiponectina confrontando EAT, il TA viscerale (VAT) e sottocutaneo (SAT). EAT è risultato avere cellule più piccole con ridotta secrezione di adiponectina. La dimensione adipocitaria sia in EAT che SAT è positivamente correlata con l’insulino resistenza, e mostra associazione negativa con l’espressione locale di adiponectina. I soggetti affetti da patologia cardiovascolare presentano inoltre adipociti significativamente più grandi in EAT.
Nell’articolo 2 abbiamo focalizzato la nostra attenzione sugli effetti della patologia diabetica su EAT, mostrando maggiore espressione genica di MCP-1, CD-68 e ridotta di adiponectina, così come dimensioni adipocitarie maggiori in soggetti diabetici rispetto ai non diabetici.
In alcuni dati ancora non pubblicati abbiamo inoltre valutato le caratteristiche immunoistochimiche di infiltrazione lipidica e macrofagica del miocardio della stessa popolazione di pazienti.
Alla tesi è stato inoltre aggiunto come articolo 3 il risultato di uno studio condotto nel corso di un’esperienza all’estero della durata di un anno presso il Lipid Laboratory KI di Stoccolma Svezia. Lasciando il soggetto di EAT, il lavoro si concentra su TA e gli aspetti genetici dell’obesità. Niemann-Pick C1 (NPC-1) è stato recentemente implicato come gene di suscettibilità per l’obesità attraverso uno studio genome wide. Abbiamo approfondito quindi il rapporto tra NPC-1 e l’obesità nell’uomo. Le analisi mRNA hanno mostrato aumentata espressione nel paziente obeso sia in SAT che in VAT e riduzione in seguito a calo di peso. L’espressione genica di NPC-1 era maggiore nelle cellule adipocitarie isolate, rispetto al tessuto in toto, sia in SAT che in VAT, ma non era modificata nel corso della differenziazione adipocitaria. L’espressione proteica di NPC-1 rispecchiava l’espressione genica.Obesity and type 2 diabetes are characterized by mild systemic inflammation, enlargement of fat depots, and uncontrolled release of free fatty acids into the circulation; they are both strongly associated with metabolic and cardiovascular disorders, such as dyslipidemia, coronary heart disease, high blood pressure and myocardial infarct.
White adipose tissue has been widely accepted to be much more than a static fuel storage organ. Its capability of regulating homeostatic and metabolic mechanisms has been underlined during the last 20 years; several studies have proposed adipose tissue as an endocrine organ, secreting hormones, adipokines and other biologically active agents acting locally or in a systemic manner.
Adipose tissue depots are not uniform; their characteristics change in different areas of the body, displaying distinct structural and functional properties and having different putative roles in pathologies.
Epicardial adipose tissue (EAT) is a peculiar adipose tissue depot, which has recently been the center of many studies. It’s located predominantly on the right free wall of the heart, surrounding coronary arteries and being directly in contact with the myocardial layer. EAT has been shown to secrete many different adipokines and is supposed to have a role in the generation and progression of coronary artery diseases.
The aim of this thesis was to better characterize EAT and the underlying myocardial layer.
In paper 1 we investigated adipocyte cell size and adiponectin secretion comparing EAT, visceral AT (VAT) and subcutaneous AT (SAT). EAT resulted to have smaller adipocytes and lower adiponectin secretion levels. Adipocyte size, both in EAT and in SAT, is positively related with insulin resistance, shows negative association with local adiponectin gene expression, and bigger in subjects with coronary artery disease. Adiponectin gene expression is significantly lower in EAT than in SAT.
In paper 2 we focused our attention on the effect of diabetic state on EAT, showing higher MCP-1, CD-68, lower adiponectin level, and bigger adipocytes in subjects with than those without diabetes.
We also analyzed thorough immunohistochemistry and present as unpublished data, the characteristics of fat and macrophagic infiltration of the myocardium of the same cohort of patients.
Additionally, the result of a one year internship conducted at Lipid Laboratory in KI Sweden, has been included in the thesis, as paper 3. Leaving the subject of EAT, the paper is focused on adipose tissue and it’s molecular and genetic aspects in obesity. Since the gene Niemann-Pick C1 (NPC-1) has recently being implicated in susceptibility to obesity, through a genome wide association study, we dig into the relationship between NPC-1 and obesity in humans. The analysis of NPC-1 mRNA ad protein in obesity, showed that NPC1 mRNA was significantly increased in obese individuals in SAT and VAT and down-regulated by weight loss. NPC-1 mRNA was enriched in isolated fat cells of WAT, in SAT versus VAT, but not modified during adipocyte differentiation. NPC-1 protein mirrored expression of mRNA in lean and obese individual
Myosteatosis and myofibrosis: Relationship with aging, inflammation and insulin resistance
No full textThe mechanisms impairing muscle quality and leading to myofibrosis (MF) and myosteatosis (MS) are incompletely known. In biopsies of paraspinous muscle (PM) of 16 elderly men undergoing elective vertebral surgery, we histologically determined the area of MF and MS expressed as muscle quality index (MQI), in order to investigate the relation between them, as well as the main predictors of muscle quality. Total PM area and intermuscular adipose tissue (IMAT) were evaluated by MRI and body composition by DXA. Circulating fasting glucose, insulin, hs-CRP, leptin, adiponectin and IL-6 were measured and HOMA index calculated. Quantification of gene expression in PM and in subcutaneous adipose tissue (SAT) overlying the muscle was performed by rt-PCR. The degree of MS and MF was significantly and positively related to each other and positively associated with BMI, waist, FM and FM% as well as with IMAT. The area of PM was negatively related with MF even after adjustment for weight. Leptin was positively associated with MF and MS, whereas hs-CRP to MF. In backward regression analyses, larger waist and smaller PM area explained 90% of MF variance, whereas leptin about 80% of MS variance. IL-6 expression in SAT was significantly higher in participants with higher MQI values. In PM biopsies we found significantly higher expression of SOCS-3 and a trend toward higher expression of myostatin with greater degrees of MQI. MS and MF are related phenomena that concur to alter muscle quality and both should be considered in further studies on the evolution of sarcopenia. © 2013 Elsevier Ireland Ltd
Sarcopenia, Cachexia and Congestive Heart Failure in the Elderly
No full textSkeletal muscle abnormalities and loss are frequently present in patients with mild or moderate cardiac heart failure (CHF) and may contribute to fatigue and dyspnea. These muscle abnormalities may be associated with age related body composition changes, such as sarcopenia. Muscle damage has also been observed in subjects with cardiac cahexia, a serious CHF complication, associated with poor prognosis independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Loss of muscle mass is a feature of cachexia, whereas most sarcopenic subjects are not cachectic. Individuals with no weight loss, no anorexia, and no measurable systemic inflammatory response may be sarcopenic. Patients with severe CHF show multiple marked histological abnormalities of skeletal muscle, such as muscle fiber atrophy. These abnormalities are different in sarcopenia and cachexia. The majority of mechanisms involved in sarcopenia play a role even in the determination of cachexia and they are amplified in cachexia where they may induce both muscle damage as well as other abnormalities, such as fat and weight loss, through activation of lypolisis or anorexia. To distinguish cachexia and sarcopenia in CHF patients, even if not easy, should be clinically relevant, because no specific treatment is available for cachectic patients whereas treatment options are possible for sarcopenia
LPS response pattern of inflammatory adipokines in an in vitro 3T3-L1 murine adipocyte model
No full textOBJECTIVE: In vitro 3T3-L1 mouse cells represent a reliable model to investigate the inflammatory phenotype of adipocytes activated by bacteria-derived lipopolysaccharide (LPS). In this study we have evaluated the differential expression of adipokines in response to increasing doses of LPS and various incubation times.
METHODS: 3T3-L1 mouse adipocytes were treated with E. coli LPS (from 0 to 10 μg/ml) for a time course ranging from 4 to 24 h, 4 h each. A time point at 2 h was also included to highlight early activation by LPS. mRNA expression by RT-PCR on cell lysates and ELISA assays on cell culture supernatants were performed.
RESULTS: Cells activated by increasing doses of LPS upregulated TNF-α expression in the first 2 h, but this expression slowed down within 6-8 h, while IL-6 expression was increasing. This reduction was also observed for CXCL12/SDF1α. Unlike IL-10, IL-6 expression was constantly upregulated by prolonging incubation with LPS. TNF-α and CXCL12 gene expression occurred early in the time-course and exhibited a second increase following the first 4-6 h of incubation with LPS. Optimal expression of most adipokines needed 6-8 h of a prolonged treatment with LPS at 37 °C. The chemokines MIP-1α/CCL3 and MIP-1β/CCL4 were maximally expressed within the first 8 h, then significantly reduced in the following times. IL-10 expression was upregulated by low doses of LPS and downregulated by prolonging time with the bacterial endotoxin. ELISA analysis of released products generally confirmed the result from gene expression experiments.
CONCLUSION: These data, while assessing previously reported results, highlighted new evidence about the time-dependency in LPS-mediated adipokine production, thus contributing to the comprehension of the inflammatory response of adipocyte
Pancreatic Fat Accumulation and Its Relationship with Liver Fat Content and Other Fat Depots in Obese Individuals.
No full textBackgrounds and Aims: We assessed the associations between pancreatic fat accumulation and other fat compartments, including liver fat and visceral adipose tissue as well as insulin resistance and other metabolic abnormalities in obese individuals. Subjects and Methods: We studied 42 Caucasian adults with obesity (20 men and 22 women; mean BMI 35.2±4 kg/m2), who had no history of liver diseases or excessive alcohol consumption, in which subcutaneous, visceral, liver and pancreatic fat contents were quantified by an in-opposed phase magnetic resonance imaging (MRI) technique. Results: Compared with patients in the lower tertile (<5.6%, n=15), those in the upper tertile of liver fat content had more visceral adipose tissue, greater insulin resistance and had higher values of BMI, blood pressure, triglycerides and lower HDL-cholesterol and adiponectin. Notably, pancreatic fat accumulation also significantly increased across tertiles of liver fat content. In univariate analysis, the strongest correlates of pancreatic fat were visceral and liver fat contents (r=0.80 and r=0.54, p<0.001-0.0001, respectively). Pancreatic fat accumulation was also moderately associated with insulin resistance and other metabolic syndrome features. However, when adjusted for age, gender and visceral adipose tissue, the associations of pancreatic fat accumulation with liver fat and other metabolic abnormalities were no longer significant. Conclusions: There are significant associations between pancreatic fat accumulation and liver fat content as well as insulin resistance and other metabolic abnormalities in obese, but otherwise healthy, individuals. However, these associations are largely mediated by the amount of visceral adipose tissue
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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