Labruna, Giuseppe (2013) Bariatric surgery improves blood metabolic profile and miRNA based regulation of gene expression in subcutaneous adipose tissue from morbid obese patients. [Tesi di dottorato]

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Obesity is a multifactorial disorder influenced by the interaction of genetic, behavioral and environmental factors, control of appetite and energy expenditure, and the availability of high-calorie food. Adipocyte and adipose tissue dysfunctions are the primary defects in obesity and may link obesity to such disorders as increased insulin resistance, type 2 diabetes, fatty liver disease, hypertension, dyslipidemia, atherosclerosis and cancer. Bariatric procedures have been shown to be more effective in the management of morbid obesity than lifestyle interventions and pharmacotherapy. The aim of this study was to investigate if the significant and sustained weight loss after laparoscopic adjustable gastric banding (LAGB) resulted in an improvement in the metabolism of obese subjects in terms of serum biochemical parameters and phenotypic characteristics (cell size and number) of subcutaneous adipose tissue (SAT). Moreover, we investigated if miRNA based regulation of gene expression could be involved in the mechanisms underlying the weight loss. We evaluated 20 severely obese subjects before LAGB (T0, mean body mass index [BMI] 44.9 kg/m2) and after the loss of >30% excess weight (T1, mean BMI 31.5 kg/m2). We also evaluated 10 normal weight subjects. We collected SAT and serum samples from all subjects. Conventional biochemical parameters were measured by routine laboratory procedures, and leptin and adiponectin by Luminex xMAP technology. Five-micron sections were prepared from all paraffin-embedded SAT blocks. Slides were then stained with hematoxylin & eosin. Macrophagic infiltration were evaluated by CD68 immunohistochemical analysis. Levels of insulin, homeostasis model assessment-insulin resistance, triglycerides and liver markers as well as the leptin/adiponectin ratio were significantly lower at T1 vs T0 (p<0.05). The number of SAT adipocytes was greater and their size smaller at T1 than at T0 (p<0.05). Moreover, the morphological characteristics of SAT adipocytes at T1 did not differ from those of control adipocytes (p=0.89). Weight loss induced by bariatric surgery resulted in a significant reduction in the inflammation level, as measured by CD68 score. We found that 4% of miRNAs was differently expressed in T1 vs T0, of these 3% was up-expressed and 1% was down-expressed. Bioinformatic analysis of deregulated miRNAs showed several target genes which were involved in relevant pathways among which: pathways in cancer, regulation of endocytosis, MAPK signaling, TGF-beta signaling. LAGB induces an improvement in the obese metabolic status, which could result in a decreased risk of obese-associated diseases. Moreover, the normalization of adipocyte features at T1 vs T0 suggests a regression of SAT inflammation. Furthermore, our data support that the improvement of the metabolic status induced by bariatric surgery in our obese patients could be obtained also by miRNA-based regulation of gene expression.

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