Francesca Favaretto

University of Padova, Padova, Veneto, Italy

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Publications (8)17.57 Total impact

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    ABSTRACT: INTRODUCTION: Alström Syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called 'ciliopathies' and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thusfar no study has specifically investigated this aspect in a large population. MATERIAL AND METHODS: Twenty-three ALMS patients (age 1-52 years, 11 M, 12 F) were evaluated for anthropometric parameters (growth charts and Standard Deviation Score (SDS) of height, weight, BMI), GH secretion by growth-hormone-releasing-hormone + arginine test (GHRH-arg), bone age, and hypothalamic-pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. RESULTS: The length-for-age measurements from birth to 36 months showed normal growth with most values falling within -0,67 SDS to +1.28 SDS. A progressive decrease of stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (> 16-20 years: mean SDS -2.22±1.16). The subset of 12 ALMS patients tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154.7±10.6 cm vs 162.9±4.8 cm, p= 0.009), and a mild increase of BMI (Kg/m2) (27.8±4.8 vs 24.1±2.5, p=0.007). Peak GH after GHRH-arg was significantly lower in ALMS patients in comparison to controls (11.9±6.9 ug/L vs 86.1±33.2 ug/L, p <0,0001). Severe GHD was evident biochemically in 50% of ALMS patients. The 10 adult ALMS patients with GHD showed a reduced height in comparison to those without GHD (149.7±6.2 cm vs 161.9±9.2 cm, p= 0.04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. CONCLUSIONS: Our study shows that 50% of non-obese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion. © 2013 Blackwell Publishing Ltd.
    Clinical Endocrinology 02/2013; · 3.40 Impact Factor
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    ABSTRACT: Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia, and alterations of glucose metabolism that often lead to the development of type 2 diabetes at a young age. To study the relationship between weight and metabolism in a group of ALMS patients and matched controls. Fifteen ALMS patients (eight males, seven females; aged 3-51) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic oral glucose tolerance test (OGTT) conditions were measured. Furthermore, anthropometric and body composition data were obtained from an international group of 27 ALMS patients (13 males, 14 females, age range: 4-29 yr). In ALMS we observed an inverse correlation between age and standard deviation scores for height, weight, and body mass index. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, whereas insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index, HOMA%β-cell and insulinogenic index in ALMS, but unlike the insulin-resistance indices, the β-cell function indices showed a significant reduction with age. In ALMS the progression from the early onset obesity toward the impaired fasting glucose or impaired glucose tolerance and overt diabetes is mostly because of a progressive failure of β-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.
    Pediatric Diabetes 07/2011; 13(1):59-67. · 2.08 Impact Factor
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    ABSTRACT: Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.
    PLoS ONE 01/2011; 6(4):e19081. · 3.73 Impact Factor
  • Digestive and Liver Disease - DIG LIVER DIS. 01/2011; 43.
  • Digestive and Liver Disease - DIG LIVER DIS. 01/2010; 42.
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    ABSTRACT: Alström syndrome (ALMS) is an autosomal recessive genetic disease with characteristic phenotypical features including multi-organ fibrosis, insulin resistance, obesity and type 2 diabetes. ALMS1, a ubiquitously expressed gene mutated in ALMS patients, gives rise to a protein of unknown function localized to basal bodies of ciliated cells and centrosomes. Together with Bardet-Biedl syndrome, ALMS is a member of genetic ciliopathies, but the link between cilia/centrosome deficits and metabolic abnormalities remains to be determined. In this study for the first time we quantified Alms1 expression in a cellular model of adipogenesis during the differentiation of 3T3-L1 cells. An early decrease in Alms1 mRNA was observed during preadipocyte to adipocyte conversion. However, acute treatment of preadipocytes with the adipogenic factors did not result in significant change of Alms1 expression. In addition, to study the possible relationship between Alms1 and the degree of fat cell insulin sensitivity, as assessed with an insulin-dependent 2-[1-3H]-deoxyglucose uptake assay, we induced either a reduction or an increase in 3T3-L1 adipocytes insulin sensitivity by a chronic treatment with insulin or rosiglitazone respectively. In all these conditions Alms1 expression remained unchanged. In conclusion, our results show that Alms1 is expressed at higher level in preadipocytes suggesting a role of the gene in the early phase of adipogenesis. Moreover, changes in fat cell insulin sensitivity do not imply any effect on Alms1 expression.
    International Journal of Molecular Medicine 07/2008; 21(6):731-6. · 1.96 Impact Factor
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    ABSTRACT: To elucidate the pathogenesis of HAART-associated lipodystrophy, by investigating the effects of antiretroviral drugs on adipocyte differentiation and gene expression profile. Analysis of gene expression profile by DNA microarrays and quantitative RT-PCR of 3T3-L1 preadipocytes treated with the nucleoside reverse transcriptase inhibitors (NRTI) lamivudine, zidovudine, stavudine, and zalcitabine, and with the protease inhibitors (PI) indinavir, saquinavir, and lopinavir during maturation into adipocytes. Under standard adipogenic differentiation protocols, PI significantly inhibited adipocyte differentiation, as demonstrated by cell viability assay and Oil Red O staining and quantification, whereas NRTI had mild effects on adipogenesis. Gene expression profile analysis showed that treatment with NRTI modulated the expression of transcription factors, such as Aebp1, Pou5f1 and Phf6, which could play a key role in the determination of the adipocyte phenotype. PI also modulated gene expression toward inhibition of adipocyte differentiation, with up-regulation of the Wnt signaling gene Wnt10a and down-regulation of the expression of genes encoding master adipogenic transcription factors (e.g., C/EBPalpha and PPARgamma), oestrogen receptor beta, and adipocyte-specific markers (e.g., Adiponectin, Leptin, Mrap, Cd36, S100A8). This study identifies new genes modulated by PI and NRTI in differentiating adipocytes. Abnormal expression of these genes, which include master adipogenic transcription factors and genes involved in lipid metabolism and cell cycle control, could contribute to the understanding of the pathogenesis of HAART-associated lipodystrophy.
    AIDS 09/2006; 20(13):1691-705. · 6.41 Impact Factor
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    Francesca Favaretto
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    ABSTRACT: In this work we realized a molecular and functional characterization of P2 receptors in several adipose tissue depots (subcuteneous, visceral, preadipocytes/stromal vascular fraction and adipocytes by RT-PCR, qPCR, sequencing, fluorescent dye Ca2+ sensitive, and immunoenzymatic assay. We evaluated also a gene expression in dermal fibroblasts from Alstrom patients using DNA microarray analysis. We found a modulation of genes coding proteins cell cycle related, extracellular matrix, cellular movement and insulin pathway.