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Endocrinology  2009;151(1):195-202.
Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be of pathophysiological importance in obesity and Metabolic Syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11β-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here we have tested the functional consequences of 2 single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11β-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5′-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared to the common G allele, the A allele of rs13306421, a polymorphism located 2 nucleotides 5′ to the translation initiation site, gave higher 11β-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of “leaky scanning”. These data suggest that this polymorphism may have direct functional consequences on levels of 11β-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence as it was not detected in a population of 600 European caucasian women.
PMCID: PMC3971150  PMID: 19934376
steroid metabolism; glucocorticoid; obesity; SNP; translation; regulation
2.  Is a GnRH Antagonist Protocol Better in PCOS Patients? A Meta-Analysis of RCTs 
PLoS ONE  2014;9(3):e91796.
To review published randomized controlled trials (RCTs) evaluating the outcomes of in vitro fertilization/intra-cytoplasmic sperm injection (IVF/ICSI) utilization of gonadotropin-releasing hormone (GnRH) antagonists for ovarian stimulation in polycystic ovarian syndrome (PCOS) patients compared with classic luteal long agonist protocols.
A meta-analysis of prospective randomized trials published in English between 2002 and 2013.
Patient(s) and Interventions
Nine RCTs examining PCOS patients undergoing IVF/ICSI including 588 women who underwent long agonist protocols and 554 women who underwent GnRH antagonist protocols.
Main Outcome Measure(s)
Clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR) and ovarian hyperstimulation syndrome (OHSS) rate.
Nine RCTs were included in this analysis. The CPR-per-embryo transferred was similar in the two groups (relative risk (RR): 0.97, 95% confidence interval (CI): 0.85–1.10). Non-significant estimates comparing the two protocols were found for age, BMI, total dose of gonadotropin administered, number of days of stimulation and number of oocytes retrieved. After meta-analysis of 4 of the RCTs, it was concluded that a GnRH antagonist protocol is better than an agonist long protocol to reduce the rate of severe OHSS (odds ratio (OR): 1.56, 95% CI: 0.29–8.51).
With respect to CPR, a GnRH antagonist protocol is similar to a GnRH agonist long protocol. However, for severe OHSS, a GnRH antagonist protocol is significantly better in PCOS patients.
PMCID: PMC3958392  PMID: 24642641
3.  Metabolic Syndrome Risk after Gestational Diabetes: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(1):e87863.
A number of studies have been conducted to investigate the risk of metabolic syndrome (MS) after gestational diabetes mellitus (GDM), but the results are contradictory. Accordingly, we performed a systematic review and meta-analysis to assess the association between these two conditions. The aim was to better understand the risks of MS with prior gestational diabetes.
Pubmed, ISI Web of Science, and Cochrane databases from September 1, 1979 to July 11, 2013 were searched to identify relevant studies. 17 studies containing 5832 women and 1149 MS events were included. We calculated the odds ratio (OR) with 95% confidence interval (CI) in analysis for each study using a random-effect or fixed-effect model. We also determined heterogeneity among these 17 articles and their publication bias.
Women with a history of gestational diabetes had a significantly higher risk of MS than those who had a normal pregnancy (OR, 3.96; 95% CI, 2.99 to 5.26), but had significant heterogeneity (I2 = 52.6%). The effect remained robust (OR, 4.54; 95% CI, 3.78–5.46) in the subgroup of Caucasians, but no association (OR, 1.28; 95% CI, 0.64–2.56) was found in Asians. Heterogeneity was reduced (body mass index (BMI) matched group I2 = 14.2%, BMI higher in the GDM group I2 = 13.2%) in the subgroup of BMI. In addition, mothers with higher BMI in the GDM group had higher risk of MS than those in the BMI matched group (BMI higher in GDM group OR, 5.39; 95% CI, 4.47–6.50, BMI matched group OR, 2.53; 95% CI, 1.88–3.41).
This meta-analysis demonstrated increased risk of MS after gestational diabetes. Therefore, attention should be given to preventing or delaying the onset of MS in GDM mothers, particularly in Caucasian and obese mothers.
PMCID: PMC3909287  PMID: 24498216
4.  Emerging Concepts About Prenatal Genesis, Aberrant Metabolism and Treatment Paradigms in Polycystic Ovary Syndrome 
Endocrine  2012;42(3):526-534.
The interactive nature of the 8th Annual Meeting of the Androgen Excess & PCOS Society Annual Meeting in Munich, Germany (AEPCOS 2010) and subsequent exchanges between speakers led to emerging concepts in PCOS regarding its genesis, metabolic dysfunction, and clinical treatment of inflammation, metabolic dysfunction, anovulation and hirsutism. Transition of care in congenital adrenal hyperplasia from pediatric to adult providers emerged as a potential model for care transition involving PCOS adolescents.
PMCID: PMC3485440  PMID: 22661293
Developmental programming; clomiphene citrate; aromatase inhibitors; metformin; lifestyle intervention; advanced glycated end products; inflammation; statins; congenital adrenal hyperplasia; hirsutism
5.  The Potential Association between Obstructive Sleep Apnea and Diabetic Retinopathy in Severe Obesity—The Role of Hypoxemia 
PLoS ONE  2013;8(11):e79521.
Obstructive sleep apnea (OSA) is common in obese patients with type 2 diabetes mellitus (DM) and may contribute to diabetic microvascular complications.
To investigate the association between OSA, hypoxemia during sleep, and diabetic retinal complications in severe obesity. This was a prospective observational study of 93 obese patients mean (SD) age: 52(10) years; mean (SD) body mass index (BMI): 47.3(8.3) kg/m2) with DM undergoing retinal screening and respiratory monitoring during sleep. OSA was defined as apnea-hypopnea index (AHI) of ≥15 events/hour, resulting in two groups (OSA+ vs. OSA−).
Forty-six patients were OSA+: median (95% CI) AHI = 37(23–74)/hour and 47 were OSA–ve (AHI = 7(4–11)/hour). Both groups were similar for ethnicity, BMI, cardiovascular co-morbidities, diabetes duration, HbA1c, and insulin treatment (p>0.05). The OSA+ group was significantly more hypoxemic. There was no significant difference between OSA+ and OSA− groups for the presence of retinopathy (39% vs. 38%). More OSA+ subjects had maculopathy (22% vs. 13%), but this did not reach statistical significance. Logistic regression analyses showed that AHI was not significantly associated with the presence of retinopathy or maculopathy (p>0.05). Whilst minimum oxygen saturation was not significantly associated with retinopathy, it was an independent predictor for the presence of maculopathy OR = 0.79 (95% CI: 0.65–0.95; p<0.05), after adjustment.
The presence of OSA, as determined by AHI, was not associated with diabetic retinal complications. In contrast, severity of hypoxemia during sleep (minimum oxygen saturations) may be an important factor. The importance of hypoxia in the development of retinal complications in patients with OSA remains unclear and further studies assessing the pathogenesis of hypoxemia in patients with OSA and diabetic retinal disease are warranted.
PMCID: PMC3832592  PMID: 24260240
6.  Concomitant Effects of Ramadan Fasting and Time-Of-Day on Apolipoprotein AI, B, Lp-a and Homocysteine Responses during Aerobic Exercise in Tunisian Soccer Players 
PLoS ONE  2013;8(11):e79873.
To examine the time-of-day and Ramadan fasting (RF) effects on serum apolipoprotein-AI (Apo-AI) and B (Apo-B), lipoprotein particles-a (Lp-a), high-sensitive C-reactive-protein (hs-CRP), and homocysteine (Hcy) during the Yo-Yo intermittent recovery test (YYIRT).
Performance and biochemical measures were completed at two times-of-day (07:00 and 17:00 h), 1-week before RF (BR), the second week of RF (SWR), and the fourth week of RF (ER).
For each session, subjects performed the YYIRT, and blood samples were taken before and 3-min after the test for biochemical measures.
Fifteen soccer players.
Main Outcome Measures
Total distance during the YYIRT, core temperature, body composition, dietary intakes, lipid (HDL-C, LDL-C, Apo-AI, B and Lp-a) and inflammatory (hs-CRP and Hcy) profiles.
Performances during the YYIRT were higher in the evening than the morning BR (P < 0.05), but this fluctuation was not observed during RF. Moreover, LDL-C, ApoB, and Lp-a were stable throughout the daytime BR. However, during RF, they decreased at 17:00 h (P < 0.05). Likewise, HDL-C and Apo-AI increased after the exercise and were higher at 17:00 h BR (P < 0.001). Moreover, these parameters increased during RF (P < 0.01). Furthermore, Hcy and hs-CRP increased during the exercise (P < 0.01) with higher evening levels BR. During ER, the diurnal pattern of Hcy was inversed (P < 0.001).
This study concluded that caloric restriction induced by RF seems to ameliorate lipid and inflammatory markers of cardiovascular health during intermittent exercise performed in the evening.
PMCID: PMC3823586  PMID: 24244572
7.  Prediction of Reproductive Outcomes According to Different Serum Anti-Müllerian Hormone Levels in Females Undergoing Intracystoplasmic Sperm Injection 
PLoS ONE  2013;8(9):e75685.
Background and aim of the study
Serum anti-Müllerian hormone (AMH) is a reliable marker of ovarian reserve, and it has been shown to be correlated with reproductive outcomes in grouped analyses. However, practical data is scarce for the physician and the patients to predict these outcomes in an individual couple according to serum AMH measured prior to assisted reproduction technology (ART) procedures.
Study Design
To address this question, we performed an analytic observational study including 145 females undergoing intracytoplasmic sperm injection (ICSI) in a single center. Results were analyzed according to serum AMH; subgroup analyses were performed by grouping patients according to patient’s age and FSH levels.
The risk of cycle cancelation decreased from 64% in patients with serum AMH ≤3 pmol/L (0.42 ng/mL) to 21% with AMH ≥15 pmol/L (2.10 ng/mL). Cycle cancelation occurred in approximately two-thirds of the patients with AMH ≤ 3 pmol/L irrespective of the FSH level. However, with higher AMH values the risk of cycle cancelation decreased more significantly in patients with normal FSH. The rate of good response increased from almost null in patients with AMH ≤3 pmol/L to 61% in those with AMH ≥15 pmol/L. The positive correlation between good response and AMH was also significant, but with lower absolute rates, when patients were grouped according to their age or FSH levels. Pregnancy rate increased moderately, but significantly, from 31% with AMH ≤3 pmol/L to 35% with AMH ≥15 pmol/L.
We provide estimates of reproductive outcomes according to individualized values of serum AMH, in general and in subgroups according to patient’s age or serum FSH, which are helpful for the clinician and the couple in their decision making about starting an assisted reproductive treatment.
PMCID: PMC3775779  PMID: 24069435
8.  Polycystic Ovary Syndrome Is a Risk Factor for Type 2 Diabetes 
Diabetes  2012;61(9):2369-2374.
Polycystic ovary syndrome (PCOS) recently has been identified as a risk factor associated with type 2 diabetes. However, the evidence derives from cross-sectional observational studies, retrospective studies, or short-term prospective studies. This long-term prospective study of a large cohort of women with PCOS, followed from youth to middle age, aimed at estimating, for the first time, the incidence and potential predictors of type 2 diabetes in this population. A total of 255 women with PCOS were followed for at least 10 years (mean follow-up 16.9 years). Six women were patients with diabetes at baseline, and another 42 women developed type 2 diabetes during the follow-up. The incidence rate of type 2 diabetes in the study population was 1.05 per 100 person-years. The age-standardized prevalence of diabetes at the end of follow-up was 39.3%, which is significantly higher with respect to that of the general Italian female population of a similar age (5.8%). The likelihood of developing type 2 diabetes significantly increased as BMI, fasting glucose, and glucose area under the curve at baseline increased and significantly decreased as sex hormone–binding globulin (SHBG) levels at follow-up increased. This study demonstrates that the risk of type 2 diabetes is markedly elevated in middle-aged women with PCOS and suggests including BMI, glucose, and SHBG-circulating levels in the risk stratification.
PMCID: PMC3425413  PMID: 22698921
9.  PCOS Forum: Research in Polycystic Ovary Syndrome Today and Tomorrow 
Clinical endocrinology  2011;74(4):424-433.
To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area.
Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re-examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have long-term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial.
PMCID: PMC3742326  PMID: 21158892
steroids; androgens; folliculogenesis; inflammation; anovulation
10.  Elderly Men Have Low Levels of Anti-Müllerian Hormone and Inhibin B, but with High Interpersonal Variation: A Cross-Sectional Study of the Sertoli Cell Hormones in 615 Community-Dwelling Men 
PLoS ONE  2013;8(8):e70967.
The Sertoli cells of the testes secrete anti-Müllerian hormone (Müllerian inhibiting Substance, AMH) and inhibin B (InhB). AMH triggers the degeneration of the uterine precursor in male embryos, whereas InhB is part of the gonadal-pituitary axis for the regulation of sperm production in adults. However, both hormones are also putative regulators of homeostasis, and age-related changes in these hormones may therefore be important to the health status of elderly men. The levels of AMH in elderly men are unknown, with limited information being available about age-related changes in InhB. We have therefore used ELISAs to measure Sertoli cell hormone levels in 3 cohorts of community-dwelling men in New Zealand. In total, 615 men were examined, 493 of which were aged 65 or older. Serum AMH and InhB levels inversely correlated with age in men older than 50 years (p<0.001) but not in the younger men. A minority of elderly men had undetectable levels of AMH and InhB. The variation in hormone levels between similarly aged men increased with the age of men. AMH and InhB partially correlated with each other as expected (r = 0.48, p<0.001). However, the ratio of the two Sertoli hormones varied significantly between men, with this variation increasing with age. Elderly men selected for the absence of cardiovascular disease had AMH levels similar to those of young men whereas their InhB levels did not differ from aged-matched controls. These data suggests that Sertoli cell number and function changes with age, but with the extent and nature of the changes varying between men.
PMCID: PMC3733803  PMID: 23940675
11.  Prevalence, Mass, and Glucose-Uptake Activity of 18F-FDG-Detected Brown Adipose Tissue in Humans Living in a Temperate Zone of Italy 
PLoS ONE  2013;8(5):e63391.
The 18F-fluorodeoxyglucose (18F-FDG)-detected brown adipose tissue (BAT), is enhanced by cold stimulus and modulated by other factors that still have to be disentangled. We investigated the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in a population of adults living in the temperate climatic zone of the Rome area.
Methods and Findings
We retrospectively analyzed 6454 patients who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) examinations. We found 18F-FDG BAT in 217 of the 6454 patients (3.36%). Some of them underwent more than one scan and the positive scans were 278 among 8004 (3.47%). The prevalence of patients with at least one positive scan was lower in men (1.77%; 56 of 3161) compared with women (4.88%; 161 of 3293). The BAT positive patients were most frequently younger, thinner and with lower plasma glucose levels compared with BAT negative patients. The amount of BAT in the defined region of interest, the activity of BAT and the number of positive sites of active BAT were similar in both sexes. The prevalence of patients with 18F-FDG positive PET/CT was highest in December-February, lower in March-May and September-November, and lowest in June-August and was positively correlated with night length and negatively correlated with ambient temperature. Changes in day length and variations of temperature, associated with the prevalence of positive BAT patients. Among the patients who had multiple scans, outdoor temperature was significantly lower and day length was shorter on the occasion when BAT was detected.
This study identifies day length, outdoor temperature, age, sex, BMI, and plasma glucose levels as major determinants of the prevalence, mass, and activity of 18F-FDG-detected BAT.
PMCID: PMC3648481  PMID: 23667608
12.  11C-meta-hydroxyephedrine PET/CT imaging allows in vivo study of adaptive thermogenesis and white-to-brown fat conversion 
Molecular Metabolism  2013;2(3):153-160.
Several lines of evidence suggest that novel pharmacological approaches aimed at converting white adipose tissue (WAT) into brown adipose tissue (BAT) may represent an effective therapeutic strategy for obesity and related disorders. (18)F-fluorodeoxyglucose (18F-FDG) is the only positron emission tomography (PET) tracer commonly used to study BAT function, and so far no functional tools have been described to investigate in vivo white-to-brown fat conversion. In this report, we show that the PET tracer 11C-meta-hydroxyephedrine (11C-MHED, a norepinephrine analogue) is a useful tool to investigate the sympathetic nervous system (SNS) activity in BAT of lean and dietary obese mice. Moreover, we demonstrate that 11C-MHED is a specific marker of the SNS-mediated thermogenesis in typical BAT depots, and that this tracer can detect in vivo WAT to BAT conversion.
PMCID: PMC3773828  PMID: 24049730
Brown adipose tissue; Sympathetic activity; PET/CT imaging
13.  Glucose Tolerance and Weight Loss in Obese Women with Obstructive Sleep Apnea 
PLoS ONE  2013;8(4):e61382.
The association of obstructive sleep apnea (OSA) with glucose intolerance and the beneficial effect of lifestyle intervention have been poorly investigated in women particularly before menopausal status. The study explored 1) whether OSA is associated with impaired glucose homeostasis in obese non diabetic premenopausal and menopausal women and 2) the effects of a 3- month lifestyle intervention on glucose homeostasis in OSA women.
Design and Methods
We consecutively recruited 98 obese women (39 premenopausal) from those referred for a weight loss intervention. Ambulatory nocturnal polysomnography, body composition, oral glucose tolerance test, insulin sensitivity and β cell function were assessed before and after intervention.
41% of premenopausal and 64% of menopausal women had OSA which was associated with worse glucose homeostasis before menopausal status. Mean and minimal nocturnal oxygen saturation (SaO2) was associated with neck/height ratio (NHR), independently of total and central obesity. Mean and minimal nocturnal SaO2 and NHR were correlated with insulin sensitivity and fasting glucose. In multivariate analyses, nocturnal mean SaO2 was negatively and independently correlated with fasting glucose (p<0.0001) and NHR with insulin sensitivity (p<0.0001). In OSA women, the intervention induced a 5% weight reduction and a significant increase in minimal nocturnal SaO2, insulin sensitivity and β cell function. Changes in fasting glucose and insulin sensitivity were associated with those in minimal nocturnal SaO2 (p<0.05) and not with weight loss.
In obese women, glucose homeostasis worsens due to nocturnal hypoxia and increased neck circumference through mechanisms partially independent of obesity. OSA is more clearly associated with glucose intolerance in premenopausal than in menopausal women. In OSA women, the improvement of nocturnal hypoxia induced by lifestyle modifications is associated with that of glucose homeostasis.
PMCID: PMC3629198  PMID: 23613841
14.  The Association between Self-Reported Sleep Quality and Metabolic Syndrome 
PLoS ONE  2013;8(1):e54304.
Short and long sleep duration are associated with metabolic syndrome. However, there is limited research on the association between sleep quality and metabolic syndrome, and thus the aim of this study is to investigate this relationship.
Materials and Methods
The cross-sectional baseline data were collected from the decoded database of the Prevention Health Center of National Cheng Kung University Hospital from 2002 to 2006. The diagnosis of metabolic syndrome was according to the statement of the American Heart Association/National Heart, Lung, and Blood Institute. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). A higher global PSQI score indicates poorer sleep quality, and a global PSQI score greater than five differentiates poor from good sleepers.
Of the 3,435 subjects recruited, 899 (26.2%) had metabolic syndrome. Subjects with metabolic syndrome had higher PSQI and prevalence of poor sleepers than those without metabolic syndrome. The multivariate lineal regression analysis showed that female gender, metabolic syndrome, sleep duration, snoring, alcohol drinking, and habitual exercise were independent predictors of PSQI. When substituting metabolic syndrome with the five components, hyperglycemia and low high-density lipoprotein cholesterol (HDL-C) were positively associated with PSQI. The multivariate logistic regression analyses showed that female gender, metabolic syndrome, sleep duration, and snoring were independently associated with being poor sleepers. Of the five components, only low HDL-C was an independent predictor of being poor sleepers.
Subjects with metabolic syndrome have higher global PSQI scores and a higher risk of being poor sleepers. Of the five components of metabolic syndrome, hyperglycemia and low HDL-C are independently associated with the global PSQI scores, while low HDL-C is an independent predictor of being poor sleepers.
PMCID: PMC3544823  PMID: 23342127
15.  Glucocorticoids and Type 2 Diabetes: From Physiology to Pathology 
Type 2 diabetes mellitus is the result of interaction between genetic and environmental factors, leading to heterogeneous and progressive pancreatic β-cell dysfunction. Overweight and obesity are major contributors to the development of insulin resistance and impaired glucose tolerance. The inability of β cells to secrete enough insulin produces type 2 diabetes. Abnormalities in other hormones such as reduced secretion of the incretin glucagon-like peptide 1 (GLP-1), hyperglucagonemia, and raised concentrations of other counterregulatory hormones also contribute to insulin resistance, reduced insulin secretion, and hyperglycaemia in type 2 diabetes. Clinical-overt and experimental cortisol excess is associated with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance, and low HDL-cholesterol levels, which can lead to diabetes. It was therefore suggested that subtle abnormalities in cortisol secretion and action are one of the missing links between insulin resistance and other features of the metabolic syndrome. The aim of this paper is to address the role of glucocorticoids on glucose homeostasis and to explain the relationship between hypercortisolism and type 2 diabetes.
PMCID: PMC3536319  PMID: 23316348
16.  Familial partial lipodystrophy, mandibuloacral dysplasia and restrictive dermopathy feature barrier-to-autointegration factor (BAF) nuclear redistribution 
Cell Cycle  2012;11(19):3568-3577.
Prelamin A processing impairment is a common feature of a restricted group of rare genetic alterations/disorders associated with a wide range of clinical phenotypes. Changes in histone posttranslational modifications, alterations in non-histone chromatin proteins and chromatin disorganization have been specifically linked to impairment of specific, distinct prelamin A processing steps, but the molecular mechanism involved in these processes is not yet understood . In this study, we show that the accumulation of wild-type prelamin A detected in restrictive dermopathy (RD), as well as the accumulation of mutated forms of prelamin A identified in familial partial lipodystrophy (FPLD) and mandibuloacral dysplasia (MADA), affect the nuclear localization of barrier-to-autointegration factor (BAF), a protein able to link lamin A precursor to chromatin remodeling functions. Our findings, in accordance with previously described results, support the hypothesis of a prelamin A involvement in BAF nuclear recruitment and suggest BAF-prelamin A complex as a protein platform usually activated in prelamin A-accumulating diseases. Finally, we demonstrate the involvement of the inner nuclear membrane protein emerin in the proper localization of BAF-prelamin A complex.
PMCID: PMC3478308  PMID: 22935701
BAF; BANF1; prelamin A; lamin A/C; laminopathies; emerin; EDMD1
17.  The empowerment of translational research: lessons from laminopathies 
The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.
PMCID: PMC3458975  PMID: 22691392
Laminopathies; Emery-Dreifuss Muscular Dystrophy; Dilated Cardiomyopathy with Conduction Defects; Mandibuloacral Dysplasia; Familial Partial Lipodystrophy Type 2; Hutchinson-Gilford Progeria Syndrome; Rare Diseases; Networking activity; interdisciplinary approach to diseases
18.  Predictors of weight loss and maintenance in patients treated with antiobesity drugs 
The prevalence of obesity and related diseases has increased enormously in the last few decades, becoming a very important medical and social issue. Because of the increasing number of people who need weight loss therapies and the high costs associated with these, the search for reliable predictors of success for weight loss and weight maintenance treatments has become a priority.
A literature review was undertaken to identify possible predictors of outcome of weight loss and weight maintenance in patients treated with antiobesity drugs.
For the majority of variables, published data are not sufficient to define their role on final outcomes. Among all considered factors, only early response to treatment appeared to be a reliable positive predictor, and diabetes a negative predictor of weight loss and maintenance.
To date, no definitive results have been obtained. Due to the great benefits of reliable predictors of outcome associated to currently available antiobesity drugs and those under development, identifying these predictors has to be supported and encouraged.
PMCID: PMC3139531  PMID: 21792322
obesity; weight loss predictors; pharmacological treatment
19.  Cannabinoid Type 1 Receptor Blockade Promotes Mitochondrial Biogenesis Through Endothelial Nitric Oxide Synthase Expression in White Adipocytes 
Diabetes  2008;57(8):2028-2036.
OBJECTIVE—Cannabinoid type 1 (CB1) receptor blockade decreases body weight and adiposity in obese subjects; however, the underlying mechanism is not yet fully understood. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) induces mitochondrial biogenesis and function in adipocytes. This study was undertaken to test whether CB1 receptor blockade increases the espression of eNOS and mitochondrial biogenesis in white adipocytes.
RESEARCH DESIGN AND METHODS—We examined the effects on eNOS and mitochondrial biogenesis of selective pharmacological blockade of CB1 receptors by SR141716 (rimonabant) in mouse primary white adipocytes. We also examined eNOS expression and mitochondrial biogenesis in white adipose tissue (WAT) and isolated mature white adipocytes of CB1 receptor–deficient (CB1−/−) and chronically SR141716-treated mice on either a standard or high-fat diet.
RESULTS—SR141716 treatment increased eNOS expression in cultured white adipocytes. Moreover, SR141716 increased mitochondrial DNA amount, mRNA levels of genes involved in mitochondrial biogenesis, and mitochondrial mass and function through eNOS induction, as demonstrated by reversal of SR141716 effects by small interfering RNA–mediated decrease in eNOS. While high-fat diet–fed wild-type mice showed reduced eNOS expression and mitochondrial biogenesis in WAT and isolated mature white adipocytes, genetic CB1 receptor deletion or chronic treatment with SR141716 restored these parameters to the levels observed in wild-type mice on the standard diet, an effect linked to the prevention of adiposity and body weight increase.
CONCLUSIONS—CB1 receptor blockade increases mitochondrial biogenesis in white adipocytes by inducing the expression of eNOS. This is linked to the prevention of high-fat diet–induced fat accumulation, without concomitant changes in food intake.
PMCID: PMC2494670  PMID: 18477809
20.  The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis 
Journal of Clinical Investigation  2003;112(3):423-431.
The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1–/–) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1–/– mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1–/– mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine–regulated transcript (CART), melanin-concentrating hormone (MCH), and prepro-orexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1–/– mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
PMCID: PMC166293  PMID: 12897210
21.  The hypothalamic–pituitary–adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects 
Obesity, particularly the abdominal phenotype, has been ascribed to an individual maladaptation to chronic environmental stress exposure mediated by a dysregulation of related neuroendocrine axes. Alterations in the control and action of the hypothalamic–pituitary–adrenal axis play a major role in this context, with the participation of the sympathetic nervous system. The ability to adapt to chronic stress may differ according to sex, with specific pathophysiological events leading to the development of stress-related chronic diseases. This seems to be influenced by the regulatory effects of sex hormones, particularly androgens. Stress may also disrupt the control of feeding, with some differences according to sex. Finally, the amount of experimental data in both animals and humans may help to shed more light on specific phenotypes of obesity, strictly related to the chronic exposure to stress. This challenge may potentially imply a different pathophysiological perspective and, possibly, a specific treatment.
PMCID: PMC3464358  PMID: 22612409
cortisol; androgens; stress; obesity

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