Publications by authors named "Lucio Gnessi"

77 Publications

Central obesity, smoking habit, and hypertension are associated with lower antibody titres in response to COVID-19 mRNA vaccine.

Diabetes Metab Res Rev 2021 May 6:e3465. Epub 2021 May 6.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

Aims: To explore variables associated with the serological response following COVID-19 mRNA vaccine.

Methods: Eighty-six healthcare workers adhering to the vaccination campaign against COVID-19 were enrolled in January-February 2021. All subjects underwent two COVID-19 mRNA vaccine inoculations (Pfizer/BioNTech) separated by 3 weeks. Blood samples were collected before the 1st and 1-4 weeks after the second inoculation. Clinical history, demographics, and vaccine side effects were recorded. Baseline anthropometric parameters were measured, and body composition was performed through dual-energy-X-ray absorptiometry.

Results: Higher waist circumference was associated with lower antibody (Ab) titres (R = -0.324, p = 0.004); smokers had lower levels compared to non-smokers [1099 (1350) vs. 1921 (1375), p = 0.007], as well as hypertensive versus normotensive [650 ± 1192 vs. 1911 (1364), p = 0.001] and dyslipideamic compared to those with normal serum lipids [534 (972) vs 1872 (1406), p = 0.005]. Multivariate analysis showed that higher waist circumference, smoking, hypertension, and longer time elapsed since second vaccine inoculation were associated with lower Ab titres, independent of BMI, age. and gender.

Conclusions: Central obesity, hypertension, and smoking are associated with lower Ab titres following COVID-19 vaccination. Although it is currently impossible to determine whether lower SARS-CoV-2 Abs lead to higher likelihood of developing COVID-19, it is well-established that neutralizing antibodies correlate with protection against several viruses including SARS-CoV-2. Our findings, therefore, call for a vigilant approach, as subjects with central obesity, hypertension, and smoking could benefit from earlier vaccine boosters or different vaccine schedules.
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http://dx.doi.org/10.1002/dmrr.3465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209952PMC
May 2021

Ketogenic Diet as a Preventive and Supportive Care for COVID-19 Patients.

Nutrients 2021 Mar 20;13(3). Epub 2021 Mar 20.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Severe obesity is associated with an increased risk of admission to intensive care units and need for invasive mechanical ventilation in patients with COVID-19. The association of obesity and COVID-19 prognosis may be related to many different factors, such as chronic systemic inflammation, the predisposition to severe respiratory conditions and viral infections. The ketogenic diet is an approach that can be extremely effective in reducing body weight and visceral fat in the short term, preserving the lean mass and reducing systemic inflammation. Therefore, it is a precious preventive measure for severely obese people and may be considered as an adjuvant therapy for patients with respiratory compromise.
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http://dx.doi.org/10.3390/nu13031004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003632PMC
March 2021

Case Report: Pituitary Morphology and Function Are Preserved in Female Patients With Idiopathic Intracranial Hypertension Under Pharmacological Treatment.

Front Endocrinol (Lausanne) 2020 8;11:613054. Epub 2021 Jan 8.

Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Idiopathic Intracranial Hypertension is a neurological disorder primarily affecting overweight women of childbearing age. It is often characterized by radiologic evidence of empty sella (ES), which is in turn frequently associated with pituitary dysfunction, with the somatotropic axis most commonly affected. No recent evidence is available relative to the presence of pituitary hormone deficiencies in adult patients with Idiopathic Intracranial Hypertension (IIH) under pharmacological therapy. We therefore explored pituitary function and morphology in a small cohort of female patients with IIH treated with acetazolamide. Fifteen female patients aged 42 ± 13 years with IIH lasting between 12 and 18 months were evaluated. All patients were affected by recurrent headaches in addition to visual changes of variable severity. IIH diagnosis was made after exclusion of other causes of raised intracranial pressure, and a specific ophthalmological evaluation was conducted to assess for the presence of papilledema. No particular endocrinological disturbances were detected during the enrolment visits, except for a high obesity prevalence (87%, BMI 35.16 ± 8.21 kg/m), one case of total thyroidectomy for papillary thyroid carcinoma and two patients with irregular menses and mild hirsutism. All the participants underwent a pituitary MRI with contrast, and two different operators performed pituitary measurements in coronal and sagittal scans for morphologic assessment. Blood samples for the anterior pituitary axis evaluation were collected, and the somatotropic axis was further evaluated with a GHRH + Arginine test; other dynamic tests were performed in case of suspected hormonal deficiency. Despite ES being found in 73% of the patients, pituitary volume was preserved, ranging from 213.85 to 642.27mm (389.20 ± 125.53mm); mean coronal pituitary height was 4.53 ± 1.33 mm. Overall, baseline anterior pituitary hormones levels were within normal ranges, and none of the patients with ES had an altered response to the GHRH + arginine stimulation test. We found one patient suffering from iatrogenic hyperthyroidism and two diagnosed with subclinical primary hypothyroidism due to Hashimoto's thyroiditis. Two young patients were suspected of having polycystic ovary syndrome, and they were therefore further investigated. In conclusion, this case series shows that, despite the high prevalence of ES, the pituitary function of IIH patients treated with acetazolamide is preserved. To date, there is no evidence regarding the trend over time or upon treatment discontinuation in regard to the pituitary function of patients with IIH, and it is therefore not possible to infer whether our finding would be replicable in such settings. We therefore suggest an endocrine follow-up over time in order to monitor for potential pituitary dysfunction.
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http://dx.doi.org/10.3389/fendo.2020.613054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819854PMC
May 2021

Nickel Sensitivity Is Associated with GH-IGF1 Axis Impairment and Pituitary Abnormalities on MRI in Overweight and Obese Subjects.

Int J Mol Sci 2020 Dec 20;21(24). Epub 2020 Dec 20.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy.

Nickel (Ni) is a ubiquitous metal, the exposure of which is implied in the development of contact dermatitis (nickel allergic contact dermatitis (Ni-ACD)) and Systemic Ni Allergy Syndrome (SNAS), very common among overweight/obese patients. Preclinical studies have linked Ni exposure to abnormal production/release of Growth Hormone (GH), and we previously found an association between Ni-ACD/SNAS and GH-Insulin-like growth factor 1 (IGF1) axis dysregulation in obese individuals, altogether suggesting a role for this metal as a pituitary disruptor. We herein aimed to directly evaluate the pituitary gland in overweight/obese patients with signs/symptoms suggestive of Ni allergy, exploring the link with GH secretion; 859 subjects with overweight/obesity and suspected of Ni allergy underwent Ni patch tests. Among these, 106 were also suspected of GH deficiency (GHD) and underwent dynamic testing as well as magnetic resonance imaging for routine follow up of benign diseases or following GHD diagnosis. We report that subjects with Ni allergies show a greater GH-IGF1 axis impairment, a higher prevalence of Empty Sella (ES), a reduced pituitary volume and a higher normalized T2 pituitary intensity compared to nonallergic ones. We hypothesize that Ni may be detrimental to the pituitary gland, through increased inflammation, thus contributing to GH-IGF1 axis dysregulation.
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http://dx.doi.org/10.3390/ijms21249733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766406PMC
December 2020

Weight Gain in a Sample of Patients Affected by Overweight/Obesity with and without a Psychiatric Diagnosis during the Covid-19 Lockdown.

Nutrients 2020 Nov 16;12(11). Epub 2020 Nov 16.

Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy.

The present study aimed at identifying psychological and psychosocial variables that might predict weight gain during the COVID-19 lockdown in patients affected by overweight/obesity with and without a psychiatric diagnosis. An online survey was administered between 25 April and 10 May 2020, to investigate participants' changes in dietary habits during the lockdown period. 110 participants were recruited and allocated to two groups, 63 patients had no psychiatric diagnosis; there were 47 patients with psychiatric diagnosis. ANOVA analyses compared the groups with respect to psychological distress levels, risk perception, social support, emotion regulation, and eating behaviors. For each group, a binary logistic regression analysis was conducted, including the factors that were found to significantly differ between groups. Weight gain during lockdown was reported by 31 of the participants affected by overweight/obesity without a psychiatric diagnosis and by 31 patients with a psychiatric diagnosis. Weight gain predictors were stress and low depression for patients without a psychiatric diagnosis and binge eating behaviors for patients with a psychiatric diagnosis. Of patients without a psychiatric diagnosis, 60% reported much more frequent night eating episodes. The risk of night eating syndrome in persons affected by overweight/obesity with no psychiatric diagnosis should be further investigated to inform the development of tailored medical, psychological, and psychosocial interventions.
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http://dx.doi.org/10.3390/nu12113525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697678PMC
November 2020

Blood SIRT1 Shows a Coherent Association with Leptin and Adiponectin in Relation to the Degree and Distribution of Adiposity: A Study in Obesity, Normal Weight and Anorexia Nervosa.

Nutrients 2020 Nov 14;12(11). Epub 2020 Nov 14.

Department of Experimental Medicine, Section of Medical Physiopathology, Food Science and Endocrinology, "Sapienza" University of Rome, Rome, Italy.

Sirtuin 1 (SIRT1) is a sensor of cell energy availability, and with leptin and adiponectin, it regulates metabolic homeostasis. Widely studied in tissues, SIRT1 is under evaluation as a plasmatic marker. We aimed at assessing whether circulating SIRT1 behaves consistently with leptin and adiponectin in conditions of deficiency, excess or normal fat content. Eighty subjects were evaluated: 27 with anorexia nervosa (AN), 26 normal-weight and 27 with obesity. Bloodstream SIRT1, leptin and adiponectin (ELISA), total and trunk fat mass (FM) %, abdominal visceral adipose tissue, liver steatosis and epicardial fat thickness (EFT) were assessed. For each fat store, the coefficient of determination (R) was used to evaluate the prediction capability of SIRT1, leptin and adiponectin. Plasma SIRT1 and adiponectin coherently decreased with the increase of FM, while the opposite occurred with leptin. Mean levels of each analyte were different between groups ( < 0.005). A significant association between plasma variables and FM depots was observed. SIRT1 showed a good predictive strength for FM, particularly in the obesity group, where the best R was recorded for EFT (R = 0.7). Blood SIRT1, adiponectin and leptin behave coherently with FM and there is synchrony between them. The association of SIRT1 with FM is substantially superimposable to that of adiponectin and leptin. Given its homeostatic roles, SIRT1 may deserve to be considered as a plasma clinical/biochemical parameter of adiposity and metabolic health.
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http://dx.doi.org/10.3390/nu12113506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696683PMC
November 2020

Very Low-Calorie Ketogenic Diets to Treat Patients With Obesity and Chronic Kidney Disease.

J Ren Nutr 2021 Jul 22;31(4):340-341. Epub 2020 Oct 22.

Section of Medical Pathophysiology, Department of Experimental Medicine, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1053/j.jrn.2020.09.001DOI Listing
July 2021

Current Evidence to Propose Different Food Supplements for Weight Loss: A Comprehensive Review.

Nutrients 2020 Sep 20;12(9). Epub 2020 Sep 20.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

The use of food supplements for weight loss purposes has rapidly gained popularity as the prevalence of obesity increases. Navigating through the vast, often low quality, literature available is challenging, as is providing informed advice to those asking for it. Herein, we provide a comprehensive literature revision focusing on most currently marketed dietary supplements claimed to favor weight loss, classifying them by their purported mechanism of action. We conclude by proposing a combination of supplements most supported by current evidence, that leverages all mechanisms of action possibly leading to a synergistic effect and greater weight loss in the foreseen absence of adverse events. Further studies will be needed to confirm the weight loss and metabolic improvement that may be obtained through the use of the proposed combination.
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http://dx.doi.org/10.3390/nu12092873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551574PMC
September 2020

Is Growth Hormone Insufficiency the Missing Link Between Obesity, Male Gender, Age, and COVID-19 Severity?

Obesity (Silver Spring) 2020 11 25;28(11):2038-2039. Epub 2020 Sep 25.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Viale Regina Elena, Rome, Italy.

Evidence has emerged regarding an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with worse prognosis in elderly male patients with obesity, and blunted growth hormone (GH) secretion represents a feature of this population subgroup. Here, a comprehensive review of the possible links between GH-insulinlike growth factor 1 axis impairment and coronavirus disease 2019 (COVID-19) severity is offered. First, unequivocal evidence suggests that immune system dysregulation represents a key element in determining SARS-CoV-2 severity, as well as the association with adult-onset GH deficiency (GHD); notably, if GH is physiologically involved in the development and maintenance of the immune system, its pharmacological replacement in GHD patients seems to positively influence their inflammatory status. In addition, the impaired fibrinolysis associated with GHD may represent a further link between GH-insulin-like growth factor 1 axis impairment and COVID-19 severity, as it has been associated with both conditions. In conclusion, several sources of evidence have supported a relationship between GHD and COVID-19, and they also shed light upon potential beneficial effects of recombinant GH treatment on COVID-19 patients.
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http://dx.doi.org/10.1002/oby.23000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461181PMC
November 2020

Is obesity the missing link between COVID-19 severity and air pollution?

Environ Pollut 2020 Nov 3;266(Pt 3):115327. Epub 2020 Aug 3.

UNESCO Chair for Health Education and Sustainable Development Federico II University of Naples Corso Umberto I, 40 - 80138, Napoli, Centralino, Italy.

In the previous publication "Can atmospheric pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy?" Conticini et al. hypothesized that the surplus of lethality of the novel SARS-CoV-2 in Northern Italy may be at least in part explained by the evidence of highest pollution reported in this area, as both severe COVID-19 and smog exposure are correlated to an innate immune system hyper-activation with subsequent lung inflammation and injury. Since this hypothesis alone does not fully explain why specific subgroups of patients are at major risk, we hypothesized that obesity may be one of the links between COVID-19 severity and high level of air pollution. First, obesity is a predisposing factor for SARS-Cov-2 infection and worse COVID-19 outcomes, and unequivocal evidence demonstrated that fat mass excess is independently associated with several pulmonary diseases and lung inflammation. Moreover, it has been shown that obesity may intensify the detrimental effects of air pollution on the lungs, and this is not surprising if we consider that these conditions share an excessive activation of the immune system and a lung inflammatory infiltrate. Finally, fat mass excess has also been speculated to be itself a consequence of air pollutants exposure, which has been proved to induce metabolic disruption and weight gain in murine models. In conclusion, although many variables must be taken into account in the analysis of the pandemic, our observations suggest that obesity may act as effect modifier of smog-induced lung-injury, and the concomitant presence of these two factors could better explain the higher virulence, faster spread and greater mortality of SARS-CoV-2 in Northern Italy compared to the rest of the country.
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http://dx.doi.org/10.1016/j.envpol.2020.115327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397942PMC
November 2020

Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19.

Metabolism 2020 10 23;111:154319. Epub 2020 Jul 23.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

Background: Obesity was recently identified as a major risk factor for worse COVID-19 severity, especially among the young. The reason why its impact seems to be less pronounced in the elderly may be due to the concomitant presence of other comorbidities. However, all reports only focus on BMI, an indirect marker of body fat.

Aim: To explore the impact on COVID-19 severity of abdominal fat as a marker of body composition easily collected in patients undergoing a chest CT scan.

Methods: Patients included in this retrospective study were consecutively enrolled among those admitted to an Emergency Department in Rome, Italy, who tested positive for SARS-Cov-2 and underwent a chest CT scan in March 2020. Data were extracted from electronic medical records.

Results: 150 patients were included (64.7% male, mean age 64 ± 16 years). Visceral fat (VAT) was significantly higher in patients requiring intensive care (p = 0.032), together with age (p = 0.009), inflammation markers CRP and LDH (p < 0.0001, p = 0.003, respectively), and interstitial pneumonia severity as assessed by a Lung Severity Score (LSS) (p < 0.0001). Increasing age, lymphocytes, CRP, LDH, D-Dimer, LSS, total abdominal fat as well as VAT were found to have a significant univariate association with the need of intensive care. A multivariate analysis showed that LSS and VAT were independently associated with the need of intensive care (OR: 1.262; 95%CI: 1.0171-1.488; p = 0.005 and OR: 2.474; 95%CI: 1.017-6.019; p = 0.046, respectively).

Conclusions: VAT is a marker of worse clinical outcomes in patients with COVID-19. Given the exploratory nature of our study, further investigation is needed to confirm our findings and elucidate the mechanisms underlying such association.
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http://dx.doi.org/10.1016/j.metabol.2020.154319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377788PMC
October 2020

Baseline HOMA IR and Circulating FGF21 Levels Predict NAFLD Improvement in Patients Undergoing a Low Carbohydrate Dietary Intervention for Weight Loss: A Prospective Observational Pilot Study.

Nutrients 2020 Jul 18;12(7). Epub 2020 Jul 18.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

Background: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease. Very low-calorie ketogenic diets (VLCKD) represent a feasible treatment as they induce profound weight loss and insulin resistance (IR) improvement. Despite the recognized benefits on NAFLD deriving from pharmacological administration of fibroblast growth factor 21 (FGF21), whose endogenous counterpart is a marker of liver injury, little is known about its physiology in humans.

Aim: To identify predictors of NAFLD improvement as reflected by the reduction of the non-invasive screening tool hepatic steatosis index (HSI) in obese patients undergoing a weight loss program.

Methods: Sixty-five obese patients underwent a 90-day dietary program consisting of a VLCKD followed by a hypocaloric low carbohydrate diet (LCD). Anthropometric parameters, body composition, and blood and urine chemistry were assessed.

Results: Unlike most parameters improving mainly during the VLCKD, the deepest HSI change was observed after the LCD ( = 0.02 and < 0.0001, respectively). Baseline HOMA-IR and serum FGF21 were found to be positive (R = 0.414, = 0009) and negative (R = 0.364, = 0.04) independent predictors of HSI reduction, respectively.

Conclusions: We suggest that patients with IR and NAFLD derive greater benefit from a VLCKD, and we propose a possible role of human FGF21 in mediating NAFLD amelioration following nutritional manipulation.
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http://dx.doi.org/10.3390/nu12072141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400878PMC
July 2020

Scientific evidence underlying contraindications to the ketogenic diet: An update.

Obes Rev 2020 10 10;21(10):e13053. Epub 2020 Jul 10.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

First identified as a feasible treatment for intractable epilepsy, the ketogenic diet (KD) has recently gained popularity thanks to growing evidence on applications such as weight loss, most importantly, but also NAFLD, cancer, neurologic conditions and chronic pain. As with any treatment, whether pharmacologic or not, the KD might not be an appropriate intervention for every individual, and a number of contraindications have been proposed, now deeply rooted into clinical practice, excluding de facto many patients that could benefit from its use. However, many of these concerns were expressed due to the absence of clinical studies conducted on fragile populations, and an assessment of lately emerged evidence relative to KD safety is currently lacking and much needed. We herein provide a critical revision of the literature behind each safety alert, in order to guide through the treatment options in the case of subjects with an indication to the KD and a borderline safe situation. Based on available evidence, the possible use of this diet as a therapeutic intervention should be assessed on a patient-to-patient basis by adequately skilled medical doctors, keeping in mind current recommendations, but reading them through the knowledge of the current state of the art.
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http://dx.doi.org/10.1111/obr.13053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539910PMC
October 2020

Very-Low-Calorie Ketogenic Diets With Whey, Vegetable, or Animal Protein in Patients With Obesity: A Randomized Pilot Study.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Experimental Medicine, University of Rome "La Sapienza," Rome, Italy.

Context: We compared the efficacy, safety, and effect of 45-day isocaloric very-low-calorie ketogenic diets (VLCKDs) incorporating whey, vegetable, or animal protein on the microbiota in patients with obesity and insulin resistance to test the hypothesis that protein source may modulate the response to VLCKD interventions.

Subjects And Methods: Forty-eight patients with obesity (19 males and 29 females, homeostatic model assessment (HOMA) index ≥ 2.5, aged 56.2 ± 6.1 years, body mass index [BMI] 35.9 ± 4.1 kg/m2) were randomly assigned to three 45-day isocaloric VLCKD regimens (≤800 kcal/day) containing whey, plant, or animal protein. Anthropometric indexes; blood and urine chemistry, including parameters of kidney, liver, glucose, and lipid metabolism; body composition; muscle strength; and taxonomic composition of the gut microbiome were assessed. Adverse events were also recorded.

Results: Body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, and total and low-density lipoprotein cholesterol decreased in all patients. Patients who consumed whey protein had a more pronounced improvement in muscle strength. The markers of renal function worsened slightly in the animal protein group. A decrease in the relative abundance of Firmicutes and an increase in Bacteroidetes were observed after the consumption of VLCKDs. This pattern was less pronounced in patients consuming animal protein.

Conclusions: VLCKDs led to significant weight loss and a striking improvement in metabolic parameters over a 45-day period. VLCKDs based on whey or vegetable protein have a safer profile and result in a healthier microbiota composition than those containing animal proteins. VLCKDs incorporating whey protein are more effective in maintaining muscle performance.
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http://dx.doi.org/10.1210/clinem/dgaa336DOI Listing
September 2020

Obesity treatment within the Italian national healthcare system tertiary care centers: what can we learn?

Eat Weight Disord 2021 Apr 25;26(3):771-778. Epub 2020 May 25.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

Introduction: The prevalence of obesity is soaring all over the world, and Italy is reaching the same pace. Similar to other countries, the Italian healthcare system counts on a three-tier model for obesity care, and each region has freedom in the implementation of guidelines. No national record is currently available to monitor the actual situation throughout the country.

Purpose: To provide a report of the current status on the availability of specialized public obesity care services in Italy.

Methods: Regional prevalence of obesity was extrapolated from publicly available data. Data on facilities for the management of obesity were retrieved from records provided by national scientific societies. Whenever possible, data was verified through online research and direct contact.

Results: We report a north-south and east-west gradient regarding the presence of obesity focused facilities, with an inverse correlation with the regional prevalence of obesity (R = 0.25, p = 0.03). Medical-oriented centers appear homogeneous in the multidisciplinary approach, the presence of a bariatric surgery division, the availability of support materials and groups, with no major difference on follow-up frequency. Surgery-oriented centers have a more capillary territorial distribution than the medically oriented, but not enough data was retrieved to provide a thorough description of their characteristics.

Conclusion: Obtaining a clear picture of the situation and providing consistent care across the country is a challenging task due to the decentralized organization of regions. We provide a first sketch, reporting that the model is applied unevenly, and we suggest feasible actions to improve the situation in our country and elsewhere.

Level Of Evidence: Level V, narrative review.
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http://dx.doi.org/10.1007/s40519-020-00936-1DOI Listing
April 2021

Letter to the Editor: "Our Response to COVID-19 as Endocrinologists and Diabetologists".

J Clin Endocrinol Metab 2020 07;105(7)

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1210/clinem/dgaa229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197545PMC
July 2020

Obesity and SARS-CoV-2: A population to safeguard.

Diabetes Metab Res Rev 2020 Apr 21:e3325. Epub 2020 Apr 21.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

Evidence has lately emerged regarding an increased risk of SARS-CoV-2 with worse prognosis in patients with obesity, especially among the young. Weight excess is a well-established respiratory disease risk factor, and the newly reported correlation is therefore unsurprising. The underlying pathophysiology is likely multi-stranded, ranging from complement system hyperactivation, increased Interleukin-6 secretion, chronic inflammation, presence of comorbidities such as diabetes and hypertension, and a possible local, detrimental effect within the lung. Further understanding the link between obesity and SARS-CoV-2 is crucial, as this could aid proper tailoring of immunomodulatory treatments, together with improving stratification among those possibly requiring critical care.
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http://dx.doi.org/10.1002/dmrr.3325DOI Listing
April 2020

Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: A comprehensive review of the literature.

Obes Rev 2020 08 24;21(8):e13024. Epub 2020 Mar 24.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, characterized by hepatic fat accumulation and possible development of inflammation, fibrosis, and cancer. The ketogenic diet (KD), with its drastic carbohydrate reduction, is a now popular weight loss intervention, despite safety concerns on a possible association with fatty liver. However, KDs were also reported to be beneficial on hepatic pathology, with ketone bodies recently proposed as effective modulators of inflammation and fibrosis. If the beneficial impact of weight loss on NAFLD is established, less is known on the effect of macronutrient distribution on such outcome. In a hypocaloric regimen, the latter seems not to be crucial, whereas at higher calorie intake, macronutrient ratio and, theoretically, ketosis, may become important. KDs could positively impact NAFLD for their very low carbohydrate content, and whether ketosis plays an additional role is unknown. Indeed, several mechanisms may directly link ketosis and NAFLD improvement, and elucidating these aspects would pave the way for new therapeutic strategies. We herein aimed at providing an accurate revision of current literature on KDs and NAFLD, focusing on clinical evidence, metabolic pathways involved, and strict categorization of dietary interventions.
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http://dx.doi.org/10.1111/obr.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379247PMC
August 2020

Very Low-Calorie Ketogenic Diet: A Safe and Effective Tool for Weight Loss in Patients With Obesity and Mild Kidney Failure.

Nutrients 2020 Jan 27;12(2). Epub 2020 Jan 27.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

Very low-calorie ketogenic diets (VLCKD) are an effective and increasingly used tool for weight loss. Traditionally considered high protein, ketogenic diets are often looked at with concern by clinicians due to the potential harm they pose to kidney function. We herein evaluated the efficacy and safety of a VLCKD in patients with obesity and mild kidney failure. A prospective observational real-life study was conducted on ninety-two patients following a VLCKD for approximately 3 months. Thirty-eight had mild kidney failure and fifty-four had no renal condition and were therefore designated as control. Anthropometric parameters, bioelectrical impedance and biochemistry data were collected before and at the end of the dietary intervention. The average weight loss was nearly 20% of initial weight, with a significant reduction in fat mass. We report an improvement of metabolic parameters and no clinically relevant variation regarding liver and kidney function. Upon stratification based on kidney function, no differences in the efficacy and safety outcomes were found. Interestingly, 27.7% of patients with mild renal failure reported normalization of glomerular filtrate after dietary intervention. We conclude that, when conducted under the supervision of healthcare professionals, a VLCKD is an effective and safe treatment for weight loss in patients with obesity, including those affected by mild kidney failure.
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http://dx.doi.org/10.3390/nu12020333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071259PMC
January 2020

The decline in muscle strength and muscle quality in relation to metabolic derangements in adult women with obesity.

Clin Nutr 2019 10 10;38(5):2430-2435. Epub 2019 Feb 10.

Department of Experimental Medicine-Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University, Rome, Italy.

Background & Aims: The metabolic and functional characteristics related to sarcopenic obesity have not been thoroughly explored in the earlier stages of the aging process. The aim of the present study was to examine the phenotype of sarcopenic obesity, in terms of lean body mass, muscle strength and quality, in adult women with and without the Metabolic Syndrome (MetS), and its relationship with the features of myosteatosis.

Methods: Study participants were enrolled at the Sapienza University, Rome, Italy. Body composition was assessed by DXA. The Handgrip strength test (HGST) was performed. HGST was normalized to arm lean mass to indicate muscle quality; intermuscular adipose tissue (IMAT) and intramyocellular lipid content (IMCL) were measured by magnetic resonance imaging and spectroscopy, as indicators of myosteatosis. Different indices of sarcopenia were calculated, based on appendicular lean mass (ALM, kg) divided by height squared, or weight. The NCEP-ATPIII criteria were used to diagnose the MetS. HOMA-IR was calculated. The physical activity level (PAL) was assessed through the IPAQ questionnaire.

Results: 54 women (age: 48 ± 14 years, BMI: 37.9 ± 5.4 kg/m) were included. 54% had the MetS (metabolically unhealthy, MUO). HGST/arm lean mass was lower in MUO women than women without the MetS (6.3 ± 1.8 vs. 7.8 ± 1.6, p = 0.03). No differences emerged in terms of absolute ALM (kg) or other indices of sarcopenia (ALM/h or ALM/weight) between metabolically healthy (MHO) vs. MUO women (p > 0.05). Muscle quality was negatively associated with HOMA-IR (p = 0.02), after adjustment for age, body fat, hs-CRP levels, and PAL. IMAT, but not IMCL, was significantly higher in obese women with the MetS compared to women without the MetS (p > 0.05). No association emerged between HGST/arm lean mass and IMAT or IMCL when HOMA-IR was included in the models.

Conclusion: Insulin resistance, and not sarcopenia or myosteatosis per se, was associated with muscle weakness, resulting in the phenotype of "dynapenic obesity" in middle-aged women with the metabolic syndrome.
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http://dx.doi.org/10.1016/j.clnu.2019.01.028DOI Listing
October 2019

A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss.

Obesity (Silver Spring) 2019 02 13;27(2):205-216. Epub 2018 Nov 13.

Gelesis, Inc., Boston, Massachusetts, USA.

Objective: This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity.

Methods: The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥  27 and ≤ 40 kg/m and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss.

Results: Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks.

Conclusions: Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.
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http://dx.doi.org/10.1002/oby.22347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587502PMC
February 2019

Overweight and obese patients with nickel allergy have a worse metabolic profile compared to weight matched non-allergic individuals.

PLoS One 2018 28;13(8):e0202683. Epub 2018 Aug 28.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy.

Background: A lack of balance between energy intake and expenditure due to overeating or reduced physical activity does not seem to explain entirely the obesity epidemic we are facing, and further factors are therefore being evaluated. Nickel (Ni) is a ubiquitous heavy metal implied in several health conditions. Regarding this, the European Food Safety Authority has recently released an alert on the possible deleterious effects of dietary Ni on human health given the current levels of Ni dietary intake in some countries. Pre-clinical studies have also suggested its role as an endocrine disruptor and have linked its exposure to energy metabolism and glucose homeostasis dysregulation. Ni allergy is common in the general population, but preliminary data suggest it being even more widespread among overweight patients.

Objectives: The aim of this study has been to evaluate the presence of Ni allergy and its association with the metabolic and endocrine profile in overweight and obese individuals.

Methods: We have evaluated 1128 consecutive overweight and obese outpatients. 784 were suspected of being allergic to Ni and 666 were assessed for it. Presence of Ni allergy and correlation with body mass index (BMI), body composition, metabolic parameters and hormonal levels were evaluated.

Results: We report that Ni allergy is more frequent in presence of weight excess and is associated with worse metabolic parameters and impaired Growth Hormone secretion.

Conclusions: We confirm that Ni allergy is more common in obese patients, and we report for the first time its association with worse metabolic parameters and impaired function of the GH-IGF1 axis in human subjects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112671PMC
February 2019

Inverse Association of Circulating SIRT1 and Adiposity: A Study on Underweight, Normal Weight, and Obese Patients.

Front Endocrinol (Lausanne) 2018 7;9:449. Epub 2018 Aug 7.

Section of Medical Physiopathology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Sirtuins (SIRTs) are NAD+-dependent deacetylases, cellular sensors to detect energy availability, and modulate metabolic processes. SIRT1, the most studied family member, influences a number of tissues including adipose tissue. Expression and activity of SIRT1 reduce with weight gain and increase in conditions of starvation. To focus on SIRT1 plasma concentrations in different conditions of adiposity and to correlate SIRT1 with fat content and distribution, energy homeostasis and inflammation in under-weight, normal-weight, and obese individuals. 21 patients with anorexia nervosa, 26 normal-weight and 75 patients with obesity were evaluated. Body fat composition by dual-energy X-ray absorptiometry, ultrasound liver adiposity, echocardiographic epicardial fat thickness (EFT), inflammatory (ESR, CRP, and fibrinogen), and metabolic (FPG, insulin, LDL- and HDL-cholesterol, triglycerides) parameters, calculated basal metabolic rate (BMR) and plasma SIRT1 (ELISA) were measured. SIRT1 was significantly higher in anorexic patients compared to normal-weight and obese patients (3.27 ± 2.98, 2.27 ± 1.13, and 1.36 ± 1.31 ng/ml, respectively). Linear regression models for each predictor variable adjusted for age and sex showed that SIRT1 concentration was inversely and significantly correlated with EFT, fat mass %, liver fat content, BMR, weight, BMI, WC, LDL-cholesterol, insulin, ESR. Stepwise multiple regression analysis revealed that age and EFT were the best independent correlates of SIRT1 (β = -0.026 ± 0.011, = 0.025, and β = -0.516 ± 0.083, < 0.001, respectively). Plasma SIRT1 shows a continuous pattern that inversely follows the whole spectrum of adiposity. SIRT1 significantly associates with EFT, a strong index of visceral fat phenotype, better than other indexes of adiposity studied here.
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http://dx.doi.org/10.3389/fendo.2018.00449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090043PMC
August 2018

Testicular histopathology, semen analysis and FSH, predictive value of sperm retrieval: supportive counseling in case of reoperation after testicular sperm extraction (TESE).

BMC Urol 2018 Jul 4;18(1):63. Epub 2018 Jul 4.

Centre for Reproductive Medicine, European Hospital, Rome, Italy.

Background: To provide indicators for the likelihood of sperm retrieval in patients undergoing testicular sperm extraction is a major issue in the management of male infertility by TESE. The aim of our study was to determine the impact of different parameters, including testicular histopathology, on sperm retrieval in case of reoperation in patients undergoing testicular sperm extraction.

Methods: We retrospectively analyzed 486 patients who underwent sperm extraction for intracytoplasmic sperm injection and testicular biopsy. Histology was classified into: normal spermatogenesis; hypospermatogenesis (reduction in the number of normal spermatogenetic cells); maturation arrest (absence of the later stages of spermatogenesis); and Sertoli cell only (absence of germ cells). Semen analysis and serum FSH, LH and testosterone were measured.

Results: Four hundred thirty patients had non obstructive azoospermia, 53 severe oligozoospermia and 3 necrozoospermia. There were 307 (63%) successful sperm retrieval. Higher testicular volume, lower levels of FSH, and better histological features were predictive for sperm retrieval. The same parameters and younger age were predictive factors for shorter time for sperm recovery. After multivariable analysis, younger age, better semen parameters, better histological features and lower values of FSH remained predictive for shorter time for sperm retrieval while better semen and histology remained predictive factors for successful sperm retrieval. The predictive capacity of a score obtained by summing the points assigned for selected predictors (1 point for Sertoli cell only, 0.33 points for azoospermia, 0.004 points for each FSH mIU/ml) gave an area under the ROC curve of 0.843.

Conclusions: This model can help the practitioner with counseling infertile men by reliably predicting the chance of obtaining spermatozoa with testicular sperm extraction when a repeat attempt is planned.
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http://dx.doi.org/10.1186/s12894-018-0379-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032772PMC
July 2018

Mangosteen Extract Shows a Potent Insulin Sensitizing Effect in Obese Female Patients: A Prospective Randomized Controlled Pilot Study.

Nutrients 2018 May 9;10(5). Epub 2018 May 9.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

There is a widely acknowledged association between insulin resistance and obesity/type 2 diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits—known for their antioxidant properties—have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety and efficacy of treatment with mangosteen extract on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. Twenty-two patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (homeostatic model assessment-insulin resistance, HOMA-IR −53.22% vs. −15.23%, = 0.004), and no side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible supplementary role of mangosteen extracts in the treatment of obesity, insulin resistance, and inflammation.
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http://dx.doi.org/10.3390/nu10050586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986466PMC
May 2018

Androgens and Hypertension in Men and Women: a Unifying View.

Curr Hypertens Rep 2017 May;19(5):44

Department of Health Sciences and Mother and Child Care, University of Palermo, Palermo, Italy.

Purpose Of Review: This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality.

Recent Findings: Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be a major determinant of the increased prevalence of hypertension. The relationship between androgen signalling and NF-kB might explain the pathophysiological mechanism leading to the development of endothelium dysfunction and hypertension.
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http://dx.doi.org/10.1007/s11906-017-0740-3DOI Listing
May 2017

An Exploratory Study on the Influence of Psychopathological Risk and Impulsivity on BMI and Perceived Quality of Life in Obese Patients.

Nutrients 2017 Apr 26;9(5). Epub 2017 Apr 26.

Department of Experimental Medicine-Medical Physiopathology, Food Science and Endocrinology Section, Sapienza University of Rome, 00185 Rome, Italy.

The present study aimed to assess the psychological profiles of adult male and female obese patients, as well as to verify the possible influence of their psychopathological risk and impulsivity on their body mass index (BMI) and perceived quality of life. A total of 64 obese subjects accessing a center for care of their obesity were assessed through anthropometric and psychometric measurements. All anthropometric measures in men were higher than in women, while in turn, women showed higher psychopathological symptoms. Furthermore, the symptoms of somatization and psychoticism were predictors for a higher BMI in men, but there was no effect of psychopathological symptoms on the perceived quality of life (QoL) of male subjects. Moreover, in women, somatization and attentional impulsivity were predictors for a higher BMI, whereas no correlation was found between their psychopathological risk and perceived QoL. The results of regression analysis underlined that somatization is a "core" psychopathological symptom in obese subjects regardless of their sex, which is a potential predictor for a higher BMI. The psychological difficulties of the subjects had no effect on their perceived QoL, suggesting that they find it difficult to reflect on the impact that obesity has on their life.
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http://dx.doi.org/10.3390/nu9050431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452161PMC
April 2017

Disability, Physical Inactivity, and Impaired Health-Related Quality of Life Are Not Different in Metabolically Healthy vs. Unhealthy Obese Subjects.

Nutrients 2016 Nov 25;8(12). Epub 2016 Nov 25.

Department Experimental Medicine-Medical Physiopathology, Food Science and Endocrinology Section, Sapienza University of Rome, Rome 00185, Italy.

Background: Obesity represents a major health hazard, affecting morbidity, psychological status, physical functionality, quality of life, and mortality. The aim of the present study was to explore the differences between metabolically healthy (MHO) and metabolically unhealthy (MUO) obese subjects with regard to physical activity, disability, and health-related quality of life (HR-QoL).

Methods: All subjects underwent a multidimensional evaluation, encompassing the assessment of body composition, metabolic biomarkers and inflammation, physical activity level (IPAQ questionnaire), disability (TSD-OC test), and HR-QoL (SF-36 questionnaire). MHO and MUO were defined based on the absence or the presence of the metabolic syndrome, respectively.

Results: 253 subjects were included (54 men and 199 women; age: 51.7 ± 12.8 vs. 50.3 ± 11.7 years, = 0.46; BMI: 38.1 ± 5.7 vs. 38.9 ± 6.7 kg/m², = 0.37). No significant difference was observed in body composition. There was no difference between MHO and MUO considering inflammation (hs-CRP: 6517.1 ± 11,409.9 vs. 5294.1 ± 5612.2 g/L; = 0.37), physical inactivity (IPAQ score below 3000 METs-min/week in 77.6% of MHO vs. 80% of MUO subjects; = 0.36), obesity-related disability (TSD-OC score > 33%, indicating a high level of obesity-related disability, in 20.2% of MHO vs. 26.5% of MUO subjects; = 0.28), and the HR-QoL (SF-36 total score: 60 ± 20.8 vs. 62.8 ± 18.2, = 0.27).

Discussion And Conclusion: The metabolic comorbidity and the impairment of functional ability and psycho-social functioning may have a different timing in the natural history of obesity. Alterations in the physical activity level and mobility disabilities may precede the onset of metabolic abnormalities. (Trial registration 2369 prot 166/12-registered 23 February 2012; Amendment 223/14-registered 13 February 2014).
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http://dx.doi.org/10.3390/nu8120759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5188414PMC
November 2016

Assessment of trabecular bone score (TBS) in overweight/obese men: effect of metabolic and anthropometric factors.

Endocrine 2016 Nov 27;54(2):342-347. Epub 2016 Jan 27.

Department of Experimental Medicine, Medical Pathophysiology, Food and Science and Endocrinology Section, "Sapienza" University of Rome, Rome, Italy.

The "trabecular bone score" (TBS) indirectly explores bone quality, independently of bone mineral density (BMD). We investigated the effects of anthropometric and metabolic parameters on TBS in 87 overweight/obese men. We assessed BMD and TBS by DXA, and some parameters of glucose metabolism, sex-and calciotropic hormone levels. Regression models were adjusted for either age and BMI, or age and waist circumference, or age and waist/hip ratio, also considering BMI >35 (y/n) and metabolic syndrome (MS) (y/n). Correlations between TBS and parameters studied were higher when correcting for waist circumference, although not significant in subjects with BMI >35. The analysis of covariance showed that the same model always had a higher adjusted r-square index. BMD at lumbar spine and total hip, fasting glucose, bioavailable testosterone, and sex hormone-binding globulin are the only covariates having a significant effect (p < 0.05) on the variations of TBS. The presence of MS negatively affected only the association between TBS and BMD at total hip. We did not find any significant effect of BMI >35 on TBS values or significant interaction terms between each covariate and either BMI >35 or the presence of MS. Obesity negatively affected TBS, despite unchanged BMD. Alterations of glucose homeostasis and sex hormone levels seem to influence this relationship, while calciotropic hormones have no role. The effect of waist circumference on TBS is more pronounced than that of BMI.
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http://dx.doi.org/10.1007/s12020-016-0857-1DOI Listing
November 2016