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SommarioL’obesità è una malattia metabolica cronica associata a diverse complicanze. Alla base non vi è solo l’alimentazione, poiché il bilancio energetico è regolato da interazioni tra fattori genetici, comportamentali e ambientali. Gli studi di associazione sul genoma identificano diversi geni legati all’obesità, suggerendo nuovi orizzonti terapeutici nel genome editing: la tecnologia CRISPR/Cas9, modificando il DNA o modulando l’espressione genica nelle cellule eucariotiche, fa luce sui meccanismi genetici e potrebbe essere un valido strumento terapeutico. Questa rassegna riassume la genetica dell’obesità e i trattamenti disponibili, discutendo i progressi della ricerca sul genome editing nella conoscenza e terapia dell’eccesso di grasso corporeo.

Defined as a condition of body fat excess leading to significant morbidity, obesity is a chronic metabolic illness associated with a significant number of diseases. The incidence of obesity does not solely depend on dietary habits, with energy balance being regulated by the complex interactions between genetic, behavioural and environmental factors. Genome-wide association studies (GWASs) have demonstrated that several genes are linked to obesity, and these findings shed light on a growing number of novel potential therapeutics for weight management, including genome editing. In this regard, the cutting-edge technology known as clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas), thanks to its ability to edit DNA or modulate gene expression in eukaryotic cells, undoubtedly enables to understand the genetic mechanisms implicated in obesity and could be a promising tool for its treatment. This chapter summarizes the genetics underlying obesity and currently available obesity treatments, further discussing the research progress of genome editing in the knowledge and treatment of body fat excess.

PURPOSE OF REVIEW The low fat diet (LFD) is currently the first choice to treat nonalcoholic fatty liver disease (NAFLD) alongside with physical activity. However, low carbohydrate diets (LCDs) and ketogenic diets have gained attention lately, thanks to their favourable impact in reducing intrahepatic triglyceride content. We therefore aimed at providing an update on recent evidence evaluating the hepatoprotective effects of such dietary interventions. RECENT FINDINGS Novel findings confirmed previous evidence by showing beneficial effects on liver fat content reduction for both LFDs and LCDs. The further restriction of carbohydrates to less than 50 g/day, usually leading to ketosis, confirmed to produce an improvement in NAFLD, with very low-calorie ketogenic diets possibly proving particularly beneficial thanks to the significant weight loss that can be obtained. SUMMARY Most of the latest evidence shows that carbohydrate restriction plays a fundamental role in the modulation of lipid metabolism leading to similar efficacy in improving NAFLD compared with LFDs. The hepatoprotective role of carbohydrate restriction appears to be boosted when ketogenesis is induced, when the total calorie intake is extremely reduced, or, possibly, when dietary interventions have reduced content in free sugars, making such interventions valuable tools to deal with NAFLD.

Overnutrition and its sequelae have become a global concern due to the increasing incidence of obesity and insulin resistance. A ketogenic diet (KD) is widely used as a dietary treatment for metabolic disorders. Sirtuin1 (SIRT1), a metabolic sensor which regulates fat homeostasis, is modulated by dietary interventions. However, the influence of nutritional ketosis on SIRT1 is still debated. We examined the effect of KD on adipose tissue, liver, and serum levels of SIRT1 in mice. Adult C57BL/6J male mice were randomly assigned to two isocaloric dietary groups and fed with either high-fat KD or normal chow (NC) for 4 weeks. Serum SIRT1, beta-hydroxybutyrate (βHB), glucose, and triglyceride levels, as well as SIRT1 expression in visceral (VAT), subcutaneous (SAT), and brown (BAT) adipose tissues, and in the liver, were measured. KD-fed mice showed an increase in serum βHB in parallel with serum SIRT1 (r = 0.732, p = 0.0156), and increased SIRT1 protein expression in SAT and VAT. SIRT1 levels remained unchanged in BAT and in the liver, which developed steatosis. Normal glycemia and triglycerides were observed. Under a KD, serum and white fat phenotypes show higher SIRT1, suggesting that one of the molecular mechanisms underlying a KD’s potential benefits on metabolic health involves a synergistic interaction with SIRT1.

Ketone bodies (KBs) and Sirtuin-1 (SIRT1) have received increasing attention over the past two decades given their pivotal function in a variety of biological contexts, including transcriptional regulation, cell cycle progression, inflammation, metabolism, neurological and cardiovascular physiology, and cancer. As a consequence, the modulation of KBs and SIRT1 is considered a promising therapeutic option for many diseases. The direct regulation of gene expression can occur in vivo through histone modifications mediated by both SIRT1 and KBs during fasting or low-carbohydrate diets, and dietary metabolites may contribute to epigenetic regulation, leading to greater genomic plasticity. In this review, we provide an updated overview of the epigenetic interactions between KBs and SIRT1, with a particular glance at their central, synergistic roles for metabolic health.

AimsTo explore variables associated with the serological response following COVID-19 mRNA vaccine.MethodsHealthcare 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 three weeks. Blood samples were collected before the first 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.ResultsEighty-six patients were enrolled. Those with central obesity had lower antibody (Ab) titers compared with those with no central obesity [1426(1436)vs1971(1819), p=0.04]; smokers had a blunted response compared to non-smokers [1099(1350)vs1921(1375), p=0.007], as well as hypertensive vs normotensive [650±1192vs1911(1364), p=0.001] and dyslipidemic 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 titers, independent of BMI, age and gender. The association between waist circumference and Ab titers was lost when controlling for body fat, suggesting that visceral accumulation may explain this result.ConclusionsIt is currently impossible to determine whether lower SARS CoV-2 Abs lead to higher likelihood of developing COVID-19. However, neutralizing abs correlate with protection against several viruses including SARS-CoV-2, and the finding that central obesity, hypertension and smoking are associated with a blunted response warrants further attention. Our findings must lead to a vigilant approach, as these subjects could benefit from earlier vaccine boosters or different vaccine schedules.

With the prevalence of obesity alarmingly increasing, it is of primary interest to identify those factors predicting the success of anti-obesity therapeutic strategies currently adopted in clinical practice, and in particular, those of bariatric procedures showing the greatest success in terms of weight loss and maintenance in both the short and long term. Given sex-related differences in psychosocial status, hormonal homeostasis, and body fat distribution, it is likely that the response to different weight management strategies differs by sex. The objective was to elucidate the effect of sex on different bariatric procedures' efficacy and safety outcomes. Searches of PubMed, Cochrane, and Embase databases were performed, followed by hand-searching of reference lists from all relevant articles. We included all the studies evaluating the effect of bariatric procedures on body mass index loss (BMIL), and/or percentage excess weight loss (%EWL), and/or percentage excess body mass index loss, and/or percentage of responders, and/or short-/long-term complications and co-morbidity resolution, broken down by sex. Twenty-seven studies with a total of 114,919 patients were included. Men were more likely to achieve greater BMIL, consistent with higher male baseline BMI, and women were 2.87 times more likely to be classified as weight responders (95% confidence interval [CI]: 1.90-4.34), as well as to perform better in terms of %EWL (95% CI: .13-.54). Upon subgroup analysis based on bariatric procedure, women were more likely to be successful in terms of %EWL upon bioenteric intragastric balloon (BIB) placement (.72, 95% CI: .42-1.02). There was no sex difference regarding investigated co-morbidity resolution (hypertension, diabetes, and obstructive sleep apnea syndrome) or occurrence of short-term complications, whereas women were more likely to develop long-term complications, with an odds ratio of 1.97 (95% CI: 1.57-2.49). Sex does not have a clear effect on efficacy outcomes of bariatric procedures. Differentiating by procedure, BIB may be more effective in women, although results are discordant based on the weight loss outcome considered. If the short-term postoperative complication rate is similar across both sexes, long-term complications occur more frequently in women. To clarify the real effect of sex on bariatric procedure-derived health benefits, it is crucial to report sex-stratified results in future studies, as well as evaluate body composition changes that go beyond simple body weight reduction.

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.

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.

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.

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 (R2) 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 (p &lt, 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 R2 was recorded for EFT (R2 = 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.

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.

Sirtuin1 (SIRT1) and sclerostin play important roles in adipose tissue and bone metabolism. We evaluated the circulating SIRT1 and sclerostin relationship with mass and quality of bone while considering the degree of adiposity. Sixty-six premenopausal women (16 underweight, 25 normal weight and 25 with obesity), aged

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.