Clinical Characteristics of Patients With Acquired Partial Lipodystrophy: A Multicenter Retrospective Study.

BACKGROUND: Barraquer-Simons syndrome (BSS) is a rare, acquired form of lipodystrophy characterized by progressive loss of upper body subcutaneous fat, which affects face, upper limbs, and trunk. The pathogenesis of the disease is not entirely known and may involve autoimmune mechanisms. AIM: This study aimed to provide a comprehensive picture of the clinical, immunological, and metabolic features of a large cohort of patients with BSS. Our primary objectives included the validation of existing diagnostic tools, the evaluation of novel diagnostic approaches, and the exploration of potential disease triggers or genetic predispositions. SUBJECTS AND METHODS: Twenty-six patients were diagnosed with BSS based on accepted criteria defined by international guidelines. Anthropometric parameters, biochemical tests, organ- and non-organ-specific autoantibodies, HLA status, and screening of the LMNB2 gene were performed. RESULTS: Patients were predominantly females (73%); fat loss occurred mostly during childhood (77%) at a median age of 8 years. Among various anthropometric measures, the ratio between the proportion of fat mass in upper limbs and lower limbs showed the best predictive value for diagnosis. A total of 11.5% of patients had diabetes, 34.6% dyslipidemia, and 26.9% hepatic steatosis. Seventy-five percent of children and 50% of adults had C3 hypocomplementemia; 76% of patients were positive for 1 or more autoantibodies. HLA-DRB1 11:03 had higher allelic frequencies compared with the general population. A single variant in the LMNB2 gene was found in 1 patient. CONCLUSION: BSS has a childhood onset and is often associated with autoimmune diseases. Skinfold thickness measurements and fat assessment by dual energy X-ray absorptiometry are useful tools to identify the disease. C3 hypocomplementemia and the presence of autoantibodies may be used as additional diagnostic supportive criteria but the prevalence of C3 hypocomplementemia may be lower than previously reported.

A new mutation in the CAVIN1/PTRF gene in two siblings with congenital generalized lipodystrophy type 4: case reports and review of the literature.

Lipodystrophy syndromes are characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction and may have a genetic background. Congenital generalized lipodystrophy type 4 (CGL4) is an extremely rare subtype, caused by mutations in the polymerase I and transcript release factor (PTRF) gene. It encodes for a cytoplasmatic protein called caveolae-associated protein 1 (Cavin-1), which, together with caveolin 1, is responsible for the biogenesis of caveolae, being a master regulator of adipose tissue expandability. Cavin-1 is expressed in several tissues, including muscles, thus resulting, when dysfunctional, in a clinical phenotype characterized by the absence of adipose tissue and muscular dystrophy. We herein describe the clinical phenotypes of two siblings in their early childhood, with a phenotype characterized by a generalized reduction of subcutaneous fat, muscular hypertrophy, distinct facial features, myopathy, and atlantoaxial instability. One of the siblings developed paroxysmal supraventricular tachycardia leading to cardiac arrest at 3 months of age. Height and BMI were normal. Blood tests showed elevated CK, a mild increase in liver enzymes and triglycerides levels, and undetectable leptin and adiponectin concentrations. Fasting glucose and HbA1c were normal, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was mildly elevated. Both patients were hyperphagic and had cravings for foods rich in fats and sugars. Genetic testing revealed a novel pathogenic mutation of the CAVIN1/PTRF gene (NM_012232 exon1:c T21A:p.Y7X) at the homozygous state. The diagnosis of lipodystrophy can be challenging, often requiring a multidisciplinary approach, given the pleiotropic effect, involving several tissues. The coexistence of generalized lack of fat, myopathy with elevated CK levels, arrhythmias, gastrointestinal dysmotility, and skeletal abnormalities should prompt the suspicion for the diagnosis of CGL4, although phenotypic variability may occur.

Oxidative and DNA damage in obese patients undergoing bariatric surgery: A one-year follow-up study.

The pathogenesis of obesity and related comorbidities has long been associated with oxidative stress. The excess of adipose tissue contributes to the production of free radicals that sustain both a local and a systemic chronic inflammatory state, whereas its reduction can bring to an improvement in inflammation and oxidative stress. In our work, using the fluorescent lipid probe BODIPY® 581/591 C11 and the γH2AX foci assay, a well-known marker of DNA double strand breaks (DSB), we evaluated the extent of cell membrane oxidation and DNA damage in peripheral blood lymphocytes of normal weight (NW) controls and obese patients sampled before and after bariatric surgery. Compared to NW controls, we observed a marked increase in both the frequencies of oxidized cells or nuclei exhibiting phosphorylation of histone H2AX in preoperatory obese patients. After bariatric surgery, obese patients, resampled over one-year follow-up, improved oxidative damage and reduced the presence of DSB. In conclusion, the present study highlights the importance for obese patients undergoing bariatric surgery to also monitor these molecular markers during their postoperative follow-up.

Circulating Levels of MiRNAs From 320 Family in Subjects With Lipodystrophy: Disclosing Novel Signatures of the Disease.

Lipodystrophy (LD) indicates a group of rare disorders, with generalized or partial loss of white adipose tissue (WAT) often associated with metabolic derangements. Heterogeneity/wide spectrum of the disease and lack of biomarkers make diagnosis often difficult. MicroRNAs are important to maintain a correct WAT function and WAT is a source of circulating miRNAs (cmiRs). miRNAs from 320 family were previously detected in the WAT and variably associated to the metabolic syndrome. Our aim was then to investigate if LD can result in altered abundance of cmiRs-320. We collected samples from a cohort of LD subjects of various subtypes and from age matched controls. Use of quantitative PCR determined that cmiRs- 320a-3p, 320b, 320c, 320e are upregulated, while 320d is downregulated in LD. CmiRs-320 power as classifiers was more powerful in the most extreme and defined forms of LD, including the generalized and the Dunnigan subtypes. cmiR-320a-3p showed significant inverse relationships with plasma leptin (P < 0.0001), typically low in LD. The hepatic enzymes gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and the marker of inflammation C-reactive protein (CRP) were inversely related to cmiR 320d (P < 0.05, for CRP and GGT; P < 0.01, for AST and ALT). Gene ontology analysis revealed cell-cell adhesion as a process regulated by 320 miRNAs targets, thus disclosing a novel route to investigate origin of WAT loss/dysfunction. In conclusion, cmiRs-320 constitute novel biomarkers of LD, abundance of miR320a-3p is inversely associated to indicators related to WAT function, while downregulation of cmiR-320d predicts an altered hepatic profile and higher inflammation.

The complex interactions among serotonin, insulin, leptin, and glycolipid metabolic parameters in human obesity.

OBJECTIVE: To provide evidence to the link between serotonin (5-HT), energy metabolism, and the human obese phenotype, the present study investigated the binding and function of the platelet 5-HT transporter (SERT), in relation to circulating insulin, leptin, and glycolipid metabolic parameters. METHODS: Seventy-four drug-free subjects were recruited on the basis of divergent body mass index (BMIs) (16.5-54.8 Kg/m2). All subjects were tested for their blood glycolipid profile together with platelet [3H]-paroxetine ([3H]-Par) binding and [3H]-5-HT reuptake measurements from April 1st to June 30th, 2019. RESULTS: The [3H]-Par Bmax (fmol/mg proteins) was progressively reduced with increasing BMIs (P < .001), without changes in affinity. Moreover, Bmax was negatively correlated with BMI, waist/hip circumferences (W/HC), triglycerides (TD), glucose, insulin, and leptin, while positively with high-density lipoprotein (HDL) cholesterol (P < .01). The reduction of 5-HT uptake rate (Vmax, pmol/min/109 platelets) among BMI groups was not statistically significant, but Vmax negatively correlated with leptin and uptake affinity values (P < .05). Besides, [3H]-Par affinity values positively correlated with glycemia and TD, while [3H]-5-HT reuptake affinity with glycemia only (P < .05). Finally, these correlations were specific of obese subjects, while, from multiple linear-regression analysis conducted on all subjects, insulin (P = .006) resulting negatively related to Bmax independently from BMI. CONCLUSIONS: Present findings suggest the presence of a possible alteration of insulin/5-HT/leptin axis in obesity, differentially impinging the density, function, and/or affinity of the platelet SERT, as a result of complex appetite/reward-related interactions between the brain, gut, pancreatic islets, and adipose tissue. Furthermore, they support the foremost cooperation of peptides and 5-HT in maintaining energy homeostasis.

Autoimmunity in lipodystrophy syndromes.

Lipodystrophy syndromes are rare, heterogeneous disorders characterized by the complete or partial deficiency of adipose tissue and are classified according to the extent of fat loss in generalized or partial subtypes, or based on the pathogenic mechanisms in genetic or acquired. While in most cases of congenital forms of lipodystrophy a genetic alteration can be identified, the pathogenic mechanisms responsible for the acquired diseases are not fully clarified. Based on the evidence of a positive association between most acquired lipodystrophies and autoimmune disorders including immune mediated alterations in the adipose tissue of patients affected by acquired lipodystrophy, a reaction against white adipose tissue antigens is postulated. Recent acquisitions have shed new light on the possible pathogenic mechanisms and identified novel forms of acquired lipodystrophy which are possibly immune-mediated. The aim of this review is to give an update on acquired lipodystrophies describing pathogenic mechanisms involved and the relationships between acquired lipodystrophies and other autoimmune disorders. Larger studies based on international disease registries are needed to collect accurate information on the prevalence, risk factors, genetic predisposition, natural history, disease markers and treatment efficacy of these ultrarare disorders.

Obesity-related gut hormones and cancer: novel insight into the pathophysiology.

The number of cancers attributed to obesity is increasing over time. The mechanisms classically implicated in cancer pathogenesis and progression in patients with obesity involve adiposity-related alteration of insulin, sex hormones, and adipokine pathways. However, they do not fully capture the complexity of the association between obesity-related nutritional imbalance and cancer. Gut hormones are secreted by enteroendocrine cells along the gastrointestinal tract in response to nutritional cues, and act as nutrient sensors, regulating eating behavior and energy homeostasis and playing a role in immune-modulation. The dysregulation of gastrointestinal hormone physiology has been implicated in obesity pathogenesis. For their peculiar function, at the cross-road between nutrients intake, energy homeostasis and inflammation, gut hormones might represent an important but still underestimated mechanism underling the obesity-related high incidence of cancer. In addition, cancer research has revealed the widespread expression of gut hormone receptors in neoplastic tissues, underscoring their implication in cell proliferation, migration, and invasion processes that characterize tumor growth and aggressiveness. In this review, we hypothesize that obesity-related alterations in gut hormones might be implicated in cancer pathogenesis, and provide evidence of the pathways potentially involved.

Partial Lipodystrophy and LMNA p.R545H Variant.

Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.

Metreleptin for the treatment of progressive encephalopathy with/without lipodystrophy (PELD) in a child with progressive myoclonic epilepsy: a case report.

BACKGROUND: A number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes. CASE PRESENTATION: We describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient's lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy. CONCLUSIONS: Metreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.

Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation.

Atypical progeroid syndrome (APS) comprises heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations, and comorbidities that affect skeleton, muscles, and/or the heart. We describe 3 patients that were referred to our center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia manifesting around 10 to 15 years of age recurrently associated with: (1) partial lipodystrophy; (2) proteinuric nephropathy; (3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); and (4) sensorineural hearing impairment. In all patients, genetic testing revealed a missense heterozygous lamin A/C gene (LMNA) mutation c.1045 C > T (p.Arg349Trp). Ten patients with LMNA p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.

Correction to: Immunological features of patients affected by Barraquer-Simons syndrome.

Following the publication of the original article [1], the authors have requested to amend the Abstract and Discussion section as follows.

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease.

Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase ß (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144*) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.

Immunological features of patients affected by Barraquer-Simons syndrome.

BACKGROUND: C3 hypocomplementemia and the presence of C3 nephritic factor (C3NeF), an autoantibody causing complement system over-activation, are common features among most patients affected by Barraquer-Simons syndrome (BSS), an acquired form of partial lipodystrophy. Moreover, BSS is frequently associated with autoimmune diseases. However, the relationship between complement system dysregulation and BSS remains to be fully elucidated. The aim of this study was to provide a comprehensive immunological analysis of the complement system status, autoantibody signatures and HLA profile in BSS. Thirteen subjects with BSS were recruited for the study. The circulating levels of complement components, C3, C4, Factor B (FB) and Properdin (P), as well as an extended autoantibody profile including autoantibodies targeting complement components and regulators were assessed in serum. Additionally, HLA genotyping was carried out using DNA extracted from peripheral blood mononuclear cells. RESULTS: C3, C4 and FB levels were significantly reduced in patients with BSS as compared with healthy subjects. C3NeF was the most frequently found autoantibody (69.2% of cases), followed by anti-C3 (38.5%), and anti-P and anti-FB (30.8% each). Clinical data showed high prevalence of autoimmune diseases (38.5%), the majority of patients (61.5%) being positive for at least one of the autoantibodies tested. The HLA allele DRB1*11 was present in 54% of BSS patients, and the majority of them (31%) were positive for *11:03 (vs 1.3% in the general population). CONCLUSIONS: Our results confirmed the association between BSS, autoimmunity and C3 hypocomplementemia. Moreover, the finding of autoantibodies targeting complement system proteins points to complement dysregulation as a central pathological event in the development of BSS.

Treatment of Hypothyroid Patients With L-Thyroxine (L-T4) Plus Triiodothyronine Sulfate (T3S). A Phase II, Open-Label, Single Center, Parallel Groups Study on Therapeutic Efficacy and Tolerability.

Sodium salt of levothyroxine (L-T4) is the treatment of choice of hypothyroidism. Yet, L-T4 monotherapy produces supoptimal 3,5,3'-triiodothyronine (T3)/T4 ratio in serum, as compared to normal subjects, and a minority of hypothyroid individuals on L-T4 complain for an incomplete well-being. Orally administered 3,5,3'-triiodothyronine sulfate (T3S) can be converted to T3 in humans, resulting in steady-state serum T3 concentrations for up to 48 h. In this study (EudraCT number 2010-018663-42), 36 thyroidectomized hypothyroid patients receiving 100 (group A), 125 (group B), or 150 µg (group C) L-T4 were enrolled in a 75 days study in which 25 µg L-T4 were replaced by 40 µg of T3S. A significant, progressive reduction in mean FT4 values was observed, being the largest in the group A and the smallest in group C, while no relevant variations in FT3 and total T3 serum values were observed in the three groups. TSH serum levels increased in all groups, the highest value being observed in group A. Lipid parameters did not show clinically significant changes in all groups. No T3S-related changes in the safety laboratory tests were recorded. No adverse event was judged as related to experimental treatment, and no patient discontinued the treatment. Twelve patients judged the L-T4+T3S treatment better than L-T4 alone, while no patient reported a preference for L-T4 over the combined treatment. In conclusion, the results of this study indicate that a combination of L-T4+T3S in hypothyroid subjects may allow mainteinance of normal levels of serum T3, with restoration of a physiological FT4/FT3 ratio and no appearance of adverse events. Further studies are required to verify whether the LT4+T3S chronic combined treatment of hypothyroidism is able to produce additional benefits over L-T4 monotherapy.

Serum IGF-binding protein 2 (IGFBP-2) concentrations change early after gastric bypass bariatric surgery revealing a possible marker of leptin sensitivity in obese subjects.

PURPOSE: Expression of IGFBP-2 in mice is regulated by leptin. Over-expression of IGFBP-2 is associated with reduced caloric intake and resistance to weight gain. Hormonal variations contributing to weight loss occur very early after bariatric surgery but have not been fully elucidated. We evaluated IGFBP-2 serum changes after bariatric surgery and their relationship with leptin variations to test the hypothesis that an increase of leptin sensitivity may explain some of the effects of gastric bypass. METHODS: This is a historical prospective study. Fifty-one obese patients (41 women e 10 men), 9 non-obese surgical controls and 41 lean matched controls were studied. Serum IGFBP-2 and leptin were measured after bariatric bypass surgery at various time points up to 18 months, after non-bariatric laparoscopic surgery in a control group, and in lean matched controls. RESULTS: Compared to lean controls, serum IGFBP-2 levels were lower in obese patients. After gastric bypass, IGFBP-2 significantly increased at 3 days and became normal before the occurrence of relevant changes in body weight, remaining stable up to 18 months after surgery. IGFBP-2/leptin ratio increased early after surgery and became normal after one year. CONCLUSIONS: After gastric bypass, serum IGFBP-2 increases in a window of time when variations of hormones mediating the effects of bariatric surgery occur. Our results suggest that IGFBP-2, a leptin-regulated protein, may be an in-vivo marker of leptin action. If this is the case, an early improvement of leptin sensitivity might contribute to the anorectic effect of gastric bypass.

Weight Loss and Variation of Levothyroxine Requirements in Hypothyroid Obese Patients After Bariatric Surgery.

BACKGROUND: Obesity and hypothyroidism are both common disorders within the general population. Obese hypothyroid subjects require higher doses of levothyroxine (LT4) compared with normal weight individuals. Previous studies on the effects of bariatric surgery on LT4 dose requirements in hypothyroid subjects have provided conflicting results. The aim of this study was to evaluate the LT4 requirements in a group of obese subjects with acquired hypothyroidism, before and after weight loss achieved by bariatric surgery. METHODS: Ninety-three obese hypothyroid subjects (mean age = 48 ± 9 years; mean body mass index = 45.9 ± 5.6 kg/m(2)), were evaluated before and 28 ± 8 months after bariatric surgery. Changes in the LT4 dose, anthropometric measures, and hormone values were evaluated. In 20 patients, data of body composition, assessed by dual energy X-ray absorptiometry, were also analyzed. RESULTS: On average, after weight loss, a significant reduction of the total dose of LT4 was documented (from 130.6 ± 48.5 to 116.2 ± 38.6 µg/day; p < 0.001). The LT4 dose had to be reduced in 47 patients, was unchanged in 34, and had to be increased in 12 patients affected by autoimmune thyroiditis. Reduction of the LT4 dose was proportional to reduction of the lean body mass. CONCLUSIONS: The weight loss achieved with modern surgical bariatric procedures is associated with a reduction of LT4 requirements in most hypothyroid subjects, which appears to be related to a decrease of the lean body mass. Occasionally, a concurrent decline of residual thyroid function, as it occurs in autoimmune thyroiditis, can counteract this phenomenon and eventually produce an increase of LT4 needs. It is believed that during the weight loss phase that follows bariatric surgery, there is no need for preventive adjustments of the LT4 dose, but serum thyroid hormones and thyrotropin should be periodically monitored in order to detect possible variations of LT4 requirements and to allow proper corrections of the therapy.

Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome.

OBJECTIVE: Progressive lipodystrophy is one of the major features of the rare MDPL syndrome. Until now, 9 patients affected by this syndrome have been described and a recent study identified in 4 of them an in-frame deletion (Ser605del) of a single codon in the POLD1 gene. Sequence alterations of the POLD1 gene at different sites have been previously reported in human colorectal and endometrial carcinomas. MATERIALS/METHODS: A 48-year-old woman was admitted to our department for the assessment of a previously diagnosed lipodystrophy. She did not report a family history of diabetes or other metabolic disorders. Hypertriglyceridemia was diagnosed incidentally when she was 25years old. At that time she was also diagnosed with sensorineural bilateral hearing loss. At physical examination she presented lipoatrophy affecting nearly the entire body, mandibular hypoplasia, bird-like face, beaked nose, progeroid facial features, with crowded teeth, small mouth and uvula. Abdominal ultrasound showed hepatomegaly and hepatosteatosis. Fat mass index measured with DXA was 4.59kg/m(2), indicating a fat deficit; the oral glucose tolerance test showed an impaired glucose tolerance. RESULTS: Sequence analysis of the entire coding region of the POLD1 gene, disclosed a novel heterozygous mutation in exon 13 (R507C). CONCLUSION: The MDPL patient herein described harbors a novel mutation in the exonuclease domain of POLD1. This new variant provides further evidence for a role of POLD1 in the pathogenesis of MDPL. The mechanisms that link changes at various sites of the protein with different diseases remain to be clarified.

The expression of platelet serotonin transporter (SERT) in human obesity.

BACKGROUND: Serotonin (5-HT) is a well-known modulator of eating behavior. However, the molecular mechanisms linking its action to body weight balance have been only partially elucidated. Since platelets are a suitable peripheral model to study 5-HT transport, metabolism and release, we herein evaluated the expression of the platelet 5-HT re-uptake system (SERT) by [3H]-paroxetine binding assay. A cohort of 114 unrelated individuals (34 males, 80 females; age, mean ± SD: 38.57 ± 12.47 years) without major psychiatric disorders, was recruited following a naturalistic design regarding age or gender and classified accordingly to their body mass index (BMI). Subjects were divided into 5 groups: normal-weight (NW), overweight (OW) and grade I-III obese (OB) individuals. For gender analyses, data were transformed into [3H]-paroxetine density (Bmax)/BMI ratios to overcome both the disparity of women vs. men number and anthropometric differences between sexes. RESULTS: [3H]-paroxetine Bmax (SERT density, fmol/mg proteins) was reduced in platelet membranes of grade II (p < 0.01) and III (p < 0.001) obese subjects vs. controls and in overweight subjects (p < 0.05) vs. grade III obese individuals. Considering all patients together, a strong negative correlation between Bmax and BMI (r = -0.449; P < 0.0001) was demonstrated. Conversely, [3H]-paroxetine KD (dissociation constant, nM) did not differ among groups. No gender-related variation concerning Bmax/BMI ratios was observed in this cohort of subjects. CONCLUSIONS: The down-regulation of SERT in platelet membranes of severe human obesity (BMI > 35 Kg/m2) confirms the involvement of 5-HT system in body weight gain. Moreover, this findings may help to elucidate those monoamine-endocrine networks acting on fat storage, adipocyte signaling and energy balance. Targeting 5-HT/5-HT-related markers will possibly uncover the existence of human obesity subtypes.

Contribution of 32 GWAS-identified common variants to severe obesity in European adults referred for bariatric surgery.

The prevalence of severe obesity, defined as body mass index (BMI) ≥ 35.0 kg/m(2), is rising rapidly. Given the disproportionately high health burden and healthcare costs associated with this condition, understanding the underlying aetiology, including predisposing genetic factors, is a biomedical research priority. Previous studies have suggested that severe obesity represents an extreme tail of the population BMI variation, reflecting shared genetic factors operating across the spectrum. Here, we sought to determine whether a panel of 32 known common obesity-susceptibility variants contribute to severe obesity in patients (n = 1,003, mean BMI 48.4 ± 8.1 kg/m(2)) attending bariatric surgery clinics in two European centres. We examined the effects of these 32 common variants on obesity risk and BMI, both as individual markers and in combination as a genetic risk score, in a comparison with normal-weight controls (n = 1,809, BMI 18.0-24.9 kg/m(2)); an approach which, to our knowledge, has not been previously undertaken in the setting of a bariatric clinic. We found strong associations with severe obesity for SNP rs9939609 within the FTO gene (P = 9.3 × 10(-8)) and SNP rs2815752 near the NEGR1 gene (P = 3.6 × 10(-4)), and directionally consistent nominal associations (P<0.05) for 12 other SNPs. The genetic risk score associated with severe obesity (P = 8.3 × 10(-11)) but, within the bariatric cohort, this score did not associate with BMI itself (P = 0.264). Our results show significant effects of individual BMI-associated common variants within a relatively small sample size of bariatric patients. Furthermore, the burden of such low-penetrant risk alleles contributes to severe obesity in this population. Our findings support that severe obesity observed in bariatric patients represents an extreme tail of the population BMI variation. Moreover, future genetic studies focused on bariatric patients may provide valuable insights into the pathogenesis of obesity at a population level.

Description of an AGPAT2 pathologic allelic variant in a 54-year-old Caucasian woman with Berardinelli-Seip syndrome.

A 54-year-old Italian female patient was admitted to our Department with the diagnosis of type 2 diabetes poorly controlled with insulin therapy. The patient was born by consanguineous parents (first degree cousins); she had acromegaloid features, diffuse lipoatrophy and muscular pseudo-hypertrophy since childhood. To confirm the clinical hypothesis of congenital generalized lipodystrophy (CGL) or Berardinelli-Seip syndrome, the sequences of AGPAT2 (encoding for 1-acyl-sn-glycerol-3-phosphate acyltransferase beta) and BSCL2 (encoding for seipin) candidate genes were analyzed. DNA analysis showed the presence of a homozygous mutation in exon 3 of the AGPAT2 gene (P112L). This is the first description of a Caucasian subject with CGL who carries the pathologic allelic variant P112L of the AGPAT2 gene.