White Adipose Tissue Expansion in Multiple Symmetric Lipomatosis Is Associated with Upregulation of CK2, AKT and ERK1/2.

Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by overgrowing lipomatous tissue (LT) in the subcutaneous adipose tissue (SAT). What LT is and how it expands are not completely understood; previous data suggested that it could derive from brown AT precursors. In six MSL type I patients, we compared LT morphology by histological and immunohistochemistry (IHC) analysis, gene expression, by qPCR, kinase activity, by Western Blot and in vitro assay to paired-control SAT using AT from patients with pheochromocytoma as a human browning reference. In the stromal vascular fraction (SVF), we quantified adipose stem cells (ASCs) by flow cytometry, the proliferation rate, white and beige adipogenic potential and clonogenicity and adipogenicity by a limiting dilution assay. LT displayed white AT morphology and expression pattern and did not show increased levels of the brown-specific marker UCP1. In LT, we evidenced AKT, CK2 and ERK1/2 hyperactivation. LT-SVF contained increased ASCs, proliferated faster, sprouted clones and differentiated into adipocytes better than the control, displaying enhanced white adipogenic potential but not increased browning compared to SAT. In conclusion, LT is a white AT depot expanding by hyperplasia through increased stemness and enhanced white adipogenesis upregulating AKT, CK2 and ERK1/2, which could represent new targets to counteract MSL.

Absence of 18 F-fluorodeoxyglucose uptake using Positron Emission Tomography/Computed Tomography in Madelung's disease: A case report.

Madelung's disease is characterized by the manifestation of multiple ectopic lipomas, usually found in the cervical-thoracic region, however, clinical manifestation may vary among patients. It has been postulated that lipomas associated with Madelung's disease are linked to brown adipose tissue (BAT) due to the presence of uncoupling protein 1 (UCP1). Therefore, we here investigated whether BAT activity is present in a patient with Madelung's disease. 18 F-fluorodeoxyglucose (18 F-FDG) uptake using PET/CT after a cooling procedure was measured together with body temperature and energy expenditure. Finally, adipose tissue biopsies were taken from the lipomas for gene expression analysis and histology. 18 F-FDG uptake was not detected after the cooling procedure in the lipomas. Furthermore, adipose tissue biopsies derived from the lipomas did not express UCP1. We thus conclude that cold-stimulated BAT activity was not detected in lipomas associated with Madelung's disease. Additional research in other patients is needed to unravel the role of dysfunctional BAT in Madelung's disease.

MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue.

BACKGROUND: Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. OBJECTIVE: To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. METHODS: We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. RESULTS: Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. CONCLUSION: MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

Multiple symmetric lipomatosis and gynecomastia: A case report and relative literature review.

Multiple symmetric lipomatosis is a rare disease characterized by a symmetrical accumulation of massive adipose tissue on the neck, the superior part of the trunk, and limbs. Here, we reported an extremely rare case of multiple symmetric lipomatosis in a 46-year-old Chinese man, who has a history of heavy drinking and smoking and presented with diffuse lipomatosis and bilateral breast enlargement. Hyperuricemia and impaired glucose tolerance test were all found in this patient. A brief review of the literature was also made in this article.

Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy.

Despite considerable progress in identifying causal genes for lipodystrophy syndromes, the molecular basis of some peculiar adipose tissue disorders remains obscure. In an Israeli-Arab pedigree with a novel autosomal recessive, multiple symmetric lipomatosis (MSL), partial lipodystrophy and myopathy, we conducted exome sequencing of two affected siblings to identify the disease-causing mutation. The 41-year-old female proband and her 36-year-old brother reported marked accumulation of subcutaneous fat in the face, neck, axillae, and trunk but loss of subcutaneous fat from the lower extremities and progressive distal symmetric myopathy during adulthood. They had increased serum creatine kinase levels, hypertriglyceridemia and low levels of high-density lipoprotein cholesterol. Exome sequencing identified a novel homozygous NC_000019.9:g.42906092C>A variant on chromosome 19, leading to a NM_005357.3:c.3103G>T nucleotide change in coding DNA and corresponding p.(Glu1035*) protein change in hormone sensitive lipase (LIPE) gene as the disease-causing variant. Sanger sequencing further confirmed the segregation of the mutation in the family. Hormone sensitive lipase is the predominant regulator of lipolysis from adipocytes, releasing free fatty acids from stored triglycerides. The homozygous null LIPE mutation could result in marked inhibition of lipolysis from some adipose tissue depots and thus may induce an extremely rare phenotype of MSL and partial lipodystrophy in adulthood associated with complications of insulin resistance, such as diabetes, hypertriglyceridemia and hepatic steatosis. © 2016 Wiley Periodicals, Inc.

Multiple symmetric lipomatosis: substantial subcutaneous adipose tissue accumulation did not induce glucose and lipid metabolism dysfunction.

OBJECTIVE: To study whether substantial subcutaneous adipose tissue (SCAT) can induce glucose and lipid metabolism dysfunction and possible underlying mechanisms. METHODS: We report a male patient with multiple symmetrical lipomatosis (MSL) suffering from increased adipose tissue accumulation in abdomen and back for 7 years, accompanied by the gradual expansion of excess adipose tissue to the nuchal region, upper thorax, upper arms and shoulders. Four obese male adults of similar age and body mass index were chosen as controls (only 4 subjects consented to blood and tissue sampling).Blood samples were collected before anesthesia in the early morning after overnight fasting, and tissue samples from all subjects and the patient were obtained under general anesthesia. Glucose tolerance, insulin resistance in the oral glucose tolerance test and insulin-releasing test were studied. A pathologic examination was made and expression of SCAT-related genes was determined. RESULTS: Although adipose tissue mainly accumulated in SCAT, the patient had no impaired glucose tolerance, insulin resistance and dyslipidemia. Importantly, the circulating adiponectin concentration was higher than in the control group (50.3 +/- 3.2 vs. 28.4 +/- 2.2 microg/ml, p < 0.05). Accordingly, adiponectin and leptin mRNA expression in SCAT was higher than in the control group (1.83 and 3.75 times, p < 0.05) but TNF-alpha and IL-6 mRNA levels were lower (decreased by 79 and 45%, p < 0.05). Furthermore, pathologically, adipocyte size in the patient's SCAT was smaller than in the control group (66.2 +/- 6.1 vs. 78.9 +/- 6.6 and 98.6 +/- 12.8 microm in SCAT and omentum adipose tissue, respectively, p < 0.05). CONCLUSION: In spite of the patient's SCAT accumulation, glucose and lipid metabolism dysfunction was absent. The mechanism may involve the interaction of different factors, including the subcutaneous formation of small adipocytes, the secretion of protective adipokines such as adiponectin and anti-inflammatory effects of SCAT.

[Metabolical characteristics in patients with multiple symmetrical lipomatosis]. / Metabolische Besonderheiten bei Patienten mit Multipler Symmetrischer Lipomatose.

BACKGROUND AND OBJECTIVE: Multiple symmetrical lipomatosis (MSL) is a rare cause of obesity. As the cause is unknown the therapeutic options are unsatisfactory. This study was undertaken to elucidate whether there are singular metabolic and endocrine characteristics in such patients. PATIENTS AND METHODS: Data were collected from 15 patients with MSL who had been referred to our clinic during the last ten years. Various metabolic and endocrine parameters as well as bone density were measured. The possible presence of an obstructive sleep apnoea syndrome was also looked for. RESULTS: Five of the 15 patients fulfilled the International Diabetes Federation's criteria of a metabolic syndrome. The parathormone level was elevated in seven patients, but there were no other endocrine abnormalities. DISCUSSION: No endocrine abnormalities other than an elevation of parathormone (of no clinical significance) are associated with MSL. But the prevalence of the (cardio)metabolic syndrome is relatively high. Thus an elevated risk of cardiovascular disease in these patients is likely.

Multiple symmetric lipomatosis - a reflection of new concepts about obesity.

Multiple symmetric lipomatosis (MSL) is characterized by subcutaneous accumulation of nonencapsulated adipose tissue. In type 2 MSL accumulation occurs on proximal limbs, upper back and hips. This sometimes unrecognized disease is similar to an exaggerated female fat distribution and can be confused with simple obesity. Obesity is a heterogeneous disorder and we suppose that type 2 MSL might have a place on the edge of the obesity spectrum. Several contemporary concepts about adipose tissue could be recognized in the model of MSL. Changes in fat distribution among different depots of adipose tissue in obesity have emerged as origin of its metabolic complications. Decreased insulin resistance and raised adiponectin have been found in MSL just as in some other conditions with accumulation of the subcutaneous adipose tissue (SAT). In that context, MSL may present as a model for possible favourable metabolic impact of SAT depots. Adipogenesis in MSL is not a consequence of energy excess but it is an active hyperplastic proliferation of SAT. This kind of behaviour of some adipocytes in several subcutaneous areas in MSL suggests that the energy unrelated adipogenesis could contribute to the expansion of at least a part of SAT depot in obesity in general. Contrary to current concept that the signals for adipogenesis are dependent only on the energy equation, allowing this additional mechanism would imply a new approach to issues of obesity, foremost to differentiate its particular types for which these concepts may be relevant.

Adiponectin, resistin and subclinical inflammation--the metabolic burden in Launois Bensaude Syndrome, a rare form of obesity.

The aim of the study was to investigate, whether the degree of metabolic risk factors for atherosclerotic complications in a very rare kind of obesity, the Multiple Symmetrical Lipomatosis, also known as the Launois-Bensaude Syndrome (LBS), are comparable or different from "simple" truncal obesity. 10 patients with LBS (Body mass index 34.4 +/- 1.8 kg/m(2), age: 62 +/- 3 yrs) were compared with 19 BMI - matched patients with "simple" truncal obesity and obstructive sleep apnoea syndrome (OSAS) and 20 BMI- matched patients with "simple" truncal obesity without OSAS. Markers of subclinical inflammation and thrombocyte activation (sCD62p = soluble p-selectin, highly sensitive C-Reactive protein = CRP, Interleukin-6 = IL-6, ICAM-1 = Intracellular Adhesion Molecule-1, Vascular Cell Adhesion Molecule = VCAM -1, leptin), as well as adiponectin and resistin were studied. The prevalence of atherogenic risk factors as hypertension (80%), type 2 diabetes (30%), OSAS (50%), smoking (30%) and alcohol abuse (80%) was high in the (obese) LBS group. The markers of subclinical inflammation and thrombocyte activation showed an indifferent picture with lower levels of circulating IL-6 and sCD62p, comparable CRP and higher ICAM-1 and VCAM-1 than in controls. Leptin and adiponectin were higher than in controls. However, the accumulation of "classic" cardiovascular risk factors in the LBS group was well reflected by the presence of symptomatic cardiovascular disease in 3 of the 10 LBS patients, putting LBS patients - if obese - at an atherosclerotic risk at least comparable to obese persons.

Total and regional body composition and energy expenditure in multiple symmetric lipomatosis.

AIMS: The aim of the present study was to investigate possible alterations in body composition and resting energy expenditure (REE) in type 1 multiple symmetric lipomatosis (MSL). SUBJECTS AND METHODS: Thirteen men aged from 40 to 78 years affected by type I MSL were compared with 13 healthy control subjects. Fat mass (FM) and fat-free mass (FFM) were determined by DEXA using both standard analysis and specifically for the lipomatous region. REE was measured by indirect calorimetry. RESULTS: FM was higher in MSL subjects at proximal arm level, but significantly lower at distal leg level than in controls (left 1.63+/-0.55 vs. 2.26+/-0.49 kg, P<0.05; right 1.63+/-0.53 vs. 2.40+/-0.54 kg, P<0.01). Arm FFM was similar in the two groups, while distal leg FFM was significantly lower in MSL cases (left: 7.8+/-1.3 vs. 8.7+/-0.8 kg, P<0.05; right: 8.0+/-1.5 vs. 9.2+/-0.9 kg, P<0.05). FFM strongly correlated with REE (r:0.86;P<0.001). REE, expressed as an absolute value and adjusted for FFM (1830+/-215 vs. 1675+/-120 kcal, P<0.05) was higher in MSL patients. CONCLUSION: In conclusion, MSL patients had a marked FFM and FM atrophy in the lower segments of the legs and an altered energy expenditure (hypermetabolism).

[Multiple symmetric lipomatosis in the otolaryngology as diagnostic and therapeutic problem]. / Tlszczakowatosc uogólniona w otolaryngologii--jako problem diagnostyczny i terapeutyczny.

Multiple symmetric lipomatosis (MSL) is a systemic disease connected with a degeneration of the adipose tissue. Association of reduced glucose tolerance, hyperinsulinemia, hyperlipoproteinemia, hyperuricemia, macrocytic anemia and renal tubular acidosis, polyneuropathy have been described. Lipomatosis was initially described in 1846 by Brodie but the exact aetiopathogenesis is still unknown. Depending on the anatomical location of the lipomatosis we can divided MSL into two types. MATERIAL, METHODS AND THERAPY: We describe the findings in three patients with symmetric lipomatosis: two (n=2) with the first and one (n=1) with the second type of the disease. The patients were diagnosed and treated in the Department of the Otolaryngology during last of two years (2002 to 2004). Patients had executing following research: ultrasonography of the neck and abdominal cavity (n=2), radiological examination of the chest (n=3), computer tomography of the neck (n=1), thin-needle biopsy (n=3), histopathological examination (n=2) and laboratory investigations (n=3). Two patients received the pharmacological treatment (magnesium and the vitamin B6) and we observed marked regress of the disease. In the patient who at first did not agree for the treatment, came up to the heavy increase mass of tumors, especially on the neck. Liposuction and the pharmacological treatment were executed in this patient. He is still in the observation. RESULTS: In case of tumors of face and neck, we have to take into account degenerative processes of the adipose tissue. Our observations indicate the efficiency of the magnesium and the vitamin B6 therapy in patients with multiple symmetric lipomatosis. The obtainment in this range of reliable conclusions require of research at the greater number of patients. We want to underline that there are any research of the influence of the magnesium and the vitamin B6 on the course of this disease in the literature.

Multiple symmetric lipomatosis: Korean experience.

BACKGROUND: Multiple symmetric lipomatosis (MSL) is a rare disorder that is characterized by abnormal adipose tissue growth mainly at the neck, abdominal wall, back, shoulder girdle, and arms. A suggested mechanism for accumulation of adipose tissue is a defect in the lipolytic pathway of fat cell. OBJECTIVE: To evaluate the clinical, morphologic, and biochemical findings in Korean patients. METHOD: A total of 32 patients with MSL were evaluated retrospectively. Ten patients were seen at our hospital. The remaining 22 patients from literature were reviewed. Biochemical analyses and neurologic studies were performed. RESULTS: All cases were a sporadic form of MSL. The age of onset ranged from 26 to 70 years (mean of 49.4 years). The male-to-female ratio was 31:1. All but two patients were alcoholics with a daily intake of more than 80 g of alcohol for at least 10 years. In metabolic studies of 17 patients, a Fredrickson type IIb or IV hyperlipoproteinemia was found in three patients. High-density lipoprotein cholesterol values were higher in three patients. A glucose tolerance test was abnormal in five patients. A high prevalence of neurologic abnormalities was observed. Clinical signs of peripheral neuropathy were present in 11 of 13 patients. Central nervous system involvement was found clinically in 3 of 13 patients. CONCLUSION: The surgical removal of the fatty tissue and abstinence from alcohol are essential for relieving the patients from functional impairment. Not only metabolic studies of lipid abnormalities but also a complete neurologic examination were required in order to improve the quality of life in MSL patients.

Adipose tissue metabolism in benign symmetric lipomatosis.

Type 2 benign symmetric lipomatosis (BSL) is characterized by abnormal growth of adipose tissue in the upper back, deltoid region, upper arms, hips, and upper thigh region. Studies of lipomatous tissue in vitro have suggested that defective lipolysis may account for excess fat accumulation; however, in vivo adipose tissue metabolism has not been evaluated. We measured systemic adipose tissue lipolysis and regional adipose tissue fatty acid uptake in a patient with type 2 BSL scheduled for elective brachioplasty. We found increased, rather than decreased, rates of systemic free fatty acid release coupled with normal fatty acid oxidation. The uptake of fatty acids was 19% greater in deltoid region lipomatous tissue than in abdominal sc fat, whereas in control studies the relative uptake of fatty acids in deltoid fat averaged 29% less than that in abdominal fat. Adipocyte size was smaller than expected in lipomatous tissue. These results suggest that type 2 BSL is a hyperplastic adipose tissue abnormality that does not impair systemic lipolysis. The pathophysiology appears similar to what has been termed hyperplastic obesity. A better understanding of this condition could lead to insights into the mechanisms of hyperplastic obesity.

Defects of mitochondrial respiratory chain in multiple symmetric lipomatosis.

Using lymphocytes from nine unrelated patients with multiple symmetric lipomatosis we investigated a possible defect in the mitochondrial respiratory chain as the biochemical cause for the disease. A significant decrease in oxygen consumption of intact lymphocytes as well as a decreased activity of the individual components of the respiratory chain were detected. These findings are consistent with the recently described deletions and point mutations of mitochondrial DNA in patients suffering from this disease.

Failure to detect brown adipose tissue uncoupling protein mRNA in benign symmetric lipomatosis (Madelung's disease).

We report a case of benign symmetric lipomatosis with hypothyroidism. Functional abnormalities and distribution of lipomas in benign symmetric lipomatosis suggest that the lipomas in this disorder may represent brown adipose tissue. In conditions where mRNAs of uncoupling protein, which is believed to be unique for brown adipose tissue mitochondria, were detected in one microgram of poly (A+) rat brown fat RNA, no signal at all was found in the lipomatous tissue, suggesting that the masses of benign symmetric lipomatosis are not functional brown adipose tissue.

Mitochondrial respiratory function in multiple symmetrical lipomatosis: report of two cases.

Madelung's disease is a rare benign disorder characterized by symmetrical deposition of adipose tissue on the neck and shoulders. The cause of Madelung's disease is obscure and may be associated with mitochondrial dysfunction. In this communication, we report two cases encountered at Cardinal Tien Hospital during 1992. Besides physical check-up and laboratory examination, adipose tissue and muscle biopsies from the biceps brachii were performed. As lipid metabolism is closely related to mitochondrial respiration, biochemical studies may be of great value in clarifying the pathogenetic mechanism of Madelung's disease. We thus determined the activities of mitochondrial respiratory enzymes (NADH cytochrome c reductase, succinate cytochrome c reductase, cytochrome c oxidase) in muscle and blood cells and revealed that the electron transport functions were all elevated. Molecular analysis of mitochondrial DNA from the muscle and blood cells of both patients failed to find large-scale deletion or point mutations.

[Multiple symmetrical lipomatosis. Metabolic effects of excision of lipomatous tissue]. / Lipomatosi multipla simmetrica. Effetti metabolici dell'exeresi di tessuto lipomatoso.

Multiple Symmetric Lipomatosis (MSL) is a syndrome characterized by the occurrence of symmetric lipomas over various regions of the body. No clear etiology has been recognized while a frequent association with systemic metabolic abnormalities has been described. The metabolic situation of a subject affected by MSL was assessed before and after surgical excision of lipomas. A condition of impaired glucose tolerance (IGT) was verified both before and after surgery by the performance of oral glucose tolerance test, glucagon test, and daily glucose profile. No significant differences were observed after the ablation of lipomatous masses with regard to glucose, IRI, IRCP and NEFA behaviour. We concluded that the resection of lipomas can not modify glucose tolerance in MSL and that lipomas can be considered as tissues metabolically independent from the rest of body fat.

[Changes in the mechanism of action of insulin on fatty tissue accumulations in lipomas, Madelung's lipomatosis and liposarcoma]. / Alteraciones en el mecanismo de acción de la insulina en los acúmulos de tejido adiposo de lipomas, lipomatosis de Madelung y liposarcoma.

In this paper, the preliminary results regarding the alterations of the biological action mechanism of insulin in several types of pathological accumulations of fat, i.e. lipomas, Madelung's Lipomatosis and liposarcoma, are presented. The results indicate significant alterations both at the insulin receptor and post-receptor levels, with reduced biological activity of this hormone, which could have and inductive role in the pathogenesis of such entities.