Echocardiographic Alterations of Cardiac Geometry and Function in Patients with Familial Partial Lipodystrophy. / Alterações Ecocardiográficas da Geometria e da Função Cardíaca em Pacientes com Lipodistrofia Familiar Parcial.

BACKGROUND: Cardiomyopathy associated with partial lipodystrophy (PL) has not been well described yet. OBJECTIVE: To characterize cardiac morphology and function in PL. METHODS: Patients with familial PL and controls were prospectively assessed by transthoracic echocardiography and with speckle-tracking echocardiography (global longitudinal strain, GLS). The relationship between echocardiographic variables and PL diagnosis was tested with regression models, considering the effect of systolic blood pressure (SBP). Significance level of 5% was adopted. RESULTS: Twenty-nine patients with PL were compared to 17 controls. They did not differ in age (p=0.94), gender or body mass index (p= 0.05). Patients with PL had statistically higher SBP (p=0.02) than controls. Also, PL patients had higher left atrial dimension (37.3 ± 4.4 vs. 32.1 ± 4.3 mm, p= 0.001) and left atrial (30.2 ± 7.2 vs. 24.9 ± 9.0 mL/m2,p=0.02), left ventricular (LV) mass (79.3 ± 17.4 vs. 67.1 ± 19.4, p=0.02), and reduced diastolic LV parameters (E' lateral, p= 0.001) (E' septal, p= 0.001), (E/E' ratio, p= 0.02). LV ejection fraction (64.7 ± 4.6 vs. 62.2 ± 4.4 %, p= 0.08) and GLS were not statistically different between groups (-17.1 ± 2.7 vs. -18.0 ± 2.0 %, p= 0.25). There was a positive relationship of left atrium (ß 5.6, p<0.001), posterior wall thickness, (ß 1.3, p=0.011), E' lateral (ß -3.5, p=0.002) and E' septal (ß -3.2, p<0.001) with PL diagnosis, even after adjusted for SBP. CONCLUSION: LP patients have LV hypertrophy, left atrial enlargement, and LV diastolic dysfunction although preserved LVEF and GLS. Echocardiographic parameters are related to PL diagnosis independent of SBP.

FUNDAMENTO: A cardiomiopatia associada à lipodistrofia parcial (LP) ainda não foi bem descrita. OBJETIVO: Caracterizar a morfologia e a função cardíaca na LP. MÉTODOS: Pacientes com LP e controles foram avaliados prospectivamente por ecocardiografia transtorácica e ecocardiografia por speckle-tracking (Strain Longitudinal Global, SLG). A relação entre as variáveis ecocardiográficas e o diagnóstico de LP foi testada com modelos de regressão, considerando o efeito da pressão arterial sistólica (PAS). Adotou-se um nível de significância de 5%. RESULTADOS: Vinte e nove pacientes com LP foram comparados com 17 controles. Eles não se diferiram quanto à idade (p=0,94), sexo ou índice de massa corporal (p= 0,05). Os pacientes com LP apresentaram PAS estatisticamente mais alta (p=0,02) em comparação aos controles. Ainda, os pacientes com LP apresentaram maior dimensão do átrio (37,3 ± 4,4 vs. 32,1 ± 4,3 mm, p= 0,001) e maior volume atrial (30,2 ± 7,2 vs. 24,9 ± 9,0 mL/m2, p=0,02), massa do Ventrículo Esquerdo (VE) (79,3 ± 17,4 vs. 67,1 ± 19,4; p=0,02), e parâmetros sistólicos reduzidos do VE (E' lateral, p= 0,001) (E' septal, p= 0,001), (razão E/E', p= 0,02). A fração de ejeção do VE (64,7 ± 4,6 vs. 62,2 ± 4,4 %, p = 0,08) e o SLG não foram estatisticamente diferentes entre os grupos (-17,1±2,7 vs-18.0 ± 2,0%, p= 0,25). Observou-se uma reação positiva do átrio esquerdo (ß 5,6; p<0,001), espessura da parede posterior (ß 1,3; p=0,011), E' lateral (ß -3,5; p=0,002) e E' septal (ß -3,2; p<0,001) com o diagnóstico de LP, mesmo após o ajuste para a PAS. CONCLUSÃO: Os pacientes com LP apresentam hipertrofia do VE, aumento do átrio esquerdo, e disfunção diastólica do VE apesar de fração de ejeção do VE e SLG preservados. Os parâmetros ecocardiográficos estão relacionados com o diagnóstico de LP, independentemente da PAS.

Impaired Muscle Mitochondrial Function in Familial Partial Lipodystrophy.

CONTEXT: Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. OBJECTIVE: To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. METHODS: Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. RESULTS: Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. CONCLUSION: Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2.

Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.

Cardiac Alterations in Patients with Familial Lipodystrophy.

Familial lipodystrophy is a rare genetic condition in which individuals have, besides metabolic changes and body fat deposits, a type of cardiomyopathy that has not been well studied. Many of the patients develop cardiovascular changes, the most commonly reported in the literature being the expression of a type of hypertrophic cardiomyopathy. This article, presented as a bibliographic review, reviews the clinical and cardiovascular imaging aspects in this scenario of cardiomyopathy in a rare metabolic disease, based on the latest scientific evidence published in the area. Despite the frequent association of congenital lipodystrophy and ventricular hypertrophy described in the literature, the pathophysiological mechanisms of this cardiomyopathy have not yet been definitively elucidated, and new information on cardiac morphological aspects is emerging in the aegis of recent and advanced imaging methods, such as cardiac magnetic resonance.

Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety.

CONTEXT: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. OBJECTIVE: To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. METHODS: We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. RESULTS: The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. CONCLUSIONS: The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.

Cardiac Alterations in Patients with Familial Lipodystrophy / Alterações Cardiovasculares em Pacientes Portadores de Lipodistrofia Familiar

Abstract Familial lipodystrophy is a rare genetic condition in which individuals have, besides metabolic changes and body fat deposits, a type of cardiomyopathy that has not been well studied. Many of the patients develop cardiovascular changes, the most commonly reported in the literature being the expression of a type of hypertrophic cardiomyopathy. This article, presented as a bibliographic review, reviews the clinical and cardiovascular imaging aspects in this scenario of cardiomyopathy in a rare metabolic disease, based on the latest scientific evidence published in the area. Despite the frequent association of congenital lipodystrophy and ventricular hypertrophy described in the literature, the pathophysiological mechanisms of this cardiomyopathy have not yet been definitively elucidated, and new information on cardiac morphological aspects is emerging in the aegis of recent and advanced imaging methods, such as cardiac magnetic resonance.

Resumo A lipodistrofia familiar é uma condição genética rara na qual indivíduos apresentam, além das alterações metabólicas e de depósitos de gordura físicos, um tipo de cardiomiopatia pouco estudada. Muitos dos pacientes desenvolvem alterações cardiovasculares, sendo a mais comumente reportada em literatura, a expressão de um tipo de cardiomiopatia hipertrófica. Este artigo, apresentado como uma revisão bibliográfica, revisa os aspectos clínicos e de imagem cardiovascular neste cenário de cardiomiopatia em doença metabólica rara, com base nas últimas evidências científicas publicadas na área. Apesar da frequente associação de lipodistrofia congênita e hipertrofia ventricular descrita em literatura, os mecanismos fisiopatológicos desta cardiomiopatia ainda não estão definitivamente elucidados, e novas informações do aspecto morfológico cardíaco surgem à égide de recentes e avançados métodos de imagem como a ressonância cardíaca magnética.

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning.

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

Bone mineral density in familial partial lipodystrophy.

OBJECTIVE: Type 1 and type 2 familial partial lipodystrophies (FPLD) are characterized by the loss or increase in subcutaneous fat in certain body regions, as well as metabolic disorders. Higher muscle volume and mass have also been described. However, so far, possible bone involvement has not been studied. The aim of this study was to evaluate bone mineral density (BMD) in patients with type 1 and type 2 FPLD. METHODS: A total of 143 women were selected and distributed into three groups (17 women with FPLD2, 82 women with FPLD1 and 44 nonlipodystrophic obese female controls). A thorough history and physical examination were carried out on all subjects, as well as the measurement of anthropometric features. BMD along with fat and fat-free mass (FFM) were determined by DXA (dual-energy X-ray absorptiometry). Statistical analyses, primarily using the χ2 , ANOVA and ANCOVA tests, were performed, using age, height, fat and FFM as covariables. RESULTS: After eliminating the possible influences of age, height, fat and FFM, we observed that there were no significant differences in total BMD between patients with FPLD and the control group, showing total BMD values of 1.092 ± 0.037 g/cm2 in the FPLD2 group, 1.158 ± 0.013 g/cm2 in the FPLD1 group and 1.173 ± 0.018 g/cm2 in the control group (P = .194). Similarly, no significant differences were found in segmental BMD. CONCLUSIONS: Unlike in other types of laminopathy in which bone is affected, in the case of FPLD, there are no differences in BMD compared to nonlipodystrophic subjects.

A lipodystrophy-causing lamin A mutant alters conformation and epigenetic regulation of the anti-adipogenic MIR335 locus.

Mutations in the Lamin A/C (LMNA) gene-encoding nuclear LMNA cause laminopathies, which include partial lipodystrophies associated with metabolic syndromes. The lipodystrophy-associated LMNA p.R482W mutation is known to impair adipogenic differentiation, but the mechanisms involved are unclear. We show in this study that the lamin A p.R482W hot spot mutation prevents adipogenic gene expression by epigenetically deregulating long-range enhancers of the anti-adipogenic MIR335 microRNA gene in human adipocyte progenitor cells. The R482W mutation results in a loss of function of differentiation-dependent lamin A binding to the MIR335 locus. This impairs H3K27 methylation and instead favors H3K27 acetylation on MIR335 enhancers. The lamin A mutation further promotes spatial clustering of MIR335 enhancer and promoter elements along with overexpression of the MIR355 gene after adipogenic induction. Our results link a laminopathy-causing lamin A mutation to an unsuspected deregulation of chromatin states and spatial conformation of an miRNA locus critical for adipose progenitor cell fate.

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.

CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

LMNA gene mutation as a model of cardiometabolic dysfunction: from genetic analysis to treatment response.

AIM: This report highlights the metabolic, endocrine and cardiovascular comorbidities in a case of familial partial lipodystrophy (FPLD), and also evaluates the efficacy and safety of metformin therapy. METHODS: Mutational analysis was carried out of the LMNA gene in a teenage girl with an FPLD phenotype. Insulin resistance, sex hormones and metabolic parameters were also evaluated, and echocardiography, electrocardiography and 24-h blood pressure monitoring were also done. RESULTS: The patient showed atypical fat distribution, insulin resistance and hypertrophic cardiomyopathy. Physical examination revealed muscle hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, yet excess fat deposits in the face, neck and dorsal cervical region. LMNA sequencing revealed a heterozygous missense mutation (c.1543A>G) in exon 9, leading to substitution of lysine by glutamic acid at position 515 (K515E). Moderate hypertension and secondary polycystic ovary syndrome were also assessed. Treatment with metformin resulted in progressive improvement of metabolic status, while blood pressure values normalized with atenolol therapy. CONCLUSIONS: Very rapid and good results with no side-effects were achieved with metformin therapy for FPLD. The association of an unusual mutation in the LMNA gene was also described.

Peroxisome proliferator-activated receptor-γ mutations responsible for lipodystrophy with severe hypertension activate the cellular renin-angiotensin system.

OBJECTIVE: Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular renin-angiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients' cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ. Approach and Results- We identified 2 novel PPARG mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients' fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II-mediated mitogen-activated protein kinase activity increased in patients' fibroblasts, consistent with RAS constitutive activation. Patients' cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes. CONCLUSIONS: Two novel FPLD3-linked PPARG mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension.

Lipodystrophies: disorders of adipose tissue biology.

The adipocytes synthesize and store triglycerides as lipid droplets surrounded by various proteins and phospholipids at its surface. Recently, the molecular basis of some of the genetic syndromes of lipodystrophies has been elucidated and some of these genetic loci have been found to contribute to lipid droplet formation in adipocytes. The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). So far, three CGL loci: 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1) and four FPL loci: lamin A/C (LMNA), peroxisome proliferator-activated receptor gamma (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24), have been identified. AGPAT2 plays a critical role in the synthesis of glycerophospholipids and triglycerides required for lipid droplet formation. Another protein, seipin (encoded by BSCL2 gene), has been found to induce lipid droplet fusion. CAV1 is an integral component of caveolae and might contribute towards lipid droplet formation. PPARgamma and AKT2 play important role in adipogenesis and lipid synthesis. In this review, we discuss and speculate about the contribution of various lipodystrophy genes and their products in the lipid droplet formation.

Resistance to high-fat diet-induced obesity but exacerbated insulin resistance in mice overexpressing preadipocyte factor-1 (Pref-1): a new model of partial lipodystrophy.

OBJECTIVE: White adipose tissue is a critical regulator of whole-body glucose metabolism. Preadipocyte factor-1 (Pref-1) is a secreted protein that inhibits adipocyte differentiation, both in vitro and in vivo. In this study, we have investigated the effects of Pref-1 overexpression on whole-body glucose homeostasis and its contribution to the development of insulin resistance. RESEARCH DESIGN AND METHODS: To gain insight into the role of Pref-1 on the onset of insulin resistance and type 2 diabetes, we measured body composition and whole-body insulin-stimulated glucose metabolism during a hyperinsulinemic-euglycemic clamp in Pref-1 transgenic and wild-type control mice fed a high-fat diet. RESULTS: Mice overexpressing Pref-1 were resistant to high-fat diet-induced obesity, as reflected by a marked reduction in adipose tissue mass. However, Pref-1-overexpressing mice were severely insulin resistant, mainly because of a reduction in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. The aggravated insulin resistance was associated with impaired insulin signaling and increased diacylglycerol content in skeletal muscle. CONCLUSIONS: Mice overexpressing Pref-1 are insulin resistant despite being protected from diet-induced obesity and may provide a new rodent model for the study of lipodystrophic disorders.

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence.

Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications.

[Structural organization and function of nuclear envelope].

Higher-eukaryotic membrane compartmentalization of different processes provides the control of functional activity in cells. The nuclear envelope that consists of outer and inner nuclear membranes, lamina, and nuclear pore complexes is one of the most significant and complex cell compartments. It separates DNA replication and transcription in the nucleus from RNA translation in the cytoplasm and regulates the nuclear-cytoplasmic transport of different molecules. This review describes and discusses the structural organization and biochemical composition of different nuclear envelope components (except nuclear pore complexes, which were discussed in our previous review) as well as its dynamics during mitosis in vitro and in vivo. Special attention is given to the role of lamina in a group of human genetic diseases, collectively referred to as laminopathies.

Muscle and nerve pathology in Dunnigan familial partial lipodystrophy.

OBJECTIVE: To characterize muscle and nerve pathology in Dunnigan familial partial lipodystrophy (FPLD). METHODS: We used conventional histology, immunohistochemistry, messenger RNA (mRNA) expression, gene sequencing, and clinical studies of 13 patients with neuromuscular involvement. RESULTS: The clinical findings consisted of muscle hypertrophy (12/13), severe myalgias (9/13), and multiple nerve entrapment syndromes (8/13). Skeletal muscle histology demonstrated marked Type 1 and 2 muscle fiber hypertrophy and nonspecific myopathic changes, whereas numerous paranodal myelin swellings (tomacula) were found in sural nerve biopsies. We found that myostatin mRNA expression was reduced in patients with FPLD vs controls. We sequenced the myostatin gene in our subjects, but found no mutations. We then investigated whether or not SMAD, the intracellular mediator of myostatin signaling, might be impaired in patients with FPLD. We found that in FPLD muscle, a large number of SMAD molecules adhered to the nuclear membrane and were not found within the nucleus, compared with normal muscle or muscle from a patient with a non-FPLD lamin A/C disease. CONCLUSION: The myopathy and neuropathy associated with Dunnigan familial partial lipodystrophy are distinct from other lamin A/C disorders. We hypothesize that the lipodystrophy-associated mutation interferes with SMAD signaling, linking this type of lipodystrophy to the phenotypically similar myostatin deficiency.

[Primary lipodystrophies]. / Les lipodystrophies primitives.

Primary lipodystrophies represent a heterogeneous group of very rare diseases with a prevalence of less than 1 case for 100.000, inherited or acquired, caracterized by a loss of body fat either generalized or localized (lipoatrophy). In some forms, lipoatrophy is associated with a selective hypertrophy of other fat depots. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes and hypertriglyceridemia leading to a risk of acute pancreatitis. Chronic complications are those resulting from diabetes involving the retina, kidney and nerves, cardiovascular complications and steatotic liver lesions that could result in cirrhosis. Genetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyl-transferase involved in triglyceride synthesis. Acquired generalized lipodystrophy (Lawrence syndrome) is of unknown origin but is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C belonging to the nuclear lamina, or in PPARG encoding the adipogenic transcription factor PPARgamma. Some less typical lipodystrophies, associated with signs of premature aging, have been linked to mutations in LMNA or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome) is characterized by cephalothoracic fat loss. Its aetiology is unknown but mutations in LMNB2, encoding the lamina protein lamin B2, could represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes. The genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis could be proposed. Treatment of diabetes, dyslipidemia and complications involves the classical intervention strategies. Insulino-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels reported good results with respect to the metabolic and liver alterations. The prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.