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1.
Front Endocrinol (Lausanne) ; 13: 785819, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250856

RESUMO

Lipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy.


Assuntos
Doenças Cardiovasculares , Resistência à Insulina , Lipodistrofia , Hepatopatia Gordurosa não Alcoólica , Tecido Adiposo , Animais , Doenças Cardiovasculares/complicações , Modelos Animais de Doenças , Humanos , Resistência à Insulina/genética , Lipodistrofia/genética , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/complicações , Síndrome
2.
Int J Mol Sci ; 23(2)2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35054926

RESUMO

Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.


Assuntos
Adipócitos/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/deficiência , Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Adipogenia , Tecido Adiposo/metabolismo , Animais , Complicações do Diabetes , Modelos Animais de Doenças , Estudos de Associação Genética/métodos , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Lipodistrofia/diagnóstico , Lipodistrofia/etiologia , Lipodistrofia/metabolismo , Lipólise , Roedores , Índice de Gravidade de Doença
3.
Cell Rep ; 38(2): 110213, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35021082

RESUMO

Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.


Assuntos
Adipócitos/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Mitocôndrias/metabolismo , Tecido Adiposo/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Metabolismo Energético/fisiologia , Subunidades gama da Proteína de Ligação ao GTP/deficiência , Subunidades gama da Proteína de Ligação ao GTP/fisiologia , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Eur J Endocrinol ; 185(6): 841-854, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34643546

RESUMO

OBJECTIVE: CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3. DESIGN/METHODS: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. RESULTS: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients' fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients' fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence. CONCLUSIONS: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.


Assuntos
Caveolina 1/genética , Acalasia Esofágica/genética , Lipodistrofia Generalizada Congênita/genética , Adolescente , Cavéolas/patologia , Cavéolas/ultraestrutura , Caveolina 1/metabolismo , Caveolina 2/metabolismo , Senescência Celular , Criança , Pré-Escolar , Consanguinidade , Dislipidemias/metabolismo , Acalasia Esofágica/patologia , Feminino , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Homozigoto , Humanos , Lactente , Lipodistrofia Generalizada Congênita/metabolismo , Lipodistrofia Generalizada Congênita/patologia , Masculino , Microscopia Eletrônica de Transmissão , Estresse Oxidativo , Linhagem , Proteínas de Ligação a RNA/metabolismo
5.
Eur J Pediatr ; 179(10): 1653-1654, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32710302

RESUMO

Although the patient has provided consent for publication of this case report and accompanying images, after publication of this article it has come to the authors' attention that Fig. 1 needs changes to better protect the privacy of the patient. A modified Fig. 1 is included in this Erratum. The original Fig. 1 has been removed to protect the patient's privacy.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30420836

RESUMO

Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia-reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca2+ handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O-GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart.

7.
Diabetes ; 66(4): 1030-1040, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28052965

RESUMO

Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic Bscl2-/- (seipin knockout [SKO]) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice. [18F]Fludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the O-GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the O-GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas , Glucosídeos/farmacologia , Coração/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Lipodistrofia , Tiazolidinedionas/farmacologia , Função Ventricular/efeitos dos fármacos , Animais , Compostos Benzidrílicos/uso terapêutico , Glicemia/metabolismo , Cardiomiopatia Hipertrófica , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Fluordesoxiglucose F18 , Subunidades gama da Proteína de Ligação ao GTP , Glucosídeos/uso terapêutico , Coração/diagnóstico por imagem , Proteínas Heterotriméricas de Ligação ao GTP/genética , Hiperglicemia , Hipoglicemiantes/uso terapêutico , Lipodistrofia/genética , Imageamento por Ressonância Magnética , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Pioglitazona , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Inibidores do Transportador 2 de Sódio-Glicose , Disfunção Ventricular Esquerda
8.
EMBO J ; 35(24): 2699-2716, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27879284

RESUMO

Seipin is an endoplasmic reticulum (ER) membrane protein implicated in lipid droplet (LD) biogenesis and mutated in severe congenital lipodystrophy (BSCL2). Here, we show that seipin is stably associated with nascent ER-LD contacts in human cells, typically via one mobile focal point per LD Seipin appears critical for such contacts since ER-LD contacts were completely missing or morphologically aberrant in seipin knockout and BSCL2 patient cells. In parallel, LD mobility was increased and protein delivery from the ER to LDs to promote LD growth was decreased. Moreover, while growing LDs normally acquire lipid and protein constituents from the ER, this process was compromised in seipin-deficient cells. In the absence of seipin, the initial synthesis of neutral lipids from exogenous fatty acid was normal, but fatty acid incorporation into neutral lipids in cells with pre-existing LDs was impaired. Together, our data suggest that seipin helps to connect newly formed LDs to the ER and that by stabilizing ER-LD contacts seipin facilitates the incorporation of protein and lipid cargo into growing LDs in human cells.


Assuntos
Retículo Endoplasmático/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Gotículas Lipídicas/metabolismo , Células Cultivadas , Subunidades gama da Proteína de Ligação ao GTP/genética , Técnicas de Inativação de Genes , Humanos , Modelos Biológicos
9.
Diabetes ; 65(11): 3410-3417, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27554469

RESUMO

Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip congenital lipodystrophy (BSCL) linked to seipin deficiency. Bscl2-/- mice displayed a progressive adipose tissue loss with aging as evidenced by the altered profile of residual fat pads and the decrease in adiponectin plasma levels in 12- vs. 4-week-old animals. Aiming to prevent this impairment, we treated 6-week-old Bscl2-/- mice with an FGF21 analog (LY2405319) for a period of 28 days. FGF21 treatment increased adiponectin plasma levels and normalized insulin sensitivity in Bscl2-/- mice by improving the white adipose tissue gene expression pattern. To further decipher the molecular pathways altered by seipin deficiency in mature adipocytes, we developed a unique inducible seipin knockdown cell line (SKD). SKD showed chronic activation of the p38 MAPK pathway associated with apoptotic cell death. Interestingly, FGF21 treatment exerted an antistress effect on SKD cells, reducing p38 MAPK phosphorylation and limiting mature adipocyte loss. Our data demonstrate that FGF21 treatment improves the metabolic profile of Bscl2-/- lipodystrophic mice, partly by improving mature adipocyte maintenance through suppression of cellular stress via inhibition of p38 MAPK activity.


Assuntos
Adipócitos Brancos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Proteínas Heterotriméricas de Ligação ao GTP/deficiência , Células 3T3-L1 , Adipócitos Brancos/efeitos dos fármacos , Adiponectina/sangue , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Western Blotting , Fatores de Crescimento de Fibroblastos/química , Subunidades gama da Proteína de Ligação ao GTP , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/genética , Homeostase/fisiologia , Camundongos , Camundongos Knockout , RNA Mensageiro/genética
10.
Atherosclerosis ; 250: 52-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27179706

RESUMO

BACKGROUND AND AIMS: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species. METHODS: Here, we applied targeted enrichment and next-generation sequencing (NGS) on a panel of three FHBL genes and two abetalipoproteinemia genes (APOB, PCSK9, ANGPTL3, MTTP and SAR1B). RESULTS: In this study, we identified five likely pathogenic heterozygous rare variants. These include four novel nonsense mutations in APOB (p.Gln845*, p.Gln2571*, p.Cys2933* and p.Ser3718*) and a rare variant in PCSK9 (Minor Allele Frequency <0.1%). The affected family members tested were shown to be carriers, suggesting co-segregation with low LDL-C. CONCLUSIONS: Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.


Assuntos
Apolipoproteína B-100/genética , Hipobetalipoproteinemias/genética , Mutação , Abetalipoproteinemia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , LDL-Colesterol/genética , Códon sem Sentido , Biblioteca Gênica , Variação Genética , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipobetalipoproteinemias/diagnóstico , Pessoa de Meia-Idade , Linhagem , Fenótipo , Pró-Proteína Convertase 9/genética , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Adulto Jovem
11.
J Clin Endocrinol Metab ; 101(7): 2892-904, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27144934

RESUMO

CONTEXT: Mutations in PTRF encoding cavin-1 are responsible for congenital generalized lipodystrophy type 4 (CGL4) characterized by lipoatrophy, insulin resistance, dyslipidemia, and muscular dystrophy. Cavin-1 cooperates with caveolins to form the plasma membrane caveolae, which are involved in cellular trafficking and signalling and in lipid turnover. OBJECTIVE: We sought to identify PTRF mutations in patients with CGL and to determine their impact on insulin sensitivity, adipose differentiation, and cellular autophagy. DESIGN AND PATIENTS: We performed phenotyping studies and molecular screening of PTRF in two unrelated families with CGL. Cellular studies were conducted in cultured skin fibroblasts from the two probands and from control subjects, and in murine 3T3-F442A preadipocytes. Knockdown of cavin-1 or ATG5 was obtained by small interfering RNA-mediated silencing. RESULTS: We identified two new PTRF homozygous mutations (p.Asp59Val or p.Gln157Hisfs*52) in four patients with CGL4 presenting with generalized lipoatrophy and associated metabolic abnormalities. In probands' fibroblasts, cavin-1 expression was undetectable and caveolin-1 and -2 barely expressed. Ultrastructural analysis revealed a loss of membrane caveolae and the presence of numerous cytoplasmic autophagosomes. Patients' cells also showed increased autophagic flux and blunted insulin signaling. These results were reproduced by PTRF knockdown in control fibroblasts and in 3T3-F442A preadipocytes. Cavin-1 deficiency also impaired 3T3-F442A adipocyte differentiation. Suppression of autophagy by small interfering RNA-mediated silencing of ATG5 improved insulin sensitivity and adipocyte differentiation. CONCLUSIONS: This study showed that cavin-1 deficiency resulted in maladaptative autophagy that contributed to insulin resistance and altered adipocyte differentiation. These new pathophysiological mechanisms could open new therapeutic perspectives for adipose tissue diseases including CGL4.


Assuntos
Tecido Adiposo/fisiologia , Autofagia/fisiologia , Caveolina 1/genética , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/fisiopatologia , Adipogenia/genética , Adolescente , Adulto , Animais , Autofagia/genética , Caveolina 1/deficiência , Diferenciação Celular/genética , Células Cultivadas , Criança , Pré-Escolar , Consanguinidade , Feminino , Fibroblastos/fisiologia , Humanos , Resistência à Insulina/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
12.
Eur J Pediatr ; 174(7): 975-80, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25994244

RESUMO

UNLABELLED: Berardinelli-Seip congenital lipodystrophy (BSCL) is an uncommon autosomal recessive disorder. Patients with BSCL present with a distinct phenotype since subcutaneous fat is largely lacking and musculature has become more prominent. During childhood, diabetes and acanthosis nigricans evolve and female patients may develop hirsutism. Different genes encoding this entity have been described. Achalasia is a rare esophageal motility disorder, characterized by its distinct motility pattern with absent or incomplete lower esophageal sphincter (LES) relaxations. The exact cause of achalasia is yet unknown. Here, we describe a patient with achalasia in the context of BSCL, which might be linked by a shared pathophysiologic background, as evaluated in this case report. CONCLUSION: In a BSCL patient presenting with gastrointestinal symptoms, a motility disorder of the gastrointestinal tract should be considered. WHAT IS KNOWN: • Berardinelli-Seip congenital lipodystrophy (BSCL) and achalasia are both disorders characterized by low prevalence. What is New: • Co-existence of both diseases is described in this report. Linkage by a potential common pathophysiologic background is discussed in this paper.


Assuntos
Acalasia Esofágica/complicações , Lipodistrofia Generalizada Congênita/complicações , Adolescente , Códon sem Sentido , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/genética , Feminino , Humanos , Lipodistrofia Generalizada Congênita/genética , Proteínas de Ligação a RNA/genética
13.
Curr Atheroscler Rep ; 16(9): 437, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25047893

RESUMO

Lipodystrophies are rare acquired and genetic disorders characterized by the selective loss of adipose tissue. One key metabolic feature of patients with congenital inherited lipodystrophy is hypertriglyceridemia. The precise mechanisms by which the lack of adipose tissue causes dyslipidemia remain largely unknown. In recent years, new insights have arisen from data obtained in vitro in adipocytes, yeast, drosophila, and very recently in several genetically modified mouse models of generalized lipodystrophy. A common metabolic pathway involving accelerated lipolysis and defective energy storage seems to contribute to the dyslipidemia associated with congenital generalized lipodystrophy syndromes, although the pathophysiological changes may vary with the nature of the mutation involved. Therapeutic management of dyslipidemia in patients with lipodystrophy is primarily based on specific approaches using recombinant leptin therapy. Preclinical studies suggest a potential efficacy of thiazolidinediones that remains to be assessed in dedicated clinical trials.


Assuntos
Dislipidemias/congênito , Predisposição Genética para Doença , Hipertrigliceridemia/congênito , Lipodistrofia/congênito , Lipodistrofia/diagnóstico , Tecido Adiposo/metabolismo , Animais , Dislipidemias/complicações , Dislipidemias/diagnóstico , Humanos , Hipertrigliceridemia/complicações , Lipodistrofia/metabolismo , Mutação/genética
14.
Biochimie ; 96: 166-72, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23831461

RESUMO

Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterized by near absence of adipose tissue and severe insulin resistance. Since the discovery of the gene in 2001, several cellular studies intended to unravel the biological function of seipin and revealed that seipin-deficiency alters adipocyte differentiation and lipid droplet morphology. However, the exact function of the protein remains unclear and the pathophysiology of BSCL in patients carrying BSCL2/seipin mutations is poorly understood. A major breakthrough in the field of seipin came recently, with the demonstration by three independent groups that Bscl2-deficient mice (Bscl2(-/-)) developed severe lipodystrophy with only residual white and brown fat pads, validating a critical role for seipin in adipose tissue homeostasis. Using in vivo, ex vivo and in vitro methods, these studies demonstrate that seipin plays a key role in adipogenesis, lipid droplet homeostasis and cellular triglyceride lipolysis. In addition to adipose tissue impairment, Bscl2(-/-) mice are diabetic and display severe hepatic steatosis. Treatment with thiazolidinediones (TZD) in Bscl2(-/-) mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype. Except an unexpected hypotriglyceridemia, Bscl2(-/-) mice phenotype represents an almost perfect picture of the human disease. This review analyses how these studies using Bscl2(-/-) mice brought new insights into seipin function and the mechanisms involved in the pathophysiology of BSCL. We also analyse some of the human data in the light of the mouse phenotyping and discuss the validity of Bscl2(-/-) mice model to test pharmaceutical approaches for treating BSCL and its associated metabolic complications.


Assuntos
Tecido Adiposo/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/genética , Lipodistrofia Generalizada Congênita/metabolismo , Adipócitos/fisiologia , Tecido Adiposo/patologia , Animais , Diferenciação Celular , Subunidades gama da Proteína de Ligação ao GTP , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Homeostase , Humanos , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Fenótipo
15.
Int J Biochem Cell Biol ; 43(6): 862-76, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21392585

RESUMO

Adipose tissue is now recognized for its major role in the control of energy metabolism and insulin sensitivity. We review here the human lipodystrophies, that are rare conditions in which total or partial fat loss is associated with severe lipid and glucose abnormalities leading to diabetes with early cardiovascular and hepatic complications. The genetic origin of a number of human lipodystrophies has been recently unraveled, emphasizing the importance of proteins of previously unknown or unexpected functions. Major adipose functions were also illuminated when studying acquired forms of lipodystrophies linked to human immunodeficiency virus-antiretrovirals. Overall, most of the proteins or functions affected by mutations or antiretrovirals result in altered adipogenesis and insulin sensitivity, triglyceride storage and formation of the unique adipocyte lipid droplet, oxidative stress and fat remodeling. Some mutations or antiretrovirals could affect directly (peroxisome proliferator-activated receptor-γ, Akt2) or indirectly (lamin A/C, human immunodeficiency virus-protease inhibitors) adipogenesis, through the transcription factors peroxisome proliferator-activated receptor gamma-γ or sterol regulatory element binding protein 1c, and insulin signaling through Akt2 that controls adipocyte lipolysis. A number of proteins mutated in genetic lipodystrophies are involved in the control of triglyceride synthesis towards the lipid droplet (1-acylglycerol-3-phosphate-O-acyltransferase 2), or its functions (seipin, cell death-inducing DFF45-like effector C, perilipin, caveolin-1, cavin-1). Decreased triglyceride storage leads to adipocyte lipotoxicity, mitochondrial dysfunction and increased oxidative stress, which could also be induced by some thymidine analogue antiretrovirals. This results in production of inflammatory mediators and deregulated release of free fatty acids. Thus, the impaired ability of adipose tissue to safely store triglycerides inside the lipid droplet results in impaired insulin sensitivity and adverted liver, muscles and heart functions leading to early complications.


Assuntos
Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/metabolismo , Lipodistrofia/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Humanos , Inflamação , Resistência à Insulina , Metabolismo dos Lipídeos , Lipodistrofia/induzido quimicamente , Lipodistrofia/genética , Lipodistrofia/patologia , Estresse Oxidativo , PPAR gama/genética , PPAR gama/metabolismo , Triglicerídeos/metabolismo
16.
N Engl J Med ; 364(8): 740-8, 2011 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-21345103

RESUMO

Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.


Assuntos
Diabetes Mellitus Tipo 1/genética , Mutação da Fase de Leitura , Hipertrigliceridemia/genética , Lipodistrofia Parcial Familiar/genética , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Acantose Nigricans/genética , Adulto , Proteínas de Transporte , Feminino , Genes Dominantes , Heterozigoto , Humanos , Resistência à Insulina/genética , Pessoa de Meia-Idade , Linhagem , Perilipina-1
17.
Endocr Dev ; 19: 1-20, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20551664

RESUMO

Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARgamma. Importantly, lamin A/Cmutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their etiology is generally unknown, they could be associated with signs of autoimmunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first-generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardiovascular and hepatic complications.


Assuntos
Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Lipodistrofia , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Humanos , Lamina Tipo A/genética , Lipodistrofia/genética , Lipodistrofia/patologia , Lipodistrofia/fisiopatologia , PPAR gama/genética
18.
J Clin Endocrinol Metab ; 95(3): 1463-8, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20097706

RESUMO

CONTEXT: Human lipodystrophies are characterized by loss of adipose tissue, insulin resistance, and metabolic complications. The mechanisms linking fat loss to severe insulin resistance remain unclear. Adipokines may have important roles as intermediary players in metabolism. OBJECTIVE: We sought to determine the plasma concentrations of leptin and adiponectin in patients with Berardinelli-Seip congenital lipodystrophy (BSCL) harboring mutations in the genes encoding either 1-acylglycerol-3-phosphate-O-acyltransferase-2 (AGPAT2) or BSCL2/seipin, in comparison with patients with other forms of inherited or acquired lipodystrophies or insulin receptor alterations. DESIGN: Leptin and total and high-molecular-weight adiponectin were measured in plasma of 16 BSCL1/AGPAT2 and 19 BSCL2/seipin patients and compared with heterozygous (n = 22) or nonmutated relatives (controls, n = 30); patients with Dunnigan-type partial lipodystrophy due to lamin A/C mutations (n = 23), HIV-related lipodystrophy (n = 124), and insulin receptor dysfunctions caused by mutations or autoantibodies (n = 17). RESULTS: Leptin was dramatically decreased in BSCL patients as compared with other subgroups. Adiponectin was decreased in BSCL as compared with controls and patients with altered insulin receptor but was discrepant between the two BSCL subgroups. Whereas total and high-molecular-weight adiponectin levels were almost undetectable in BSCL1/AGPAT2 patients, higher levels were detected in BSCL2/seipin patients, comparable with those of patients with partial lipodystrophy. Adiponectin greater than 1.6 mg/liter had a 100% negative predictive value for AGPAT2 mutations in inherited lipodystrophies. CONCLUSIONS: The presence of circulating adiponectin in BSCL2/seipin patients with near absence of adipose tissue outlines the complexity of adiponectin biology. Use of circulating adiponectin might be helpful to guide the genetic investigations in BSCL.


Assuntos
1-Acilglicerol-3-Fosfato O-Aciltransferase/deficiência , Adiponectina/sangue , Subunidades gama da Proteína de Ligação ao GTP/deficiência , Lipodistrofia Generalizada Congênita/sangue , Adolescente , Análise de Variância , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Leptina/sangue , Lipodistrofia Generalizada Congênita/genética , Masculino , Estatísticas não Paramétricas
19.
Biochimie ; 91(6): 796-803, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19278620

RESUMO

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue and severe insulin resistance. In most cases, BSCL is due to loss-of-function mutations in the genes encoding either seipin of unknown function or 1-acyl-glycerol-3-phosphate O-acyltransferase 2 (AGPAT2) which catalyses the formation of phosphatidic acid from lysophosphatidic acid. We studied the lipid profile of lymphoblastoid cell-lines from 20 BSCL patients with null mutations in the genes encoding either seipin (n=12) or AGPAT2 (n=8) in comparison to nine control cell-lines. In seipin deficient cells, we observed alterations in the pattern of lipid droplets which were decreased in size and increased in number as compared to control cells. We also observed alterations in the triglycerides content as well as in the fatty acid composition from triglycerides and phosphatidylethanolamine, with an increased proportion of saturated fatty acids at the expense of the corresponding monounsaturated fatty acids, reflecting a defect in Delta9-desaturase activity. In AGPAT2 deficient cells, no specific alterations in lipid droplet pattern nor in fatty acid composition was observed but the cellular level of lysophosphatidic acid was increased as compared to that of control and seipin deficient cells. These results indicate that seipin like AGPAT2 is involved in lipid metabolism but exerts a different function. Seipin intervenes at a proximal step in triglycerides and phospholipids biosynthesis being involved in the pathway that links fatty acid Delta9 desaturation to lipid droplet formation. These findings provide new insights into how seipin deficiency causes severe lipodystrophy.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/deficiência , Metabolismo dos Lipídeos , Lipodistrofia Generalizada Congênita/patologia , Mutação , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo , Adolescente , Adulto , Linhagem Celular Transformada , Criança , Pré-Escolar , Ácidos Graxos Insaturados/química , Feminino , Subunidades gama da Proteína de Ligação ao GTP/genética , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Humanos , Lactente , Lipídeos/análise , Lipídeos/química , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Linfócitos/ultraestrutura , Masculino , Microscopia Confocal , Microscopia Eletrônica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismo , Adulto Jovem
20.
EMBO Mol Med ; 1(5): 280-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20049731

RESUMO

Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.


Assuntos
Códon sem Sentido , Diabetes Mellitus/genética , Resistência à Insulina , Lipodistrofia/genética , Proteínas/genética , Células 3T3 , Animais , Proteínas Reguladoras de Apoptose , Sequência de Bases , Diabetes Mellitus/metabolismo , Feminino , Humanos , Lipodistrofia/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Transporte Proteico , Proteínas/metabolismo , Adulto Jovem
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