RESUMEN
Lipodystrophies have been recognized since at least the nineteenth century and, despite their rarity, tended to attract considerable medical attention because of the severity and somewhat paradoxical nature of the associated metabolic disease that so closely mimics that of obesity. Within the last 20 yr most of the monogenic subtypes have been characterized, facilitating family genetic screening and earlier disease detection as well as providing important insights into adipocyte biology and the systemic consequences of impaired adipocyte function. Even more recently, compelling genetic studies have suggested that subtle partial lipodystrophy is likely to be a major factor in prevalent insulin-resistant type 2 diabetes mellitus (T2DM), justifying the longstanding interest in these disorders. This progress has also underpinned novel approaches to treatment that, in at least some patients, can be of considerable therapeutic benefit.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Dislipidemias/metabolismo , Lipodistrofia/metabolismo , Obesidad/metabolismo , Animales , Humanos , Resistencia a la Insulina/fisiologíaRESUMEN
Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
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Peso Corporal/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Factor 15 de Diferenciación de Crecimiento/metabolismo , Metformina/farmacología , Administración Oral , Adulto , Anciano , Animales , Glucemia/análisis , Glucemia/metabolismo , Dieta Alta en Grasa , Método Doble Ciego , Ingestión de Energía/efectos de los fármacos , Enterocitos/citología , Enterocitos/efectos de los fármacos , Femenino , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/antagonistas & inhibidores , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/deficiencia , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/deficiencia , Factor 15 de Diferenciación de Crecimiento/genética , Homeostasis/efectos de los fármacos , Humanos , Intestinos/citología , Intestinos/efectos de los fármacos , Masculino , Metformina/administración & dosificación , Ratones , Ratones Obesos , Persona de Mediana Edad , Pérdida de Peso/efectos de los fármacosRESUMEN
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
It has been shown using proton magnetic resonance spectroscopy (1H MRS) that, in a group of females, whole-body insulin resistance was more closely related to accumulation of saturated intramyocellular lipid (IMCL) than to IMCL concentration alone. This has not been investigated in males. We investigated whether age- and body mass index-matched healthy males differ from the previously reported females in IMCL composition (measured as CH2:CH3) and IMCL concentration (measured as CH3), and in their associations with insulin resistance. We ask whether saturated IMCL accumulation is more strongly associated with insulin resistance than other ectopic and adipose tissue lipid pools and remains a significant predictor when these other pools are taken into account. In this group of males, who had similar overall insulin sensitivity to the females, IMCL was similar between sexes. The males demonstrated similar and even stronger associations of IMCL with insulin resistance, supporting the idea that a marker reflecting the accumulation of saturated IMCL is more strongly associated with whole-body insulin resistance than IMCL concentration alone. However, this marker ceased to be a significant predictor of whole-body insulin resistance after consideration of other lipid pools, which implies that this measure carries no more information in practice than the other predictors we found, such as intrahepatic lipid and visceral adipose tissue. As the marker of saturated IMCL accumulation appears to be related to these two predictors and has a much smaller dynamic range, this finding does not rule out a role for it in the pathogenesis of insulin resistance.
Asunto(s)
Resistencia a la Insulina , Metabolismo de los Lípidos , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Ácidos Grasos/metabolismo , Tejido Adiposo/metabolismo , Espectroscopía de Resonancia MagnéticaRESUMEN
CONTEXT: Familial partial lipodystrophy type 2 (FPLD2) results from autosomal dominant mutations in the LMNA gene, causing lack of subcutaneous fat deposition and excess ectopic fat accumulation, leading to metabolic complications and reduced life expectancy. The rarity of the condition means that the natural history of FPLD2 throughout childhood is not well understood. We report outcomes in a cohort of 12 (5M) children with a genetic diagnosis of FPLD2, under the care of the UK National Severe Insulin Resistance Service (NSIRS) which offers multidisciplinary input including dietetic, in addition to screening for comorbidities. OBJECTIVE: To describe the natural history of clinical, biochemical and radiological outcomes of children with FPLD2. DESIGN: A retrospective case note review of children with a genetic diagnosis of FPLD2 who had been seen in the paediatric NSIRS was performed. PATIENTS: Twelve (5M) individuals diagnosed with FPLD2 via genetic testing before age 18 and who attended the NSIRS clinic were included. MEASUREMENTS: Relationships between metabolic variables (HbA1c, triglycerides, fasting insulin, fasting glucose and alanine transaminase [ALT]) across time, from first visit to most recent, were explored using a multivariate model, adjusted for age and gender. The age of development of comorbidities was recorded. RESULTS: Three patients (all female) developed diabetes between 12 and 19 years and were treated with Metformin. One female has hypertrophic cardiomyopathy and four (1M) patients developed mild hepatic steatosis at a median [range] age of 14(12-15) years. Three (1M) patients reported mental health problems related to lipodystrophy. There was no relationship between biochemical results and age. Patients with diabetes had higher concentrations of ALT than patients who did not have diabetes, adjusted for age, gender and body mass index standard deviation scores. CONCLUSIONS: Despite dietetic input, some patients, more commonly females, developed comorbidities after the age of 10. The absence of relationships between biochemical results and age likely reflects a small cohort size. We propose that, while clinical review and dietetic support are beneficial for children with FPLD2, formal screening for comorbidities before age 10 may not be of benefit. Clinical input from an multidisciplinary team including dietician, psychologist and clinician should be offered after diagnosis.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Lipodistrofia Parcial Familiar , Niño , Humanos , Femenino , Adolescente , Lipodistrofia Parcial Familiar/genética , Lipodistrofia Parcial Familiar/metabolismo , Estudios Retrospectivos , Lamina Tipo A/genética , Grasa Subcutánea/metabolismoRESUMEN
PURPOSE OF REVIEW: Lipodystrophy syndromes have an estimated prevalence of 1.3-4.7 cases per million and as with other rare diseases conducting research can be challenging. The present review highlights recently published work that has provided insights into the field of non-HIV--associated lipodystrophy syndromes. RECENT FINDINGS: Lipodystrophies are a heterogenous group of disorders, as such research is often focused on specific subtypes of the condition. The identification of children carrying LMNA mutations has provided insights into the natural history of FPLD2, specifically that the adipose tissue phenotype predates the onset of puberty. Recent reports of PLIN1 heterozygous null variant carriers and the apparent absence of a lipodystrophy phenotype challenges our understanding of the molecular biology of perilipin 1 and its role in the pathogenesis of FPLD4. With a focus on therapeutics, studies delineating the differential responsiveness of PPARγ mutants to endogenous and synthetic ligands has illustrated the potential for pharmacogenetics to inform therapeutic decisions in lipodystrophy related to PPARG mutations, whereas robust human studies have provided insight into the food independent metabolic effects of leptin in lipodystrophy. Finally, rare syndromes of lipodystrophy continue to serve as an exemplar for the contribution of genetically determined adipose tissue expandability to metabolic disease in the general population. SUMMARY: Lipodystrophy research continues to illuminate our understanding of this rare disease and the possibility that lipodystrophy syndromes and the metabolic syndrome may have shared pathophysiology.
Asunto(s)
Lipodistrofia , Animales , Humanos , Lipodistrofia/complicaciones , Lipodistrofia/epidemiología , Lipodistrofia/genética , Mutación , Fenotipo , Factores de RiesgoRESUMEN
Intramyocellular lipid (IMCL) accumulation has been linked to both insulin-resistant and insulin-sensitive (athletes) states. Biochemical analysis of intramuscular triglyceride composition is confounded by extramyocellular triglycerides in biopsy samples, and hence the specific composition of IMCLs is unknown in these states. 1H magnetic resonance spectroscopy (MRS) can be used to overcome this problem. Thus, we used a recently validated 1H MRS method to compare the compositional saturation index (CH2:CH3) and concentration independent of the composition (CH3) of IMCLs in the soleus and tibialis anterior muscles of 16 female insulin-resistant lipodystrophic subjects with that of age- and gender-matched athletes (n = 14) and healthy controls (n = 41). The IMCL CH2:CH3 ratio was significantly higher in both muscles of the lipodystrophic subjects compared with controls but was similar in athletes and controls. IMCL CH2:CH3 was dependent on the IMCL concentration in the controls and, after adjusting the compositional index for quantity (CH2:CH3adj), could distinguish lipodystrophics from athletes. This CH2:CH3adj marker had a stronger relationship with insulin resistance than IMCL concentration alone and was inversely related to VO2max The association of insulin resistance with the accumulation of saturated IMCLs is consistent with a potential pathogenic role for saturated fat and the reported benefits of exercise and diet in insulin-resistant states.
Asunto(s)
Ácidos Grasos/metabolismo , Resistencia a la Insulina/fisiología , Músculo Esquelético/metabolismo , Adulto , Citidililtransferasa de Colina-Fosfato/genética , Ejercicio Físico/fisiología , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Insulina/metabolismo , Resistencia a la Insulina/genética , Lamina Tipo A/genética , Lipodistrofia/genética , Lipodistrofia/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Triglicéridos/metabolismoRESUMEN
Importance: Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown. Objective: To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their association with cardiometabolic risk. Design, Setting, and Participants: Genome-wide association studies (GWAS) for WHR combined data from the UK Biobank cohort and summary statistics from previous GWAS (data collection: 2006-2018). Specific polygenic scores for higher WHR via lower gluteofemoral or via higher abdominal fat distribution were derived using WHR-associated genetic variants showing specific association with hip or waist circumference. Associations of polygenic scores with outcomes were estimated in 3 population-based cohorts, a case-cohort study, and summary statistics from 6 GWAS (data collection: 1991-2018). Exposures: More than 2.4 million common genetic variants (GWAS); polygenic scores for higher WHR (follow-up analyses). Main Outcomes and Measures: BMI-adjusted WHR and unadjusted WHR (GWAS); compartmental fat mass measured by dual-energy x-ray absorptiometry, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting glucose, fasting insulin, type 2 diabetes, and coronary disease risk (follow-up analyses). Results: Among 452â¯302 UK Biobank participants of European ancestry, the mean (SD) age was 57 (8) years and the mean (SD) WHR was 0.87 (0.09). In genome-wide analyses, 202 independent genetic variants were associated with higher BMI-adjusted WHR (n = 660â¯648) and unadjusted WHR (n = 663â¯598). In dual-energy x-ray absorptiometry analyses (n = 18â¯330), the hip- and waist-specific polygenic scores for higher WHR were specifically associated with lower gluteofemoral and higher abdominal fat, respectively. In follow-up analyses (n = 636â¯607), both polygenic scores were associated with higher blood pressure and triglyceride levels and higher risk of diabetes (waist-specific score: odds ratio [OR], 1.57 [95% CI, 1.34-1.83], absolute risk increase per 1000 participant-years [ARI], 4.4 [95% CI, 2.7-6.5], P < .001; hip-specific score: OR, 2.54 [95% CI, 2.17-2.96], ARI, 12.0 [95% CI, 9.1-15.3], P < .001) and coronary disease (waist-specific score: OR, 1.60 [95% CI, 1.39-1.84], ARI, 2.3 [95% CI, 1.5-3.3], P < .001; hip-specific score: OR, 1.76 [95% CI, 1.53-2.02], ARI, 3.0 [95% CI, 2.1-4.0], P < .001), per 1-SD increase in BMI-adjusted WHR. Conclusions and Relevance: Distinct genetic mechanisms may be linked to gluteofemoral and abdominal fat distribution that are the basis for the calculation of the WHR. These findings may improve risk assessment and treatment of diabetes and coronary disease.
Asunto(s)
Grasa Abdominal , Adiposidad/genética , Enfermedad Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Variación Genética , Relación Cintura-Cadera , Índice de Masa Corporal , Enfermedades Cardiovasculares/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Perilipins (PLINs) play a key role in energy storage by orchestrating the activity of lipases on the surface of lipid droplets. Failure of this activity results in severe metabolic disease in humans. Unlike all other lipid droplet-associated proteins, PLINs localize almost exclusively to the phospholipid monolayer surrounding the droplet. To understand how they sense and associate with the unique topology of the droplet surface, we studied the localization of human PLINs inSaccharomyces cerevisiae,demonstrating that the targeting mechanism is highly conserved and that 11-mer repeat regions are sufficient for droplet targeting. Mutations designed to disrupt folding of this region into amphipathic helices (AHs) significantly decreased lipid droplet targetingin vivoandin vitro Finally, we demonstrated a substantial increase in the helicity of this region in the presence of detergent micelles, which was prevented by an AH-disrupting missense mutation. We conclude that highly conserved 11-mer repeat regions of PLINs target lipid droplets by folding into AHs on the droplet surface, thus enabling PLINs to regulate the interface between the hydrophobic lipid core and its surrounding hydrophilic environment.
Asunto(s)
Proteínas Portadoras/química , Gotas Lipídicas/química , Proteínas de la Membrana/química , Fosfoproteínas/química , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/química , Secuencia de Aminoácidos , Animales , Sitios de Unión , Transporte Biológico , Células COS , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Chlorocebus aethiops , Expresión Génica , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Gotas Lipídicas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Micelas , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Perilipina-1 , Perilipina-2 , Perilipina-3 , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Transporte de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/ultraestructura , Alineación de Secuencia , Transgenes , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Lipid droplets (LDs) are a conserved feature of most organisms. Vertebrate adipocytes have evolved to efficiently store and release lipids for the whole organism from a single droplet. Perilipin 1, the most abundant lipid-coat protein in adipocytes, plays a key role in regulating lipolysis. In other tissues such as liver and muscle, LDs serve very different biological functions, buffering surplus lipids for subsequent oxidation or export. These tissues express perilipins 2 or 3, rather than perilipin 1. We sought to understand the role of perilipins 2 and 3 in regulating basal lipolysis. Bimolecular fluorescence complementation studies suggested that whereas perilipin 1 prevents the activation of adipose tissue triacylglycerol lipase by its coactivator, AB-hydrolase domain containing-5 (ABHD5), perilipins 2 and 3 do so less effectively. These differences are mediated by a conserved region within the carboxy terminus of perilipin 1 that binds and stabilizes ABHD5 by retarding its degradation by the proteosome. Chimeric proteins generated by fusing the carboxy terminus of perilipin 1 to the amino terminus of perilipins 2 or 3 stabilize ABHD5 and suppress basal lipolysis more effectively than WT perilipins 2 or 3. Furthermore, knockdown of perilipin 1 in adipocytes leads to replacement of perilipin 2 on LDs. In these cells we observed reduced ABHD5 expression and LD localization and a corresponding increase in basal lipolysis. Collectively these data suggest that whereas perilipin 1 potently suppresses basal lipolysis in adipocytes, perilipins 2 and 3 facilitate higher rates of basal lipolysis in other tissues where constitutive traffic of fatty acids via LDs is a necessary step in their metabolism.
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1-Acilglicerol-3-Fosfato O-Aciltransferasa/metabolismo , Adipocitos/metabolismo , Proteínas Portadoras/metabolismo , Lipólisis/fisiología , Proteínas de la Membrana/metabolismo , Fosfoproteínas/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética , Células 3T3-L1 , Adipocitos/citología , Animales , Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Ratones , Perilipina-1 , Perilipina-2 , Perilipina-3 , Fosfoproteínas/genética , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Estructura Terciaria de Proteína , ProteolisisRESUMEN
Phosphatidylcholine (PC) is the major glycerophospholipid in eukaryotic cells and is an essential component in all cellular membranes. The biochemistry of de novo PC synthesis by the Kennedy pathway is well established, but less is known about the physiological functions of PC. We identified two unrelated patients with defects in the Kennedy pathway due to biallellic loss-of-function mutations in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in this pathway. The mutations lead to a marked reduction in PCYT1A expression and PC synthesis. The phenotypic consequences include some features, such as severe fatty liver and low HDL cholesterol levels, that are predicted by the results of previously reported liver-specific deletion of murine Pcyt1a. Both patients also had lipodystrophy, severe insulin resistance, and diabetes, providing evidence for an additional and essential role for PCYT1A-generated PC in the normal function of white adipose tissue and insulin action.
Asunto(s)
Citidililtransferasa de Colina-Fosfato/genética , Hígado Graso/genética , Lipodistrofia/congénito , Lipodistrofia/genética , Fosfatidilcolinas/química , Células 3T3-L1 , Tejido Adiposo/metabolismo , Adolescente , Alelos , Animales , Niño , HDL-Colesterol/química , Citidililtransferasa de Colina-Fosfato/metabolismo , Biología Computacional , Hígado Graso/metabolismo , Femenino , Glicerofosfolípidos/química , Humanos , Insulina/química , Lípidos/química , Lipodistrofia/metabolismo , Ratones , Mutación , Fenotipo , Distribución TisularRESUMEN
BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. METHODS AND FINDINGS: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. CONCLUSIONS: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.
Asunto(s)
Aminoácidos de Cadena Ramificada/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Adulto , Anciano , Diabetes Mellitus Tipo 2/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Suecia , Adulto JovenRESUMEN
Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. Objective: To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting, and Participants: The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50â¯775 individuals with type 2 diabetes and 270â¯269 controls and 60â¯801 individuals with coronary artery disease and 123â¯504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Exposures: Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Main Outcomes and Measures: Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Results: Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. Conclusions and Relevance: In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.
Asunto(s)
LDL-Colesterol/genética , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Variación Genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Proteínas de la Membrana/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Adulto , Anciano , LDL-Colesterol/sangre , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada/efectos adversos , Ezetimiba/administración & dosificación , Ezetimiba/efectos adversos , Estudios de Asociación Genética , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Lipoproteínas/genética , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo Genético , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Riesgo , Simvastatina/administración & dosificación , Simvastatina/efectos adversosRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Mutación del Sistema de Lectura , Hipertrigliceridemia/genética , Lipodistrofia Parcial Familiar/genética , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , Acantosis Nigricans/genética , Adulto , Proteínas Portadoras , Femenino , Genes Dominantes , Heterocigoto , Humanos , Resistencia a la Insulina/genética , Persona de Mediana Edad , Linaje , Perilipina-1RESUMEN
Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.
Asunto(s)
Resistencia a la Insulina/genética , Fosfoproteínas Fosfatasas/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Adulto , Anciano , Animales , Células CHO , Cricetinae , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Tipo 2/genética , Femenino , Mutación del Sistema de Lectura , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fosfoproteínas Fosfatasas/metabolismo , Proteína Fosfatasa 1 , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Proteins which associate with the surface of lipid droplets are intimately involved in the regulation of the droplets. Several human inherited disorders have now been linked to loss- and, in some cases, likely gain-of-function mutations in the genes encoding these proteins. These are summarised in this Graphical Review.
RESUMEN
Lipid droplets (LDs) are intracellular organelles responsible for storing surplus energy as neutral lipids. Their size and number vary enormously. In white adipocytes, LDs can reach 100 µm in diameter, occupying >90% of the cell. Cidec, which is strictly required for the formation of large LDs, is concentrated at interfaces between adjacent LDs and facilitates directional flux of neutral lipids from the smaller to the larger LD. The mechanism of lipid transfer is unclear, in part because the architecture of interfaces between LDs remains elusive. Here we visualize interfaces between LDs by electron cryo-tomography and analyze the kinetics of lipid transfer by quantitative live fluorescence microscopy. We show that transfer occurs through closely apposed monolayers, is slowed down by increasing the distance between the monolayers, and follows exponential kinetics. Our data corroborate the notion that Cidec facilitates pressure-driven transfer of neutral lipids through two "leaky" monolayers between LDs.
Asunto(s)
Gotas Lipídicas , Proteínas , Gotas Lipídicas/metabolismo , Proteínas/metabolismo , Lípidos , Metabolismo de los LípidosRESUMEN
Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.
Asunto(s)
Resistencia a la Insulina , Lipodistrofia , Humanos , Animales , Ratones , Leptina/metabolismo , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Obesidad/metabolismo , Hidrolasas/metabolismo , Lipodistrofia/genética , Lipodistrofia/metabolismo , Mitocondrias/metabolismoRESUMEN
Perilipin (PLIN1) is a constitutive adipocyte lipid droplet coat protein. N-terminal amphipathic helices and central hydrophobic stretches are thought to anchor it on the lipid droplet, where it appears to function as a scaffold protein regulating lipase activity. We recently identified two different C-terminal PLIN1 frame shift mutations (Leu-404fs and Val-398fs) in patients with a novel subtype of partial lipodystrophy, hypertriglyceridemia, severe insulin resistance, and type 2 diabetes (Gandotra, S., Le Dour, C., Bottomley, W., Cervera, P., Giral, P., Reznik, Y., Charpentier, G., Auclair, M., Delépine, M., Barroso, I., Semple, R. K., Lathrop, M., Lascols, O., Capeau, J., O'Rahilly, S., Magré, J., Savage, D. B., and Vigouroux, C. (2011) N. Engl. J. Med. 364, 740-748.) When overexpressed in preadipocytes, both mutants fail to inhibit basal lipolysis. Here we used bimolecular fluorescence complementation assays to show that the mutants fail to bind ABHD5, permitting its constitutive coactivation of ATGL, resulting in increased basal lipolysis. siRNA-mediated knockdown of either ABHD5 or ATGL expression in the stably transfected cells expressing mutant PLIN1 reduced basal lipolysis. These insights from naturally occurring human variants suggest that the C terminus sequesters ABHD5 and thus inhibits basal ATGL activity. The data also suggest that pharmacological inhibition of ATGL could have therapeutic potential in patients with this rare but metabolically serious disorder.