Effect of ß-Estradiol on Adipogenesis in a 3T3-L1 Cell Model of Prelamin A Accumulation.

The accumulation of farnesylated prelamin A has been suggested as one of the mechanisms responsible for the loss of fat in type 2 familial partial lipodystrophy due to variants in the LMNA gene. In this rare disease, fat loss appears in women after puberty, affecting sex-hormone-dependent anatomical areas. This study investigated the impact of 17-ß-estradiol on adipogenesis in murine preadipocytes subjected to a pharmacologically induced accumulation of farnesylated and non-farnesylated prelamin A. To induce the accumulation of non-farnesylated or farnesylated prelamin A, 3T3-L1 cells were treated with the farnesyltransferase inhibitor 277 or the methyltransferase inhibitor N-acetyl-S-farnesyl-l-cysteine methylester. Subsequently, the cells were induced to undergo adipocyte differentiation in the presence or absence of 17-ß-estradiol. Prelamin A accumulation was assessed through immunofluorescence, while real-time PCR and Western blot techniques were used to quantify several adipogenic genes and evaluate protein levels, respectively. The results showed that 17-ß-estradiol increased adipogenesis, although the combination of this hormone plus farnesylated prelamin A led to a reduction in the number of mature adipocytes and the expression of the different genes involved in adipogenesis. In conclusion, the influence of farnesylated prelamin A accumulation on adipogenesis manifested only in the presence of estradiol. These in vitro findings suggest a potential mechanism that could explain the characteristic phenotype in women suffering type 2 familial partial lipodystrophy.

A Very-Low-Calorie Diet Can Cause Remission of Diabetes Mellitus and Hypertriglyceridemia in Familial Partial Lipodystrophy.

There is no strong evidence that any specific diet is the preferred treatment for lipodystrophy syndromes. Here we remark on the benefits of a very-low-calorie diet (VLCD) in a patient with familial partial lipodystrophy type 2 (FPLD2). A 38-year-old female diagnosed with FPLD2, with a history of multiple comorbidities, underwent 16 weeks of VLCD with a short-term goal of improving her metabolic state rapidly to achieve pregnancy by in vitro fertilization (IVF). We observed a reduction of 12.3 kg in body weight and 1.4% in hemoglobin A1c. The decrease in the area under the curves of insulin (-33.2%), triglycerides (-40.7%), and free fatty acids (-34%) were very remarkable. Total body fat was reduced by 16%, and liver fat by 80%. Her egg retrieval rate and quality during IVF were far superior to past hyperstimulation. Our data encourage the use of this medical approach for other patients with similar metabolic and reproductive abnormalities due to adipose tissue insufficiency.

RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease.

BACKGROUND AND AIMS: Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD. APPROACH AND RESULTS: Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3 -null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1 -associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy. CONCLUSIONS: Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.

Describing the natural history of clinical, biochemical and radiological outcomes of children with familial partial lipodystrophy type 2 (FPLD2) from the United Kingdom: A retrospective case series.

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.

Cellular Metabolism and Bioenergetic Function in Human Fibroblasts and Preadipocytes of Type 2 Familial Partial Lipodystrophy.

LMNA mutation is associated with type-2 familial partial lipodystrophy (FPLD2). The disease causes a disorder characterized by anomalous accumulation of body fat in humans. The dysfunction at the molecular level is triggered by a lamin A/C mutation, impairing the cell metabolism. In human fibroblasts and preadipocytes, a trend for ATP production, mainly supported by mitochondrial oxidative metabolism, is detected. Moreover, primary cell lines with FPLD2 mutation decrease the mitochondrial ATP production if compared with the control, even if no differences are observed in the oxygen consumption rate of bioenergetic parameters (i.e., basal and maximal respiration, spare respiratory capacity, and ATP turnover). Conversely, glycolysis is only inhibited in FPLD2 fibroblast cell lines. We notice that the amount of ATP produced in the fibroblasts is higher than in the preadipocytes, and likewise in the control, with respect to FPLD2, due to a more active oxidative phosphorylation (OXPHOS) and glycolysis. Moreover, the proton leak parameter, which characterizes the transformation of white adipose tissue to brown/beige adipose tissue, is unaffected by FPLD2 mutation. The metabolic profile of fibroblasts and preadipocytes is confirmed by the ability of these cell lines to increase the metabolic potential of both OXPHOS and glycolysis under energy required independently by the FPLD2 mutation.

Case Report: A New Peroxisome Proliferator-Activated Receptor Gamma Mutation Causes Familial Partial Lipodystrophy Type 3 in a Chinese Patient.

Purpose: Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disease. Patients typically present with loss of adipose tissue and metabolic complications. Here, we reported a Chinese FPLD3 patient with a novel PPARG gene mutation. Methods: A 16-year-old female patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequencing was performed by using the extracted DNA. Moreover, we identified FPLD3 patients from previous studies, and according to the protein region affected by the gene mutation. We divided the patients into the DNA-binding domain (DBD) group or the ligand-binding domain (LBD) group, and compared the clinical features between the two groups. Results: We identified a novel gene mutation affecting the LBD of PPARγ c.929T > C (p.F310S). This mutation leads to the substitution of a phenylalanine by a serine. In our case, subcutaneous fat was significantly diminished in her face, hips and limbs. The patient was also presented with insulin resistance, diabetes mellitus, hypertriglyceridemia, fatty liver, liver dysfunction, albuminuria and diabetic peripheral neuropathy. After literature review, a total of 58 FPLD3 patients were identified and we found no difference in clinical features between the DBD group and LBD group (all P > 0.05). Conclusions: A Chinese FPLD3 patient with a novel PPARG gene mutation is described. Our case emphasized the importance of physical examination and genetic testing in young patients with severe metabolic syndromes.

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.

Adipocyte-Specific Deletion of Lamin A/C Largely Models Human Familial Partial Lipodystrophy Type 2.

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, we created mice with an adipocyte-specific loss of Lmna (Lmna ADKO). Although Lmna ADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. Lmna ADKO mice exhibit surprisingly mild metabolic dysfunction on a chow diet, but on a high-fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas Lmna ADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared with controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. Lmna ADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.

The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy.

AIMS: Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations. METHODS: Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation. RESULTS: We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30-35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor. CONCLUSIONS: Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.

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.

Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2.

Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2. OBJECTIVE: To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations. DESIGN, PATIENTS AND MEASUREMENTS: Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11ßHSD isoforms expression were assessed by qPCR. RESULTS: Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1ß, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRß overexpression in PBMC was observed in female patients compared with female controls. CONCLUSIONS: Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRß overexpression leading to a more severe phenotype in female.

Structural instability of lamin A tail domain modulates its assembly and higher order function in Emery-Dreifuss muscular dystrophy.

The C-terminal Ig-domain of lamin A plays critical roles in cell function via interaction with proteins, DNA, and chromatin. Mutations in this domain are known to cause various diseases including Emery-Dreifuss muscular dystrophy (EDMD) and familial partial lipodystrophy (FPLD). Here we examined the biophysical and biochemical properties of mutant Ig-domains identified in patients with EDMD and FPLD. EDMD-related mutant Ig-domain showed decreased stability to heat and denaturant. This result was also confirmed by experiments using full-length mutant lamin A, although the decrease in melting temperature was much less than that of the mutant Ig-domain alone. The unstable EDMD Ig-domain disrupted the proper assembly of lamin A, resulting in abnormal paracrystal formation and decreased viscosity. In contrast, FPLD-related mutant Ig-domains were thermally stable, although they lost DNA binding function. Alanine substitution experiments revealed a functional domain of DNA binding in the Ig-domain. Thus, the overall biophysical property of Ig-domains is closely associated with clinical phenotype.

Regional Body Fat Changes and Metabolic Complications in Children With Dunnigan Lipodystrophy-Causing LMNA Variants.

CONTEXT: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal-dominant disorder due to heterozygous missense lamin A/C (LMNA) mutations. Subjects with FPLD2 gradually lose fat from the upper and lower extremities but gain fat in the face and neck around puberty. However, the precise onset of body fat changes and metabolic complications during childhood remains unknown. OBJECTIVE: To compare metabolic parameters and regional body fat in children with FPLD2 with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2010. METHODS: We measured fasting serum triglycerides, glucose, and skinfold thicknesses in all children (aged 1 to 18 years) harboring FPLD2-causing LMNA mutations and determined regional body fat by dual-energy X-ray absorptiometry in those aged ≥8 years. RESULTS: Thirty-two affected females and 14 males participated. The lower limb fat in all affected females, except one, was below or equal to the first percentile and in two affected males was below the fifth percentile for NHANES. One female subject with FPLD2 followed from age 6 to 16 years revealed marked loss of extremity fat much before thelarche. Serum triglycerides were higher in females with FPLD2 aged 7 to 18 years compared with controls (median 208 vs 70 mg/dL; P < 0.0001) and showed inverse correlation with extremity skinfolds. Serum triglycerides in males with FPLD2 were not significantly different than controls. CONCLUSIONS: The onset of fat loss from the extremities, especially in girls with FPLD2, occurs well before the onset of puberty. High serum triglycerides are seen in young females with FPLD2 with severe loss of fat from the extremities.

Polycystic ovary syndrome in familial partial lipodystrophy type 2 (FPLD2): basic and clinical aspects.

Polycystic ovary syndrome (PCOS) is a common disorder with a high phenotypic variability. Frequently, it is associated with a mild to moderate insulin resistance (IR) caused by an interaction between polygenic diathesis and the environment. However, PCOS may be a complication of an underlying syndrome of severe IR such as insulin receptor autoantibodies, mutations in the insulin receptor or in the signalling pathway downstream from the insulin receptor or, most frequently, a defect in function or in the development of the subcutaneous adipose tissue. Such conditions are clinically characterized by lipodystrophy. Lipodystrophy in some cases is produced by a single-gene defect. In our experience, PCOS secondary to a missense mutation in the LMNA gene, known as familial partial lipodystrophy type 2 (FPLD2), is the most frequent form of PCOS secondary to severe IR due to genetically determined lipodystrophy. These forms should be identified as they benefit from tailored therapies.

A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations.

Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations.

The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks.

The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2. Genome modeling in fibroblasts from patients with FPLD2 caused by the lamin A R482W mutation reveals repositioning of the mesodermal regulator T/Brachyury locus towards the nuclear center relative to normal fibroblasts, suggesting enhanced activation propensity of the locus in a developmental model of FPLD2. Addressing this issue, we report phenotypic and transcriptional alterations in mesodermal and endothelial differentiation of induced pluripotent stem cells we generated from a patient with R482W-associated FPLD2. Correction of the LMNA mutation ameliorates R482W-associated phenotypes and gene expression. Transcriptomics links endothelial differentiation defects to decreased Polycomb-mediated repression of the T/Brachyury locus and over-activation of T target genes. Binding of the Polycomb repressor complex 2 to T/Brachyury is impaired by the mutated lamin A network, which is unable to properly associate with the locus. This leads to a deregulation of vascular gene expression over time. By connecting a lipodystrophic hotspot lamin A mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, we propose that the mutation rewires the fate of several lineages, resulting in multi-tissue pathogenic phenotypes.

FPLD2 LMNA mutation R482W dysregulates iPSC-derived adipocyte function and lipid metabolism.

Lipodystrophies are disorders that directly affect lipid metabolism and storage. Familial partial lipodystrophy type 2 (FPLD2) is caused by an autosomal dominant mutation in the LMNA gene. FPLD2 is characterized by abnormal adipose tissue distribution. This leads to metabolic deficiencies, such as insulin-resistant diabetes mellitus and hypertriglyceridemia. Here we have derived iPSC lines from two individuals diagnosed with FPLD2, and differentiated these cells into adipocytes. Adipogenesis and certain adipocyte functions are impaired in FPLD2-adipocytes. Consistent with the lipodystrophic phenotype, FPLD2-adipocytes appear to accumulate markers of autophagy and catabolize triglycerides at higher levels than control adipocytes. These data are suggestive of a mechanism causing the lack of adipose tissue in FPLD2 patients.

Insulin secretory defect in familial partial lipodystrophy Type 2 and successful long-term treatment with a glucagon-like peptide 1 receptor agonist.

BACKGROUND: Familial partial lipodystrophies are rare monogenic disorders that are often associated with diabetes. In such cases, it can be difficult to achieve glycaemic control. CASE REPORT: We report a 34-year old woman with familial partial lipodystrophy type 2 (Dunnigan) and diabetes; her hyperglycaemia persisted despite metformin treatment. A combined intravenous glucose tolerance-euglycaemic clamp test showed severe insulin resistance, as expected, but also showed strongly diminished first-phase insulin secretion. After the latter finding, we added the glucagon-like peptide-1 receptor agonist liraglutide to the patient's treatment regimen, which rapidly normalized plasma glucose levels. HbA1c values <42 mmol/mol (6.0%) have now been maintained for over 4 years. CONCLUSION: This case suggests that a glucagon-like peptide-1 receptor agonist may be a useful component of glucose-lowering therapy in individuals with familial partial lipodystrophy and diabetes mellitus.

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.

Evaluation of Dietary Intake, Leisure-Time Physical Activity, and Metabolic Profile in Women with Mutation in the LMNA Gene.

INTRODUCTION: Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective lack of subcutaneous fat, which is associated with insulin-resistant diabetes. The Dunnigan variety (FPLD2) is caused by several missense mutations in the lamin A/C (LMNA) gene, most of which are typically located in exon 8 at the codon position 482. OBJECTIVE: The aim of this study was to assess and compare the dietary intake, leisure-time physical activity (LTPA), and biochemical measurements (glucose, A1C, and plasma lipids) in women with FPLD2 and without (control group, CG) and to examine the associations between dietary intake and biochemical measurements (BM). METHODS: LTPA was measured with a questionnaire and metabolic equivalent (MET) hours per week (hours/week) were calculated. Dietary intake by the 3-day recall method and clinical laboratory parameters were collected. RESULTS: Characteristics of women with FPLD2: 35.8 ± 13.9 years, fat mass = 10 ± 2.3 kg and fat free mass = 41.4 ± 4.5 kg (p < 0.05). Women with FPLD2 showed a smaller intake of energy (kcal), lipids, and carbohydrates and a large intake of protein (p < 0.01) compared to CG. Comparing the 2 groups in terms of LTPA, 78% of women with FPLD2 performed insufficient physical activity. In addition, they had a higher levels of glucose, A1C, and triglycerides (TG) and lower levels of high-density lipoprotein (HDL). There was no correlation between dietary intake and biochemical measurements. CONCLUSIONS: Women with FPLD2 have a lower intake of energy (kcal), lipids, and carbohydrates and greater changes in biochemical measurements. Because this is a rare disease, future studies are needed with encouragement of the practice of physical activity and of healthy eating habits, preventing the onset of diseases.