Comprehensive analysis of morbidity and mortality patterns in familial partial lipodystrophy patients: insights from a population study.

Background: There is a lack of information on the clinical and molecular presentation of familial partial lipodystrophy (FPLD), a rare genetic disorder characterized by partial subcutaneous fat loss. Objective: This study aimed to provide a comprehensive assessment of the clinical, metabolic, and genetic features of FPLD in the Brazilian population. Methods: In a multicenter cross-sectional investigation we evaluated patients with FPLD across five Brazilian reference centers for lipodystrophies. Diagnosis of FPLD was made by clinical evaluation and genetic confirmation. Data on genetic, clinical, and metabolic characteristics were captured. Statistical analysis involved the utilization of the Kruskal-Wallis test to identify differences. Results: The study included 106 patients with genetic confirmation of FPLD. The mean age was 44 ± 15 years, and they were predominantly female (78.3%). LMNA pathogenic variants were identified in 85.8% of patients, PPARG in 10.4%, PLIN1 in 2.8%, and MFN2 in 0.9%. Diabetes mellitus (DM) was highly prevalent (57.5%), affecting 54 females (50.9%). Median triglycerides levels were 199 mg/dL (54-2724 mg/dL), severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and pancreatitis in 8.5%. Metabolic-associated fatty liver disease (MAFLD) was observed in 56.6%, and cardiovascular disease in 10.4%. The overall mortality rate was 3.8%, due to cardiovascular events. Conclusion: This study presents an extensive cohort of Brazilian patients with FPLD, predominantly DM with several multisystem complications. A comprehensive characterization of lipodystrophy syndromes is crucial for effective patient management and care.

Partial lipodystrophy: Clinical presentation and treatment.

Lipodystrophic syndromes are acquired or genetic rare diseases, characterized by a generalized or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They are probably underdiagnosed, especially for partial forms. They are characterized by a lack of adipose tissue or a lack of adipose development leading to metabolic disorders associated with often severe insulin resistance, hypertriglyceridemia and hepatic steatosis. In partial forms of lipodystrophy, these mechanisms are aggravated by excess visceral adipose tissue and/or subcutaneous adipose tissue in the upper part of the body. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counseling. Early lifestyle and dietary measures focusing on regular physical activity, and balanced diet avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndromes.

Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases.

Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephroticrange proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and tonephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

Early Atherosclerosis and Conduction Defect in a Rare Case of Dunnigan Type Familial Partial Lipodystrophy.

A 45-year-old female patient was admitted to the emergency department with syncope. Her medical history revealed a diagnosis of Familial Partial Lipodystrophy 2 (FPLD2). The patient's electrocardiogram showed a complete atrioventricular (A-V) block, and she had a history of insulin-dependent diabetes mellitus and coronary artery bypass surgery. A severe stenosis was observed in the aortic right coronary artery saphenous vein graft during coronary angiography, which was successfully revascularized. Subsequently, due to persistant syncope attacks, a permanent pacemaker was implanted after an electrophysiological study. This case highlights that serious cardiac conduction defects in patients with FPLD2 may not only be related to coronary artery disease but can also present as direct conduction defects.

Relationship of Fat Mass Ratio, a Biomarker for Lipodystrophy, With Cardiometabolic Traits.

Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR), defined as trunk fat percentage divided by leg fat percentage, as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out to 1) understand the cardiometabolic burden of individuals with high FMR in up to 40,796 participants in the UK Biobank and 9,408 participants in the Fenland study, 2) characterize the common variant genetic underpinnings of FMR, and 3) build and test a polygenic predictor for FMR. Participants with high FMR were at higher risk for type 2 diabetes (odds ratio [OR] 2.30, P = 3.5 × 10-41) and metabolic dysfunction-associated liver disease or steatohepatitis (OR 2.55, P = 4.9 × 10-7) in UK Biobank and had higher fasting insulin (difference 19.8 pmol/L, P = 5.7 × 10-36) and fasting triglycerides (difference 36.1 mg/dL, P = 2.5 × 10-28) in the Fenland study. Across FMR and its component traits, 61 conditionally independent variant-trait pairs were discovered, including 13 newly identified pairs. A polygenic score for FMR was associated with an increased risk of cardiometabolic diseases. This work establishes the cardiometabolic significance of high FMR, a biomarker for FPLD, in two large cohort studies and may prove useful in increasing diagnosis rates of patients with metabolically unhealthy fat distribution to enable treatment or a preventive therapy.

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series.

BACKGROUND: Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. AIM: This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. METHODS: In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. RESULTS: Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. CONCLUSION: Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1.

Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy.

OBJECTIVE: Glucagon-like peptide 1 receptor agonists (GLP-1RA) are widely used for the management of diabetes mellitus (DM), but their efficacy in familial partial lipodystrophy (FPLD) is unknown. In this retrospective study, we evaluated the effect of GLP-1RA in patients with FPLD. RESEARCH DESIGN AND METHODS: We analyzed data, reported with SDs, from 14 patients with FPLD (aged 58 ± 12 years; 76.47% female) and 14 patients with type 2 DM (aged 58 ± 13 years; 71% female) before and 6 months after starting GLP-1RA. RESULTS: We observed reduction in weight (95 ± 23 to 91 ± 22 kg; P = 0.002), BMI (33 ± 6 to 31 ± 6 kg/m2; P = 0.001), HbA1c (8.2% ± 1.4% to 7.7% ± 1.4%; P = 0.02), and fasting glucose (186 ± 64 to 166 ± 53 mg/dL; P = 0.04) in patients with FPLD. The change in triglycerides after treatment was greater in the FPLD group compared with the DM group (P = 0.02). We noted acute pancreatitis in two case subjects with FPLD with longer therapy. CONCLUSIONS: Our study demonstrates the relative safety and effectiveness of GLP-1RA in patients with FPLD.

Perilipin 1: a systematic review on its functions on lipid metabolism and atherosclerosis in mice and humans.

The function of perilipin 1 in human metabolism was recently highlighted by the description of PLIN1 variants associated with various pathologies. These include severe familial partial lipodystrophy and early onset acute coronary syndrome. Additionally, certain variants have been reported to have a protective effect on cardiovascular diseases. The role of this protein remains controversial in mice and variant interpretation in humans is still conflicting. This literature review has two primary objectives (i) to clarify the function of the PLIN1 gene in lipid metabolism and atherosclerosis by examining functional studies performed in cells (adipocytes) and mice and (ii) to understand the impact of PLIN1 variants identified in humans based on the variant's location within the protein and the type of variant (missense or frameshift). To achieve these objectives, we conducted an extensive analysis of the relevant literature on perilipin 1, its function in cellular models and mice, and the consequences of its mutations in humans. We also utilized bioinformatics tools and consulted the Human Genetics Cardiovascular Disease Knowledge Portal to enhance the pathogenicity assessment of PLIN1 missense variants.

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.

Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center.

Familial partial lipodystrophy (FPLD) is a rare syndrome in which a patient's phenotype is not merely dependent on the specific genetic mutation, but it is also defined by a combination of other demographic, environmental and genetic factors. In this prospective observational study in a Greek referral center, we enrolled 39 patients who fulfilled the clinical criteria of FPLD. A genetic analysis was conducted, which included sequence and deletion/duplication analyses of the LMNA and PPRARG genes, along with anthropometric and metabolic parameters. The treatment responses of patients who were eligible for treatment with metreleptin were evaluated at 3 and 12 months. In most of the patients, no significant changes were detected at the exon level, and any mutations that led to changes at the protein level were not associated with the lipodystrophic phenotype. On the contrary, various changes were detected at the intron level, especially in introns 7 and 10, whose clinical significance is considered unknown. In addition, treatment with metreleptin in specific FPLD patients significantly improved glycemic and lipidemic control, an effect which was sustained at the 12-month follow-up. More large-scale studies are necessary to clarify the genetic and allelic heterogeneity of the disease, along with other parameters which could predict treatment response.

Inguinal Fat Compensates Whole Body Metabolic Functionality in Partially Lipodystrophic Mice with Reduced PPARγ Expression.

Peroxisome proliferator-activated receptor γ (PPARγ) gene mutations in humans and mice lead to whole-body insulin resistance and partial lipodystrophy. It is unclear whether preserved fat depots in partial lipodystrophy are beneficial for whole-body metabolic homeostasis. We analyzed the insulin response and expression of metabolic genes in the preserved fat depots of PpargC/- mice, a familial partial lipodystrophy type 3 (FPLD3) mouse model resulting from a 75% decrease in Pparg transcripts. Perigonadal fat of PpargC/- mice in the basal state showed dramatic decreases in adipose tissue mass and insulin sensitivity, whereas inguinal fat showed compensatory increases. Preservation of inguinal fat metabolic ability and flexibility was reflected by the normal expression of metabolic genes in the basal or fasting/refeeding states. The high nutrient load further increased insulin sensitivity in inguinal fat, but the expression of metabolic genes became dysregulated. Inguinal fat removal resulted in further impairment of whole-body insulin sensitivity in PpargC/- mice. Conversely, the compensatory increase in insulin sensitivity of the inguinal fat in PpargC/- mice diminished as activation of PPARγ by its agonists restored insulin sensitivity and metabolic ability of perigonadal fat. Together, we demonstrated that inguinal fat of PpargC/- mice plays a compensatory role in combating perigonadal fat abnormalities.

Clinical characteristics and efficacy of pioglitazone in a Japanese patient with familial partial lipodystrophy due to peroxisome proliferator-activated receptor γ gene mutation.

Familial partial lipodystrophy (FPLD) 3 is a rare genetic disorder caused by peroxisome proliferator-activated receptor γ gene (PPARG) mutations. Most cases have been reported in Western patients. Here, we describe a first pedigree of FPLD 3 in Japanese. The proband was a 51-year-old woman. She was diagnosed with fatty liver at age 32 years, dyslipidemia at age 37 years, and diabetes mellitus at age 41 years. Her body mass index was 18.5 kg/m2, and body fat percentage was 19.2%. On physical examination, she had less subcutaneous fat in the upper limbs than in other sites. On magnetic resonance imaging, atrophy of subcutaneous adipose tissue was seen in the upper limbs and lower legs. Fasting serum C-peptide immunoreactivity was high (3.4 ng/mL), and the plasma glucose disappearance rate was low (2.07%/min) on an insulin tolerance test, both suggesting apparent insulin resistance. The serum total adiponectin level was low (2.3 µg/mL). Mild fatty liver was seen on abdominal computed tomography. On genetic analysis, a P495L mutation in PPARG was identified. The same mutation was also seen in her father, who had non-obese diabetes mellitus, and FPLD 3 was diagnosed. Modest increases in body fat and serum total adiponectin were seen with pioglitazone treatment. Attention should be paid to avoid overlooking lipodystrophy syndromes even in non-obese diabetic patients if they show features of insulin resistance.

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.

Severe loss of adipose tissue in a Vietnamese lipodystrophy patient caused by LMNA p.G465D mutation: a first clinical characterization and two-year follow-up.

OBJECTIVES: Familial partial lipodystrophy type 2 is the most well-known subtype of lipodystrophy. We describe for the first time the phenotype of a case with lipodystrophy, who carried heterozygous mutation c.G1394A (p.G465D) in the LMNA gene. CASE PRESENTATION: A 17-year-old girl was diagnosed with FPLD2 due to severe loss of subcutaneous fat in the extremities, buttocks and metabolic complications. However, there was no accumulation of fat over her face and neck, which is remarkably different from the FPLD2 clinical phenotypes. Two years of surveillance showed the challenge due to unable control of insulin resistance, glucose and lipid metabolism. Whole exome sequencing revealed the heterozygous mutation c.1394G>A at exon 11 of LMNA gene (p.G465D). CONCLUSIONS: Our case displayed an atypical phenotype of FPLD2 with metabolic anomalies, not cardiovascular diseases. The difficulties of medical management in this case pointed out the urgent need for more effective treatment for individuals suffering from this rare disease.

Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

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.