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Background: Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. Methods: This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). Results: Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. Conclusions: Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD. [ABSTRACT FROM AUTHOR]

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 (LmnaADKO). Although LmnaADKO 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. LmnaADKO 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 LmnaADKO 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. LmnaADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues. [ABSTRACT FROM AUTHOR]

Introduction: Lipodystrophy is a heterogeneous group of rare diseases characterized by various degrees of fat loss which leads to serious morbidity due to metabolic abnormalities associated with insulin resistance and subtype-specific clinical features associated with underlying molecular etiology. Areas covered: This article aims to help physicians address challenges in diagnosing and managing lipodystrophy. We systematically reviewed the literature on PubMed and Google Scholar databases to summarize the current knowledge in lipodystrophy management. Expert opinion: Adipose tissue is a highly active endocrine organ that regulates metabolic homeostasis in the human body through a comprehensive communication network with other organ systems such as the central nervous system, liver, digestive system, and the immune system. The adipose tissue is capable of producing and secreting numerous factors with important endocrine functions such as leptin that regulates energy homeostasis. Recent developments in the field have helped to solve some of the mysteries behind lipodystrophy that allowed us to get a better understanding of adipocyte function and differentiation. From a clinical standpoint, physicians who suspect lipodystrophy should distinguish the disease from several others that may present with similar clinical features. It is also important for physicians to carefully interpret clinical features, laboratory, and imaging results before moving to more sophisticated tests and making decisions about therapy. [ABSTRACT FROM AUTHOR]

Background: Body fat redistribution and metabolic abnormalities found in HIV patients receiving highly active antiretroviral therapy (HAART) contribute to an atherogenic profile, increasing cardiovascular disease risk. Objective: We aimed to evaluate adiposity measures/indexes and propose cutoffs associated with predictors of cardiovascular disease risk in HIV patients on HAART. Design: To evaluate cardiovascular disease risk in this crosssectional study, we conducted electrocardiogram exams and stress electrocardiography, measured the ankle brachial index and blood pressure arterial hypertension, conducted lipid biochemical tests, and measured blood glucose.We measured circumferences [waist (WC), hip, thigh, calf, neck, trunk] and skinfold thicknesses (biceps, triceps, subscapular, suprailiac), conducted bioelectrical impedance analysis (BIA), and calculated indexes [body mass index, waist-to-hip ratio, waist-to-thigh ratio, waist-to-calf ratio, waist-to-height ratio (WHtR), trunk-to-arm ratio, body mass index corrected for body fat mass, Body Adiposity Index, conicity index, body shape index, fat mass (percentage), and phase angle]. For evaluating the performance of all adiposity measures/indexes, we used receiver operating characteristic (ROC) curves. Results: Measures of central adiposity WC and WHtR showed the best performances--WC area under the curve (AUC) for men: 0.83 (95% CI: 0.78, 0.89; P < 0.05); WC AUC for women: 0.86 (95% CI: 0.81, 0.91; P < 0.05); WHtR AUC for men: 0.83 (95% CI: 0.78, 0.88; P < 0.05); and WHtR AUC for women: 0.85 (95% CI: 0.80, 0.91; P < 0.05). All adiposity measures/indexes presented different cutoffs from those proposed for the HIV seronegative population. The cutoffs for WC were 87.75 cm (sensitivity: 82.2%; specificity: 75.5%) for men and 90.5 cm (sensitivity: 84.0%; specificity: 73.0%) for women. Conclusions: The measures/indexes of central adiposity presented excellent associations with predictors of cardiovascular disease risk, and the use of the cutoffs proposed in the present study aims to contribute to the early identification of increasing risk of cardiovascular diseases, enabling interventions. This trial was registered at the Brazilian clinical trials registry Registro brasileiro de ensaios clínicos (Rebec) as RBR-9rcxbq. [ABSTRACT FROM AUTHOR]

Background: Familial partial lipodystrophy of the Dunnigan type is one of the most common inherited lipodystrophies variables. These individuals have important metabolic disorders that cause predisposition to various diseases. In this study we aimed to demonstrate the relation between the metabolic abnormalities, inflammatory profile and the expression of genes involved in the activation of the endoplasmic reticulum stress (ERS) in subjects with FPLD. Methods: We evaluated 14 female FPLD patients and compared with 13 female healthy individuals. The subjects were paired with their respective BMI and age and categorized into two groups: Familial partial lipodystrophy of the Dunnigan type (FPLD) and control. Patients were fasted for 12 h before blood collection for measurement of HbA1c, glucose, insulin, lipids and inflammatory markers. Subcutâneous adipose tissue was collected by puncture aspiration of submental region during ambulatorial surgical aesthetic procedure. Results: We demonstrate that patients with FPLD show increased HbA1c (p < 0.01), fasting glucose (p < 0.002) and triglycerides (p < 0.005) while HDL/cholesterol (p < 0.001) was lower when compared to healthy individuals. We found that 64.2% FPLD patients had metabolic syndrome according to International Diabetes Federation definition. We also observe increased AUC of glucose (p < 0.001) and insulin during oGTT, featuring a frame of hyperglycemia and hyperinsulinemia, suggesting insulin resistance. Also we found hyperactivation of several genes responsible for ERS such as ATF-4 (p < 0.01), ATF-6 (p < 0.01), EIF2α3K (p < 0.005), CCT4 (p < 0.001), CHOP (p < 0.01), CALR (p < 0.001) and CANX (p < 0.005), that corroborate the idea that diabetes mellitus and metabolic syndrome are associated with direct damage to the endoplasmic reticulum homeostasis. Ultimately, we note that individuals with lipodystrophy have an increase in serum interleukins, keys of the inflammatory process, as IL-1β, TNF-α and IL-6 (p < 0.05 all), compared with healthy individuals, which can be the trigger to insulin resistance in this population. Conclusion: Individuals with FPLD besides having typical dysfunctions of metabolic syndrome, show a hyperactivation of ERS associated with increased systemic inflammatory profile, which together may explain the complex clinical aspect of this diseases. Trial registration HCRP no 6711/2012 [ABSTRACT FROM AUTHOR]