Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Alterações nutricionais em pacientes com lipodistrofia associada ao HIV/Aids de uma unidade de referência do município de Belém - Pará / Nutritional changes in patients with HIV/Aids - associated lipodystrophy in a reference unit in Belém - Pará

Com o uso da chamada terapia antirretroviral altamente ativa, alguns pacientes começaram a apresentar alterações metabólicas, sendo uma delas a lipodistrofia associada ao HIV/aids, que se caracteriza pela redistribuição da gordura corporal. Objetivo: avaliar as alterações antropométricase bioquímicas em pacientes com lipodistrofia associada ao HIV/aids atendidos em uma Unidade de Referência Especializada do município de Belém- Pará. Métodos: estudo descritivo de corte transversal com pacientes lipodistróficos. Foram analisadas as variáveis sociodemográficas e econômicas,antropométricas, bioquímicas e imunológicas dos pacientes. Nas análises estatísticas foram usados os softwares Epi Info 3.5.4 e BioEstat 5.0, com significância de 5%. Resultados: dos 62 pacientes, 53,2% eram do sexo feminino, 53,2% estavam eutróficos segundo o IMC e 56,7% faziam uso de algum inibidor de protease. As mulheres apresentaram mais a forma mista da lipodistrofia e os homens, a lipoatrofia. O deficit de adequação esteve presente em 64,3% dos pacientes segundo circunferência muscular braquial, em 46,3%, segundo prega cutânea tricipital e em 65,5% de acordo com circunferência do braço. As mulheres apresentaram maiores percentuais de risco elevado para alterações metabólicas, de colesterol total e LDL-c elevado, e os homens deHDL-c baixo, de glicemia alterada e triglicerídios elevados. Entre as mulheres, 31,3% apresentaram risco alto para desenvolver doenças oportunistas e a maioria dos pacientes apresentaram risco baixo de piora na doença. Conclusão: as alterações antropométricas e bioquímicas foram frequentes nos pacientes estudados, o que torna o acompanhamento nutricional individualizado uma importante ferramenta no tratamento de pacientes que apresentam a lipodistrofia associada ao HIV.

With the use of highly active antiretroviral therapy some patients began to present metabolic changes, like HIV/aids - associated lipodystrophy, which is characterized by body fat redistribution. Objective: To evaluate the anthropometric and biochemical changes in patients with HIV/aids - associated lipodystrophy treated in a Specialized Reference Unit, in Belém - Pará. Methods: a cross-sectional descriptive study with lipodystrophic patients. Sociodemographic, economic, anthropometric, biochemical and immunological variables of the patients were analyzed. In the statistical analysis Epi Info 3.5.4 and BioEstat 5.0 softwares, with 5% significance were used. Results: 53.2% of the 62 patients were female, 53.2% were eutrophic according to BMI and 56.7% used a protease inhibitor. Women presented the mixed form of lipodystrophy more frequently and men, lipoatrophy. The adequacy deficit was present in 64.3% of patients according to arm muscle circumference, in 46.3%, according to triceps skinfold thickness and 65.5% according to arm circumference. Women presented higher percentages of very high risk for metabolic disorders, total cholesterol and high LDL-c, and men of low HDL-cand high glycemia and triglycerides. Among women, 31.3% presented a high risk of developing opportunistic infections and most patients presented lowrisk of worsening the disease. Conclusion: anthropometric and biochemical changes were frequent in patients, which makes individualized nutritional accompaniment an important tool in the treatment of patients with HIV-associated lipodystrophy.

Feed withdrawal abate regimens lipodystrophy and metabolic syndrome symptoms, such as glucose tolerance, are associated with the diameter of retroperitoneal adipocytes in rats.

Adipocyte numbers were increased by feed withdrawal (FW) regimens in cattle; thus, the effect of FW regimens was studied in male Wistar and fa/fa obese rats, as models for humans, in 2 completely randomized design experiments to abate lipodystrophy and progression of metabolic syndrome symptoms. The hypothesis was that application of FW regimens could alter adipose tissue cellularity, adipocyte size, and affect area under the curve (AUC) during glucose tolerance tests. Objectives were to determine associations among retroperitoneal and inguinal adipose tissue adipocyte number, diameter, and AUC, as affected by fortnightly or a single (at age 50 days) 24-hour FW regimen. Adipocyte marker peroxisome proliferator-activated receptor gamma expression was elevated (P = .054) in the retroperitoneal tissue of fa/fa obese rats in the fortnightly FW treatment because of a 13% increase in tissue cell density (cells per gram; P = .13). Average cell diameter in retroperitoneal adipose and AUC were negatively corelated. Regression analyses after including the square of average cell diameter indicated that average retroperitoneal adipocyte diameter (between 65 and 135 mum) and the AUC were related in a quadratic manner (R(2) = 0.14; n = 49; P = .03) for Wistar rats. Cell number of the inguinal and retroperitoneal adipocytes tended to be positively corelated (r = 0.24; P = .09 and r = 0.26; P = .07, n = 49, respectively) to the AUC and are indexes of adiposity. Results suggest that maintenance of retroperitoneal adipocytes at appropriate diameters may control progression of metabolic syndrome symptoms such as glucose tolerance.

Adherence to Mediterranean diet is favorably associated with metabolic parameters in HIV-positive patients with the highly active antiretroviral therapy-induced metabolic syndrome and lipodystrophy.

The objective of the study was to investigate whether closer adherence to a Mediterranean dietary pattern is associated with metabolic aspects of the highly active antiretroviral therapy (HAART)-induced metabolic syndrome (fat redistribution [FR], insulin resistance, dyslipidemia) in HIV-positive patients. This was a cross-sectional study. Two hundred twenty-seven HIV-infected patients were evaluated during a single outpatient visit to the General Clinical Research Center of Beth Israel Deaconess Medical Center. Usual dietary intake and physical activity habits were evaluated; the Mediterranean Diet Score (MedDietScore) was calculated. Dual-energy x-ray absorptiometry, computed tomographic findings, anthropometrics, and data from the study interviews and questionnaires were used for the assessment of body composition using specific criteria. A complete metabolic profile was available for all subjects. In the entire study sample, a weak inverse association was found between insulin resistance, estimated using the homeostasis model assessment, and MedDietScore (standardized beta = -0.15, P = .03). Interaction models revealed that this was largely driven by an inverse association in patients with FR (standardized beta = -0.13, P = .02). Moreover, MedDietScore was positively correlated with high-density lipoprotein cholesterol (standardized beta = 0.15, P = .01) and marginally negatively associated with circulating triglyceride levels (standardized beta = -0.16, P = .13) in this group of patients. Adherence to a Mediterranean dietary pattern was favorably related to cardiovascular risk factors in HIV-positive patients with FR. Further clinical studies are needed to confirm our data in different populations and to explore the underlying mechanisms.

Leptin replacement therapy but not dietary polyunsaturated fatty acid alleviates HIV protease inhibitor-induced dyslipidemia and lipodystrophy in mice.

A major complication associated with the use of protease inhibitors (PIs) in treatment of HIV-infected patients is lipid abnormalities including dyslipidemia, lipodystrophy, and liver steatosis. Previous studies revealed that these abnormalities are associated with PI-induced accumulation of activated sterol regulatory element binding proteins (SREBPs) in the nucleus of liver and adipose tissues, resulting in constitutive activation of lipid metabolism genes. This study used the mouse model to determine the potential of polyunsaturated fatty acid (PUFA) diet or leptin replacement therapy to alleviate these PI-induced metabolic abnormalities. Results showed that feeding C57BL/6 mice with a PUFA-rich diet failed to normalize plasma cholesterol and triglyceride levels in ritonavir-treated mice. The PUFA-rich diet also had no effect on ritonavir-induced interscapular fat accumulation and liver steatosis. In contrast, daily administration of leptin significantly reversed the elevated plasma cholesterol level induced by ritonavir. Leptin replacement therapy also significantly reduced the ritonavir-induced interscapular fat mass and improved liver steatosis. Taken together, these data suggest that PI-induced lipid abnormalities, especially dyslipidemia, lipodystrophy, and liver steatosis, may be reduced with leptin replacement therapy.

Increasing the amount of fat in a conjugated linoleic acid-supplemented diet reduces lipodystrophy in mice.

Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in beef and dairy products. However, when 1 g CLA/100 g diet was given to mice in a low fat diet (4 g fat/100 g diet), they showed a marked decrease in fat mass, but demonstrated symptoms of lipoatrophic diabetes, i.e., marked hepatomegaly and insulin resistance. In this study, to determine whether the decrease in adipose tissue was responsible for these adverse effects, mice were fed different doses of CLA and dietary fat. In Experiment 1, mice were fed different doses of CLA (0, 0.1 and 1 g CLA/100 g diet) in a fixed 4 g fat/100 g diet; in those fed 0.1 g CLA, subcutaneous white adipose tissue (WAT) weight was 48% lower than in mice fed 0 g CLA. The mice fed 0.1 g CLA did not exhibit hepatomegaly and insulin resistance. In Experiment 2, mice were fed for 5 mo different amounts of dietary fat (4, 13 and 34 g fat/100 g diet) in 0 or 1 g CLA/100 g diet; in mice fed 1 g CLA with 34 g fat, retroperitoneal and subcutaneous WAT weights were 76 and 79% lower, respectively, than those of mice fed 0 g CLA with 34 g fat. Mice fed 1 g CLA in the diet with 34 g fat had normal plasma insulin concentrations and a 45% greater liver weight. These data suggested that the percentage of CLA in dietary fat might be a determinant of CLA-mediated lipodystrophy.

Body habitus changes related to lipodystrophy.

Changes in body fat in persons infected with the human immunodeficiency virus (HIV) have been associated with deleterious changes in blood lipids and insulin resistance, raising concern that these changes will increase the risk for accelerated atherosclerosis. Changes in body fat are often identified in advanced disease but may also occur early after HIV infection is detected. Conflicting evidence suggests that fat maldistribution may be related to use of protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or a combination of these two classes of drugs, but the etiologies of the various changes in body fat remain uncertain. To date there have been no remedies for the loss of subcutaneous fat, but recent evidence has suggested that discontinuation of stavudine or zidovudine therapy may be associated with limited restoration of extremity fat. For fat accumulation, a number of strategies have been attempted, including treatment with human growth hormone, androgens, or metformin, and changes in diet and exercise. As in persons not infected with HIV, it is expected that the cornerstone of management, especially in the presence of central obesity, dyslipidemia, and insulin resistance, will include a diet low in saturated fat, with low-glycemic index carbohydrates, and high in fiber. Very limited evidence in persons infected with HIV has suggested that a supervised exercise program may be beneficial.

Reduction of abdominal obesity in lipodystrophy associated with human immunodeficiency virus infection by means of diet and exercise: case report and proof of principle.

Lipodystrophy associated with human immunodeficiency virus infection causes abdominal fat gain, peripheral subcutaneous fat atrophy, insulin resistance, low levels of high-density lipoprotein cholesterol, and hypertriglyceridemia. An exercise program combined with a moderate-fat, low-glycemic-index, high-fiber diet can reverse several aspects of lipodystrophy, and, until specific treatment is available, should be considered for treatment of lipodystrophy.

Eucaloric substitution of medium chain triglycerides for dietary long chain fatty acids in acquired total lipodystrophy: effects on hyperlipoproteinemia and endogenous insulin resistance.

Previous studies have suggested that reduction of dietary fat intake, with or without caloric restriction, may lead to improvement in certain of the characteristic abnormalities that accompany total lipodystrophy (TLD). We have studied the effects of eucaloric medium chain triglyceride (MCT) substitution for dietary long chain fatty acids in a patient with acquired total lipodystrophy and unusual somatic and visceral anomalies. The patient exhibited insulin resistance, carbohydrate intolerance, striking fasting- and glucose-stimulated hyperinsulinemia, hyperglucagonemia, type V hyperlipoproteinemia, and lipoprotein lipase deficiency on a normal diet. Improvement in chylomicronemia, hypertriglyceridemia, and xanthomatosis occurred during eucaloric MCT substitution. Carbohydrate intolerance decreased and fasting immunoreactive glucagon and insulin concentrations fell 37% and 83%, respectively. Plasma triglyceride polyunsaturated fatty acid concentrations decreased to very low levels. With long term MCT feeding supplemented by polyunsaturated fatty acids, hepatomegaly has gradually decreased, while body weight has remained stable. The patient has not yet required insulin therapy. These observations suggest that the abnormalities in carbohydrate metabolism are closely linked to, and perhaps dependent on, the abnormalities in lipoprotein transport in TLD. Long chain triglyceride restriction and MCT supplementation should be attempted in additional patients with the features of TLD to determine whether this is a generally effective therapeutic approach.