Peripheral Fat Loss Research Articles

PCR181 The Burden of Familial Partial Lipodystrophy (FPL) in Brazilian Patients - A Qualitative Study on Physical Symptoms, Comorbidities, and Emotional Well-Being

FPL is a rare genetic disorder characterized by the progressive loss of peripheral subcutaneous fat. Although the phenotypic characteristics of FPL are highly heterogeneous across genotypes and may also vary among individuals with the same mutation, the subsequent physical changes in appearance and psychological effects may be dramatic, especially in women. In Brazil, the human burden of FPL has not yet been documented. This qualitative study aims to document the perceived physical and emotional impact of FPL on Brazilian patients.

Conditional loss of IKK\u03b1 in Osterix\u2009+\u2009cells has no effect on bone but leads to age-related loss of peripheral fat

NF-κB has been reported to both promote and inhibit bone formation. To explore its role in osteolineage cells, we conditionally deleted IKKα, an upstream kinase required for non-canonical NF-κB activation, using Osterix (Osx)-Cre. Surprisingly, we found no effect on either cancellous or cortical bone, even following mechanical loading. However, we noted that IKKα conditional knockout (cKO) mice began to lose body weight after 6 months of age with severe reductions in fat mass and lower adipocyte size in geriatric animals. qPCR analysis of adipogenic markers in fat pads of cKO mice indicated no difference in early differentiation, but instead markedly lower leptin with age. We challenged young mice with a high fat diet finding that cKO mice gained less weight and showed improved glucose metabolism. Low levels of recombination at the IKKα locus were detected in fat pads isolated from old cKO mice. To determine whether recombination occurs in adipocytes, we examined fat pads in Osx-Cre;TdT reporter mice; these showed increasing Osx-Cre-mediated expression in peripheral adipocytes from 6 weeks to 18 months. Since Osx-Cre drives recombination in peripheral adipocytes with age, we conclude that fat loss in cKO mice is most likely caused by progressive deficits of IKKα in adipocytes.

Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study

BackgroundFamilial 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.MethodsThis 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).ResultsBaseline 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.ConclusionsAlthough limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Inhibition of Angiopoietin-Like 3 (ANGPTL3) Reduces Adipose Tissue Insulin Resistance in Patients With Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, usually affecting the trunk and limbs, but preservation in other areas, such as the face and neck. It is usually associated with dyslipidemia and diabetes mellitus, and currently, there are no approved specific therapies for this disease in the US. Reductions in circulating levels of ANGPTL3 either by homologous loss-of-function mutations in humans or by pharmacological inhibition in rodents are associated with reductions in triglyceride (and other atherogenic lipid) levels and protect from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. We performed a proof-of-concept study to assess the early efficacy and safety of targeting ANGPTL3 via antisense oligonucleotide ISIS-703802 (vupanorsen) in a small number of patients with FPLD. Four patients with FPLD (3F/1M; age range: 39–48; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant), diabetes (HbA1c>6.5%) and hypertriglyceridemia (>250 mg/dL at screening) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. The primary endpoint was the change in triglycerides at week 27. Other end-points of interest measured at the same time points included insulin secretion, sensitivity, lipid and hormonal changes in response to a 5 hour long mixed meal test and body composition measured by dual energy absorptiometry (DEXA). Treatment resulted in a 59.9±26.3 (mean±SD) % of reduction in triglycerides, 54.7±9.8% of reduction in serum ANGPTL3 levels and 50.8±27.4% of reduction in ApoCIII. Treatment with vupanorsen led to a reduction of 209.3±120.4 in adipose tissue insulin resistance (ADIPO-IR) from a baseline of 470.3±114.3 and the area under the curve (AUC) for circulating free fatty acid levels were decreased by 32.1±21.4 mmol/L/min from a baseline of 215.8±55.2 mmol/L/min. Glucose AUC and triglyceride AUC also decreased after treatment (-14.0±5.2 and -60.1±26.5 mg/dL/min, respectively). Analyzing body fat distribution using DEXA, we observed that the fat mass index (FMI) and trunk mass index (TMI) did not change from baseline, but the ratio of total fat mass/ fat mass from limbs decreased by 10.7±12.2. These data show a tendency for redistribution of central body fat to limbs. There were numerous adverse events observed that were related to common serious complications associated with diabetes and FPLD. Although limited, these results suggest that targeting ANGPTL3 with vupanorsen in patients with FPLD may have a therapeutic role by addressing multiple problems.

The Influence of Laparoscopic Sleeve Gastrectomy on Body Composition and Fat Distribution in Obese Caucasian Men and Women

BackgroundThe aim of the study was to assess changes in body composition in patients subjected to laparoscopic sleeve gastrectomy (LSG).MethodsChanges in body composition following LSG were determined in a group of 155 patients with obesity (117 women and 38 men), with dual-energy X-ray absorptiometry (DXA). Whole body fat mass (FM) and lean body mass (LBM) were determined, and abdominal fat mass (AbdF) was assessed within the region extending from the top of the pubic bone up to the line between 12th thoracic and 1st lumbar vertebras.ResultsOver the period of 12 months following LSG, body mass index decreased by 28.2 ± 9.0% (p < 0.001). The reduction of body weight by 35.4 ± 12.6 kg (p < 0.001) was the result of a decrease in FM by 23.9 ± 8.9 kg (p < 0.001) and LBM by 10.5 ± 3.8 kg (p < 0.001). AbdF decreased from 13.2 ± 3.1 to 8.2 ± 2.7 kg (p < 0.001), but abdominal fat to total fat mass ratio increased from 24.9 ± 4.7 to 28.0 ± 5.8% (p < 0.001). The loss of AbdF was more pronounced in men than in women. The rate of FM loss was attenuated with patients’ age.ConclusionsOver the period of 12 months following LSG, the reduction of FM was more than twice as much as decrease of LBM. The loss of AbdF was slower than a loss of peripheral subcutaneous fat.

1051-P: Selective Targeting of Angiopoietin-Like 3 (ANGPTL3) via the Second-Generation Antisense Oligonucleotide (ASO) ISIS-703802 (AKCEA-ANGPTL3-LRx) in Subjects with Familial Partial Lipodystrophy (FPLD)

FPLD is an extreme form of metabolic dyslipidemia and diabetes caused by selective loss of peripheral subcutaneous fat. Currently, there are no approved therapies for this rare cause of diabetes in the U.S. Reductions in circulating levels of the hepatokine ANGPTL3 either by mutations in humans or by targeted drugs in rodents are associated with reductions in triglyceride levels and provide protection from atherosclerosis, making it an attractive target for patients with FPLD and metabolic dyslipidemia. The objective of this proof-of concept, Phase 2, open-label study was to assess the early efficacy and safety of a strategy that targets ANGPTL3 via ISIS-703802 (AKCEA-ANGPTL3-LRx) in patients with FPLD. Four patients with FPLD (3F/1M; age range: 38-47; 1 with LMNA R482Q, 1 with LMNA R584H, and 2 with no causative genetic variant) with diabetes (HbA1c&amp;gt;6.5%) and hypertriglyceridemia (≥ 500 mg/dL or ≥ 200 mg/dL for patients meeting genetic or family history criteria) were included. Patients received the study drug at a subcutaneous dose of 20 mg weekly for 26 weeks. Primary endpoint was the percent change in serum triglycerides from baseline to week 27. All other endpoints were also analyzed at week 27. Treatment resulted in a 60±26 (mean±SD) % reduction in triglycerides from a baseline of 818±432 mg/dL. Consistent with antisense reduction of ANGPTL3 mRNA, circulating ANGPTL3 levels were lowered by 55±10%. Treatment was also associated with 51±27% reduction in circulating apoC3 levels, 64±24% reduction in total VLDL and chylomicron triglycerides, and 18±15% reduction in total cholesterol. In addition, HbA1c showed a modest mean absolute reduction of 0.2±1.0 % The drug was well tolerated and there were no new safety signals observed. Although a small study, these results suggest that targeting ANGPTL3 in patients with FPLD could successfully address metabolic dyslipidemia. Disclosure M. Foss-Freitas: None. B. Akinci: Advisory Panel; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Research Support; Self; Gemphire Therapeutics Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. A.H. Neidert: None. R.P. Hench: None. M. Swaidan: None. E.A. Oral: Consultant; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Regeneron Pharmaceuticals. Research Support; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Gemphire Therapeutics Inc., GI Dynamics Inc., Regeneron Pharmaceuticals. Funding Ionis Pharmaceuticals, Inc.; Akcea Therapeutics

SUN-LB012 Familial Partial Lipodystrophy Type 3: New Variant to the PPARG Gene Mutation

Objective: Familial partial lipodystrophy (FPLD) syndromes are rare and characterized by variable loss of adipose tissue in some areas of the body with excess deposition of fat in other areas, and complex metabolic derangements. We present a patient who had a new pathogenic variant identified in the PPARG gene that causes familial partial lipodystrophy type 3. Clinical case: A 48-year old Caucasian female was referred to the Endocrinology department for management of her type 2 diabetes mellitus. Her glycated hemoglobin was 12.1% and triglycerides were 2343 mg/dl. She was diagnosed with type 2 diabetes mellitus in the third decade of life. The patient had extreme insulin resistance with diabetic triopathy. She had a history of severe hypertriglyceridemia that lead to 3 episodes of pancreatitis. Family history was significant for hypertriglyceridemia in her father and a paternal uncle, both of whom died of hemorrhagic pancreatitis. Examination revealed a cushingoid appearance with facial, neck and truncal obesity and loss of peripheral fat on the buttocks, thighs and forearms. Her gastrocnemii appeared prominent. She had normal thyroid function and a normal 1 mg dexamethasone suppression test. Genetic testing revealed a new pathogenic heterozygous variant in the PPARG gene (c.1164del) that produces a premature stop codon (consistent with FPLD type 3). The patient was treated with Insulin Glargine-U300, Aspart and Pioglitazone. Three months after diagnosis, the patient passed away from myocardial infarction. Discussion: FPLD type 3 is a very rare type of autosomal dominant FPLD, reported in about 30 individuals worldwide per National Organization for Rare Disorders (NORD). It is resulted from mutation of PPARG gene, which encodes PPAR-gamma nuclear transcription factor. PPAR-gamma is a regulator of adipocyte differentiation. Loss of PPARG function leads to peripheral fat loss which primarily involves the gluteal region, calves and forearms with deposition of fat on the face, neck, and truncal areas. Metabolic complications include hypertriglyceridemia, insulin resistant diabetes, hypertension, hepatic steatosis, and pancreatitis. Management includes a calorie-restricted diet, exercise and pharmacotherapy. Conclusion: Recognition of the clinical features of FPLD including atypical fat distribution, hypertriglyceridemia, recurrent pancreatitis and severe insulin resistance can lead to early diagnosis and intervention which may reduce mortality in FPLD patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SUN-LB032 Severe Insulin Resistance and Nephrotic Range Proteinuria Reversed by Pioglitazone in a Patient With Dunnigan Type Lipodystrophy

Background: Familial partial lipodystrophy (FPLD 2 or Dunnigan lipodystrophy [DL]) is a rare disorder associated severe insulin resistance, elevated triglycerides (TG), and low serum HDL cholesterol. Proteinuric renal disease is a prevalent feature of generalized lipodystrophy, usually secondary to focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis. Case series reported that metreleptin have shown to improve proteinuria in patients with generalized lipodystrophy. Here we report a reversal of nephrotic syndrome using PPARγ agonist pioglitazone. Case: 37 yo female presented with type 2 diabetes mellitus [DM2] with severe insulin resistance. A diagnosis of DL was made based on loss of peripheral subcutaneous fat with accentuation of fat distribution in the head and face with a similar presentation in her mother. The patient developed DM2 in her 20’s. She was treated with U500 Insulin 90 U BID, Metformin 1000 mg BID, fenofibrate 145 mg, lisinopril 20 mg and Fish oil 2 g BID. Lab tests showed HBA1C 7.3%, serum creatinine (Cr) 0.7mg/dL, total cholesterol (CHOL) 280mg/dL, TG 1631 mg/dL and HDL 27mg/dL. For her proteinuria (urine albumin/Cr (1581 mg/mg), she underwent a renal biopsy which showed FSGS. She was started on pioglitazone 15 mg/day and increased to 45 mg/day. Insulin requirements improved to glargine insulin 30 units BID. Results after 22 months of treatment were HBA1C 8.1%, Cr 0.9mg/dL, CHOL 207 mg/dL, TG 168mg/dL, HDL 34mg/dL. Urine albumin/Cr ratio improved to 89 mg/mg. Discussion: Pioglitazone is a thiazolidinedione (TZD) which acts as an agonist to PPARγ. In lipodystrophy syndromes it is used to “re-differentiate” peripheral adipose tissue to more physiological locations away from liver to generalized adipose tissue, with the expectation of improving the severe insulin resistance. Her insulin requirements decreased from 180 units/day to 60 units/day. Also, serum TG improved with presumed shunting of lipids away from the liver toward peripheral adipose tissue. The reversal of the nephrotic syndrome exceeded our expectations. The mechanism for reversal of nephrotic syndrome is unknown. The blood glucose and presumed renal tubular exposure to glycosuria may not have changed as the A1c did not change significantly for the better. There may be TZD mediated downregulation of renin angiotensin aldosterone system, decreased inflammatory cytokines or adipokines which may have been associated with the nephropathy. Further studies are needed to explore this finding. Conclusion: TZD therapy is an effective mediator of improving insulin resistance and nephrotic syndrome in congenital lipodystrophy. The mechanism of action may also help in understanding the etiology of FSGS. Reference: Sarafidis, P, et al. Effect Of Thiazolidinediones On Albuminuria And Proteinuria In Diabetes Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Causes for the development of lipodystrophy among HIV and AIDS patients

Today, about 35 million people worldwide are infected with HIV. These patients often develop lipid metabolism disorder called lipodystrophy syndrome. Various clinical features of lipodystrophy are peripheral fat loss in the lower limbs, face and buttocks (lipoatrophy); central adiposity, i.e. excess fat accumulation in the abdomen, breasts or dorsocervical region (lipohypertrophy); lipoma development. These types of redistribution of the adipose tissue occur in isolation as well as combined. The article examines the following causes of the development of lipodystrophy: HIV-associated lipodystrophy, HAART-associated lipodystrophy and lipodystrophy caused by age-related changes. It is also pointed out that redistribution of the adipose tissue is more common among the HIV-patients who have had PI-based ART or nucleoside reverse transcriptase inhibitors-based ART (NRTIs).

Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome and Lipodystrophy: Pathophysiology and Current Therapeutic Interventions

The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outcome of HIV disease with a decrease in mortality and morbidity. However, the inclusion of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (tNRTIs) has strongly been linked to the development of metabolic abnormalities and lipodystrophy. Lipodystrophy is defined by the loss of peripheral subcutaneous fat and central adiposity, mainly in the abdomen, breast and dorsocervical region. These disorders are reported to be cosmetically distressing and socially stigmatizing to many patients leading to decreased adherence to antiretroviral therapy. Metabolic syndrome precedes lipodystrophy leading to increased risk of diabetes and cardiovascular diseases. With a shifted trajectory of HIV/AIDS morbidity from immunodeficiency and opportunistic infections to metabolic complications, clinical management of these patients has therefore become more complex. Currently there are no evidence-based standard guidelines for the management of HIV-associated lipodystrophy. Several pharmacological interventions such as using anti-diabetic, anti-dyslipidemic drugs or hormone replacement therapy have been tried to effectively improve metabolic syndrome and lipodystrophy but have been hampered by low efficacy, drug interactions, or unwanted side-effects. Non-pharmacological interventions including surgical manipulations, dietary and lifestyle modifications have also been tried with limited success. This review focuses on the proposed mechanisms involved in the development of metabolic syndrome and lipodystrophy, and highlights suggested potential therapeutic interventions to prevent lipodystrophy associated with HAART. J Endocrinol Metab. 2017;7(4):103-116 doi: https://doi.org/10.14740/jem364w

Antiretroviral Treatment-Associated Labia Majora Lipohypertrophy: A Rare Case and Plastic Surgical Treatment Options

The emergence of highly active antiretroviral therapy (HAART) has revolutionized the prognosis of HIV-infected patients. However, the extended use of HAART is associated with a disfiguring complication termed lipodystrophy, a disorder of body fat maldistribution causing peripheral fat loss (lipoatrophy) and central fat accumulation (lipohypertrophy). Lipoatrophy commonly affects the face, legs, buttocks and arm, whilst lipohypertrophy frequently favours the abdomen, breast and dorsocervical region. To our knowledge, we present only the second documented case in the literature of a labia majora lipohypertrophy in a HIV-positive patient receiving long-term HAART. The severity of labial abnormality caused significant physical and functional morbidities. Labiaplasty with dermolipectomy of the labia majora and excisional lipectomy of the mons pubis was successfully performed. At a 6-month follow-up, patient had no recurrence with resolution of symptoms and resumption of normal activities of daily living (ADL).

Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome and Lipodystrophy: Pathophysiology and Current Therapeutic Interventions

The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outcome of HIV disease with a decrease in mortality and morbidity. However, the inclusion of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (tNRTIs) has strongly been linked to the development of metabolic abnormalities and lipodystrophy. Lipodystrophy is defined by the loss of peripheral subcutaneous fat and central adiposity, mainly in the abdomen, breast and dorsocervical region. These disorders are reported to be cosmetically distressing and socially stigmatizing to many patients leading to decreased adherence to antiretroviral therapy. Metabolic syndrome precedes lipodystrophy leading to increased risk of diabetes and cardiovascular diseases. With a shifted trajectory of HIV/AIDS morbidity from immunodeficiency and opportunistic infections to metabolic complications, clinical management of these patients has therefore become more complex. Currently there are no evidence-based standard guidelines for the management of HIV-associated lipodystrophy. Several pharmacological interventions such as using anti-diabetic, anti-dyslipidemic drugs or hormone replacement therapy have been tried to effectively improve metabolic syndrome and lipodystrophy but have been hampered by low efficacy, drug interactions, or unwanted side-effects. Non-pharmacological interventions including surgical manipulations, dietary and lifestyle modifications have also been tried with limited success. This review focuses on the proposed mechanisms involved in the development of metabolic syndrome and lipodystrophy, and highlights suggested potential therapeutic interventions to prevent lipodystrophy associated with HAART. J Endocrinol Metab. 2017;7(4):103-116 doi: https://doi.org/10.14740/jem364w

INFLUENCE OF HEALTHY LIVING HABITS IN THE TRIGGERING OF HIV LIPODYSTROPHY SYNDROME

Patients in HAART (highly active antiretroviral therapy) showed peripheral fat loss, central fat accumulation and/or lipid and glucose metabolic manifestations, characteristics of HIV lipodystrophy syndrome (HIVLS). The present study aimed to assess the influence of healthy lifestyle habits on HIVLS effects. The sample included 51 volunteers with serum chemistry changes that matched lipodystrophy. Food Frequency and International Physical Activity Short Form questionnaires were used to form the following groups: control (proper feed and active, N = 31) and study (inadequate feed and/or inactive, N = 20). The groups were assessed regarding body anthropometry and lipodystrophy severity. Both groups were formed by active individuals. A poor diet contributed to high waist-hip ratio in males from the study group (p < 0.05). In addition, a poor diet also contributed to body weight increase, which causes elevated blood glucose in patients with HIVLS. There was no interference of healthy living habits in HIVLS physical severity. However, anthropometric parameters and serum biochemistry monitoring can provide valuable information for early diagnosis of secondary morphological changes related to antiretroviral therapy *Corresponding author: Iracema Hermes Pires de Melo Montenegro, University of Pernambuco, PetrolinaCampus, College of Nutrition, BR 203, Km 2 Vila Eduardo, Petrolina PE, 56328-903, Tel: (87) 3866-6468; Fax: (87) 3866-6470; E-mail: iracemamelo@hotmail.com Received Date: April 24, 2016 Accepted Date: August 22, 2016 Published Date: August 29, 2016

The role of adipokines in HIV lipodystrophy.

Changes in body fat distribution are frequent findings in HIV/AIDS patients, with onset shortly after initiation of combination antiretroviral therapy (cART). Lipoatrophy (loss of peripheral subcutaneous fat from the face, arms, legs and buttocks, coupled with pronounced blood vessels in the arms and legs), can occur alone or in combination with lipohypertrophy (fat accumulation on the dorsocervical and abdominal regions). These changes are associated with diabetes and insulin resistance, metabolic abnormalities and increased risk of cardiovascular diseases. The adipose tissue is now considered to be not only an energy storage organ, but also a metabolically-active endocrine organ that releases bioactive peptides (e.g., adipokines) into the bloodstream. Patients with lipodystrophy may experience marked changes in the circulating levels of adipocyte-secreted hormones, including adiponectin, leptin and resistin, to name a few. The role of adipocytokines in the pathogenesis of HIV-associated lipodystrophy is still not enough understood. The most studied of adipokines, adiponectin expression is suppressed in obesity and diabetes, and inversely-correlated with insulin resistance and serum triglycerides. Previously published studies have shown that circulating adiponectin levels are lower in patients with chronic HIV infection accompanied by adipose tissue redistribution. Furthermore, in patients treated with cART, especially those with lipodystrophy, a gradual decrease of adiponectin levels has been noticed, coupled with a consecutive increase in cardiovascular risk. On the other hand, the correlation between cART and leptin levels in HIV/AIDS patients is still up for debate. Recently published studies have either associated cART with lipodystrophy and hypoleptinemia, or denied an effect of cART on serum leptin levels. Despite promising data from animal studies, the association of resistin with insulin resistance, diabetes or obesity has not been consistent in humans. Moreover, as part of a complex network of cART-related metabolic changes, elevated resistin levels have been reported in HIV/AIDS patients when compared to uninfected individuals. The predictive value of changes in adipocytokine levels for adipose tissue redistribution and other connected metabolic disturbances should be evaluated in future studies to eventually enhance our understanding of the complex relations between HIV infection per se, drug-associated toxic effects, host genetic predisposition and several other factors participating and generating lipodystrophy and a subsequent development of the HIV metabolic syndrome.

Treating peripheral facial fat loss in patients with human immunodeficiency virus

Nurses play a fundamental role in the treatment of human immunodeficiency virus (HIV) associated facial lipoatrophy, as the treatment not only focuses on the visual facial changes, but also the psychological impact and resulting improvement of quality of life as the patient responds to reconstructive treatment. Poly-I-lactic acid injections is one of the treatment options available and allows for facial contours and volume to be restored while being minimally invasive. Nurses have the required skills to treat this iatrogenic problem, which has many complex issues around adherence to HIV therapy, stigmatisation around being HIV positive, self-esteem and body image. Treating facial lipoatrophy should be seen as medical aesthetics as it is reconstructive and not cosmetic.

The association of self-perception of body fat changes and quality of life in the Women's Interagency HIV Study

Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1671 HAART-using HIV-seropositive women (mean age 40±8 years; 54% African-American, 24% reporting <95% HAART adherence) from the Women's Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however, peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites was associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects.

Effect of Different Antiretroviral Drug Regimens on Body Fat Distribution of HIV-Infected South African Women

No African studies have examined the effect of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based and second-line protease inhibitor (PI)-based antiretroviral therapy (ART) on body composition. We compared body composition in HIV-infected black South African women receiving NNRTI-based ART (ART1, n=344), PI-based ART (ART2, n=91), and those not on ART (ART-naive, n=309). Accordingly, body composition was measured using dual energy x-ray absorptiometry (DXA) and anthropometry in a cross-sectional study. Despite similar body mass index (BMI), ART1 and ART2 had greater central fat mass (FM) [median (IQR): 44.2 (39.4-50.1) and 46.9 (39.3-52.8) vs. 41.1 (36.3-45.2) %FM, p<0.01] and less leg FM [41.2 (34.8-45.8) and 40.2 (32.9-45.7) vs. 43.9 (39.3-48.1) %FM, p<0.01] than ART-naive women. Within ART1, waist:hip was greater [0.87 (0.81-0.92) vs. 0.84 (0.78-0.89), p=0.006], while calf skinfold was lower [15.2 (9.4-21.5) vs. 17.4 (12.0-23.6) mm, p=0.033] in women receiving efavirenz compared to nevirapine. ART2 had a greater waist:hip, and abdominal, subscapular, and suprailiac skinfolds than ART1 (p<0.05). After adjusting for time on d4T (stavudine), ART2 had greater body fat than ART1 (p<0.05). With increasing time on d4T, the decrease in leg fat (%FM) was higher in ART1 than ART2 (p=0.012, for time×treatment effect). A similar interaction was reported for total time on ART treatment (p=0.002 for time×treatment effect). In conclusion, ART was associated with increased central fat and reduced peripheral fat. Changing to a PI-based regimen in ART2, which also substitutes stavudine with zidovudine, partially reversed the peripheral fat loss observed on ART1.

The influence of HLA supertype on thymidine analogue associated with low peripheral fat in HIV

To examine the relationship between human leukocyte antigen (HLA) genotype and body composition changes induced by thymidine analogue nucleoside reverse transcriptase inhibitor (NtRTI) use in HIV-positive individuals. Data collected during the Simplification with Tenofovir-Emtricitabine (TDF-FTC) or Abacavir-Lamivudine (ABC-3TC) (STEAL) study were analysed to examine the potential association of HLA genotypes with changes in body composition in treatment-experienced HIV-positive individuals. Demographic, HIV-related, body composition and HLA genotyping data from the STEAL study were used in this analysis. The mean percentage peripheral fat at study baseline was compared in participants with and without prior NtRTI use. Analyses were also carried out for each HLA supertype strata, for five HLA genes, within the thymidine-exposed group. These comparisons were made using Mann-Whitney rank-sum tests. Participants with prior NtRTI use had a significantly lower baseline mean peripheral fat percentage compared to those without NtRTI use (31.9 vs. 34.7%; P = 0.0045). However, participants carrying one or more of the three particular HLA supertype alleles, A01, B08 and DQ2, showed no significant difference in mean peripheral fat percentage at baseline by NtRTI use. Among participants with prior NtRTI exposure, there were significant differences in mean peripheral fat by HLA A01, B08 and DQ2 allele expression compared to those without expression of these alleles (A01: 34.91% vs. no A01: 30.3%; P = 0.0087; B08: 36.2% vs. no B08: 31.1%; P = 0.0317; DQ2: 35.16% vs. no DQ2: 30.06%; P = 0.0081). This analysis suggests that HIV-infected individuals carrying HLA A01, B08 or DQ2 supertype alleles may be resistant to NtRTI-induced peripheral fat loss.

Thymidine Analogues Suppress Autophagy and Adipogenesis in Cultured Adipocytes

Lipoatrophy in HIV patients can result from prolonged exposure to thymidine analogues. Mitochondrial toxicity leading to dysregulated adipogenesis and increased cell death has been proposed as a leading factor in the etiology of peripheral fat loss. We hypothesized that thymidine analogues interfere with autophagy, a lysosomal degradation pathway, which is important for mitochondrial quality control, cellular survival, and adipogenesis. We assessed the effects of zidovudine (AZT), stavudine (d4T), and lamivudine (3TC) on autophagy in eukaryotic cells and adipocytes (3T3-F442A) by fluorescence microscopy and flow cytometry. The effects were compared to interventions with established genetic and pharmacological inhibitors of autophagy and correlated to assessments of cell viability, proliferation, and differentiation. AZT and d4T, but not 3TC, inhibited both constitutive and induced autophagic activity in adipocytes. This inhibition was associated with accumulation of dysfunctional mitochondria, increased reactive oxygen species (ROS) production, increased apoptosis, decreased proliferation, and impaired adipogenic conversion. Autophagy inhibition was dose and time dependent and detectable at therapeutic drug concentrations. Similar phenotypic changes were obtained when genetic or pharmacological inhibition of autophagy was employed. Our data suggest that thymidine analogues disturb adipocyte function through inhibition of autophagy. This novel mechanism potentially contributes to peripheral fat loss in HIV-infected patients.

Peripheral fat loss and decline in adipogenesis in older humans

ObjectiveAging is associated with a redistribution of body fat including a relative loss of subcutaneous peripheral fat. These changes in body fat can have important clinical consequences since they are linked to increased risk of metabolic complications. The causes and mechanisms of loss of peripheral fat associated with aging are not clear. The aim of this study was to assess whether defects in adipogenesis contribute to fat loss in aging humans, as suggested from animal studies, and to evaluate the role of inflammation on pathogenesis of fat loss. Materials/MethodsPreadipocytes isolated from subcutaneous peripheral fat of healthy young and elderly subjects were compared in their ability to replicate and differentiate. ResultsThe results show that both the rate of replication and differentiation of preadipocytes are reduced in older subjects. The reduction in adipogenesis is accompanied by a higher plasma level of the inflammatory marker, soluble tumor necrosis factor receptor 2, and greater release of tumor necrosis factor α from fat tissue. ConclusionsThus, the gradual relative loss of peripheral fat in aging humans may in part result from a defect in adipogenesis, which may be linked to inflammation and increased release of proinflammatory cytokines from fat tissue.