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Lipodystrophy in HIV-infected patients (LDHIV) includes morphological and metabolic abnormalities, including lipid and glucose metabolism. ApoE plays a role in the transport and clearance of lipoprotein. In the general population, ApoE 112 (rs429358) and 158 (rs7412) polymorphisms were linked to severe dyslipidemia. Therefore, we investigated ApoE polymorphism using PCR-RFLP in 200 HIV patients (100 with HIV-associated lipodystrophy (HIVLD), 100 without HIVLD), as well as 100 healthy controls. We also assessed ApoE expression using qRT-PCR and measured its level using ELISA. The APOE 4/4, 3/4, and 2/4 genotypes have been associated with a decreased risk of HIV-1 infection. (P = 0.0001, OR = 0.18; P = 0.006, OR = 0.87; P = 0.006, OR = 0.09) when compared between HIV-positive individuals and healthy controls. Conversely, APOE allele 2 was linked to a higher risk of acquiring HIV-1 (P = 0.03, OR = 3.02). APOE allele 2 was linked to a higher likelihood of HIVLD severity when compared between patients with and without HIVLD (P = 0.05, OR = 2.82). When comparing patients with HIVLD to healthy controls, the APOE 4/4 and 2/4 genotypes as well as allele 4 were linked with the reduced risk of LDHIV (P = 0.0006, OR = 0.21; P = 0.01, OR = 0.18; P = 0.0002, OR = 0.40). When compared to patients without HIVLD from healthy controls, the ApoE 4/4 genotype, 2 and 4 alleles, were linked to a reduced risk of developing HIVLD (P = 0.0009, OR = 0.14; P = 0.0001, OR = 0.17; P = 0.00001, OR = 0.39). When comparing impaired to normal cholesterol levels in patients without HIVLD, the ApoE 3/4 genotype was linked with the increased risk of impaired cholesterol levels (P = 0.02, OR = 3.37). When comparing impaired and normal glucose levels in patients without HIVLD, the ApoE 4/4 genotype was associated to an elevated risk of impaired glucose levels (P = 0.03, OR = 8.27). In multivariate analysis, independent impaired cholesterol, LDL, and glucose levels were associated with a higher risk of lipodystrophy severity (P = 0.04, OR = 2.33; P = 0.001, OR = 4.05; P = 0.05, OR = 2.63). ApoE expression was up-regulated in LDHIV with a fold change value of 4.02 compared to those without HIVLD. ApoE protein level was found to be higher in patients of the HIVLD group (3.01 mg/dL) compared to those without HIVLD group (2.83 mg/dL). In conclusion, individuals with ApoE allele 2 were at higher risk for HIV-1 acquisition and severity of HIVLD, whereas those with ApoE allele 4 were at reduced HIVLD severity and development risk. It's possible that ApoE's increased level and its overexpression are related to the ApoE allele 2 in HIVLD patients. The development of LDHIV may be facilitated by the APOE 3/4 and 4/4 genotypes as well as abnormal glucose and cholesterol levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The differential diagnosis of lipodystrophy involves other disorders characterized by severe fat loss and may be sometimes challenging. Owing to the rarity of lipodystrophy, it is relevant to search for tools and assays that differentiate it from other diseases that may mimic it. We conducted a study on leptin and high molecular weight (HMW) adiponectin serum concentrations in a series of patients diagnosed with lipodystrophy and compared them with those found in anorexia nervosa, one of the illnesses that may be cause of a missed diagnosis of lipodystrophy., Methods: Leptin and HMW adiponectin serum concentrations were measured in six patients diagnosed with generalized lipodystrophy (GL), six with progeroid syndromes (PS), 13 with familial partial lipodystrophy type 1 (FPLD1, Kobberling syndrome), 10 with familial partial lipodystrophy type 2 (FPLD2, Dunnigan syndrome), 18 with acquired partial lipodystrophy (APL) and 12 affected by anorexia nervosa (AN). Measurements were compared to those obtained in 12 normal weight healthy subjects., Results: Serum leptin concentrations were reduced to a similar degree in GL, PS and AN, proportionally to the extent of fat loss. Serum concentrations of HMW adiponectin were found extremely low in patients with GL and PS, while comparable to normal weight subjects in patients with AN., Conclusion: Serum HMW adiponectin can be regarded as a useful tool to discriminate between generalized lipodystrophy syndromes (including PS) and AN., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Lipodystrophies (LDs) are rare, complex disorders of the adipose tissue characterized by selective fat loss, altered adipokine profile and metabolic impairment. Sirtuins (SIRTs) are class III NAD + -dependent histone deacetylases linked to fat metabolism. SIRT1 plays a critical role in metabolic health by deacetylating target proteins in tissue types including liver, muscle, and adipose. Circulating SIRT1 levels have been found to be reduced in obesity and increased in anorexia nervosa and patients experiencing weight loss. We evaluated circulating SIRT1 levels in relation to fat levels in 32 lipodystrophic patients affected by congenital or acquired LDs compared to non-LD subjects (24 with anorexia nervosa, 22 normal weight, and 24 with obesity). SIRT1 serum levels were higher in LDs than normal weight subjects (mean ± SEM 4.18 ± 0.48 vs. 2.59 ± 0.20 ng/mL) and subjects with obesity (1.7 ± 0.39 ng/mL), whereas they were close to those measured in anorexia nervosa (3.44 ± 0.46 ng/mL). Our findings show that within the LD group, there was no relationship between SIRT1 levels and the amount of body fat. The mechanisms responsible for secretion and regulation of SIRT1 in LD deserve further investigation.

Context: Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency decreases energy expenditure (EE), which is corrected following leptin replacement. In humans, data are mixed regarding leptin-mediated effects on EE., Objective: To determine the effects of metreleptin on EE in patients with lipodystrophy., Design, Setting, and Patients: Nonrandomized crossover study of 25 patients with lipodystrophy (National Institutes of Health, 2013-2018)., Intervention: The initiation cohort consisted of 17 patients without prior exposure to metreleptin, studied before and after 14 days of metreleptin. The withdrawal cohort consisted of 8 previously metreleptin-treated patients, studied before and after 14 days of metreleptin withdrawal., Main Outcomes: 24-h total energy expenditure (TEE), resting energy expenditure (REE), autonomic nervous system activity [heart rate variability (HrV)], plasma-free triiodothyronine (T3), free thyroxine (T4), epinephrine, norepinephrine, and dopamine., Results: In the initiation cohort, TEE and REE decreased by 5.0% (121 ± 152 kcal/day; P = 0.006) and 5.9% (120 ± 175 kcal/day; P = 0.02). Free T3 increased by 19.4% (40 ± 49 pg/dL; P = 0.01). No changes in catecholamines or HrV were observed. In the withdrawal cohort, free T3 decreased by 8.0% (P = 0.04), free T4 decreased by 11.9% (P = 0.002), and norepinephrine decreased by 34.2% (P = 0.03), but no changes in EE, epinephrine, dopamine, or HrV were observed., Conclusions: Metreleptin initiation decreased EE in patients with lipodystrophy, but no changes were observed after metreleptin withdrawal. Thyroid hormone was higher on metreleptin in both initiation and withdrawal cohorts. Decreased EE after metreleptin in lipodystrophy may result from reductions in energy-requiring metabolic processes that counteract increases in EE via adipose tissue-specific neuroendocrine and adrenergic signaling., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Complement overactivation has been reported in most patients with Barraquer-Simons syndrome (BSS), a rare form of acquired partial lipodystrophy. Complement Factor D (FD) is a serine protease with a crucial role in the activation of the alternative pathway of the complement system, which is mainly synthesized by adipose tissue. However, its role in the pathogenesis of BSS has not been addressed. In this study, plasma FD concentration was measured in 13 patients with BSS, 20 patients with acquired generalized lipodystrophy, 22 patients with C3 glomerulopathy (C3G), and 50 healthy controls. Gene expression and immunohistochemistry studies were assayed using atrophied adipose tissue from a patient with BSS. We found significantly elevated FD levels in BSS cases compared with the remaining cohorts ( p < 0.001). There were no significant differences in FD levels between sexes but FD was strongly and directly associated with age in BSS ( r = 0.7593, p = 0.0036). A positive correlation between FD and C3 was seen in patients with C3G, characterized by decreased FD levels due to chronic C3 consumption, but no correlation was detected for BSS. Following mRNA quantification in the patient's adipose tissue, we observed decreased C FD and C3 but elevated C5 transcript levels. In contrast, the increased FD staining detected in the atrophied areas reflects the effects of persistent tissue damage on the adipose tissue, thus providing information on the ongoing pathogenic process. Our results suggest that FD could be a reliable diagnostic biomarker involved in the pathophysiology of BSS by promoting unrestrained local complement system activation in the adipose tissue environment.

A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.

Objective . Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods . GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results . Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) ( p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions . Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment., Competing Interests: K.M. has consulted for Aegerion Pharmaceuticals. S.K., A.H., J.E.-K., M.S., M.F., and A.T. declare no conflict of interest.

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.

BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.

Purpose: To collect data capable of pointing out the effects of the ultracavitation treatment on the liver of rabbits after adipose tissue application, by means of histological analyses of the liver and hematological and biochemical exams., Methods: This is an experimental study with 12 albino rabbits as sample, which were divided into 3 groups and submitted to a hypercaloric diet for one month. Subsequently, subjects underwent UCV treatment: 3 minutes, 30 W, continuous mode at 100%, every 2 ERAS = 441.02 J/cm2, intensity of 10w/cm2. They were then euthanized and underwent biopsy after 24 hours., Results: After 48 hours from the ultracavitation treatment, the animals' livers presented greater amount of fat infiltration if compared to the amount presented 96 hours after the treatment. However, laboratory tests showed no alterations. Values were maintained within normal parameters of cholesterol, triglycerides, liver enzymes, hemoglobin and hematocrit levels., Conclusions: This study has identified that infiltrates may appear on livers after the treatment, despite high hematological and biochemical tests results. The fat infiltrates reduction 96 h after treatment suggests lower risks to animal health, if the period between applications is respected.

Kindlin-2 regulates integrin-mediated cell adhesion to and migration on the extracellular matrix. Our recent studies demonstrate important roles of kindlin-2 in regulation of mesenchymal stem cell differentiation and skeletal development. In this study, we generated adipose tissue-specific conditional knockout of kindlin-2 in mice by using Adipoq-Cre BAC-transgenic mice. The results showed that deleting kindlin-2 expression in adipocytes in mice caused a severe lipodystrophy with drastically reduced adipose tissue mass. Kindlin-2 ablation elevated the blood levels of nonesterified fatty acids and triglycerides, resulting in massive fatty livers in the mutant mice fed with high-fat diet (HFD). Furthermore, HFD-fed mutant mice displayed type II diabetes-like phenotypes, including elevated levels of fasting blood glucose, glucose intolerance, and peripheral insulin resistance. Kindlin-2 loss dramatically reduced the expression levels of multiple key factors, including PPARγ, mTOR, AKT, and β-catenin proteins, and suppressed adipocyte gene expression and differentiation. Finally, kindlin-2 loss drastically reduced leptin production and caused a high bone mass phenotype. Collectively, these studies establish a critical role of kindlin-2 in control of adipogenesis and lipid metabolism as well as bone homeostasis.

Aim: To estimate clinical significance of lipohypertrophy (LH) without visual and palpable changes, detected by ultrasonography of subcutaneous fat., Materials and Methods: This study included 140 diabetic patients who received insulin in basal-bolus regimen. Ultrasonography of subcutaneous fat was performed for LH diagnostics in these diabetic patients. Than clinical significance of LH without visual and palpable changes was estimated. HbA1c level, fasting and postprandial glucose, episodes of hypoglycemia, body mass index (BMI) and scheme of insulinotherapy were evaluated at the moment of LH, after 3 and 6 months in all patients., Results: After changing injection sites, good results were demonstrated by measuring glucose and HbA1c level. Thus fasting glucose decreased from 9.03±1.98 mmol/l to 7.11±0.95 mmol/l (p=0.023). Postprandial glucose reduced from 10.27±2.72 mmol/l to 9.34±1.21 mmol/l (p=0.011). HbA1c level reduced from 9.27±1.75% to 7.43±1.02% (p=0.002). Also BMI decreased from 33.75±3.49 kg/m2 to 30.5±2.96 kg/m2 (p=0.018)., Conclusion: LH without visual and palpable changes could worsen compensation of glycemic control and leads to hypoglycemia and chronic Somogyi rebound. So, LH without visual and palpable is as important and clinically significant as classic LH.

Homozygous mutations in Triggering Receptor Expressed on Myeloid cells 2 gene (TREM2) are one of the major causes of Nasu Hakola Disease (NHD). We analysed Peripheral Blood Mononuclear Cells (PBMC) profile of 164 inflammatory factors in patients with NHD carrying the TREM2 Q33X mutation as compared with heterozygous and wild type individuals. Several molecules related to bone formation and angiogenesis were altered in NHD compared to non-carriers: Bone Morphogenetic Protein (BMP)-1 mRNA levels were significantly increased in PBMC (2.32 fold-increase; P = 0.01), as were Transforming Growth Factor Beta (TGFB)3 levels (1.51 fold-increase; P = 0.02). Conversely, CXCL5 and Pro Platelet Basic Protein (PPBP) were strongly downregulated (-28.26, -9.85 fold-decrease over non-carriers, respectively, P = 0.01), as well as Platelet Factor 4 Variant 1 (PF4V1; -41.44, P = 0.03). Among other inflammatory factors evaluated, Interleukin (IL)-15 and Tumor Necrosis Factor Superfamily Member (TNFSF)4 mRNA levels were decreased in NHD as compared with non-carriers (-2.25 and -3.87 fold-decrease, P = 0.01 and 0.001, respectively). In heterozygous individuals, no significant differences were observed, apart from IL-15 mRNA levels, that were decreased at the same extent as NHD (-2.05 fold-decrease over non-carriers, P = 0.002). We identified a signature in PBMC from patients with NHD consisting of strongly decreased mRNA levels of CXCL5, PPBP, PF4V1, mildly decreased IL-15 and TNFSF4 and mildly increased BMP-1 and TGFB3., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lipohypertophy (LH) is the most common skin complication of incorrect injection technique which does not only represent an aesthetic defect but also severely disrupts insulin pharmacokinetics/pharmacodynamics. As a consequence of that, hormone release is delayed and unexplained/unpredictable hypoglycemia occurs, both deteriorating metabolic control while negatively affecting adherence to treatment and quality of life. The economic burden due to unwanted intra-LH injections is accounted for by inappropriately high insulin requirements, increased emergency-related hospitalizations, and loss of work days. Greater attention has to be paid by diabetes care teams to education programs with periodic refreshers to achieve better metabolic control and reduce the economic burden of diabetes., (Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Background: Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant., Methods: Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy., Results: With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover)., Conclusion: Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake., Trial Registration: ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Objective: Fetuin B is an adipokine/hepatokine which is significantly elevated in insulin resistance/type 2 diabetes mellitus and hepatic steatosis. Regulation of fetuin B in patients with lipodystrophy (LD) - a disease group which is characterized by subcutaneous adipose tissue loss, hypertriglyceridemia, hepatic steatosis, insulin resistance, and dysregulation of several adipokines - has not been elucidated so far., Material and Methods: Serum fetuin B levels were determined in 37 patients with LD, as well as in a control cohort consisting of 37 non-LD participants matched for age, gender, and body mass index. Furthermore, fetuin B was correlated with parameters of lipid metabolism, glucose control, renal function, and inflammation., Results: Median fetuin B serum levels were not significantly different between patients with LD (2980.7 µg/l; interquartile range: 841.7 µg/l) and non-LD controls (2647.3 µg/l; interquartile range: 923.6 µg/l; p = .105). Fetuin B was associated with age, body mass index, markers of renal function, and C reactive protein (CRP) in univariate correlation analyses. The associations with age and creatinine remained significant in multiple linear regression analysis., Conclusions: Fetuin B serum concentrations are not significantly different between patients with LD and non-LD controls. Fetuin B does not seem to be a major pathogenetic factor in LD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced ∼50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various autoimmune and inflammatory human diseases., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Growth factor signaling via insulin receptor (IR) and IGF-1 receptor (IGF1R) plays several important roles in the pathogenesis of metabolic syndrome and diabetes. OSI-906 (linsitinib), an anti-tumor drug, is an orally bioavailable dual inhibitor of IR and IGF1R. To investigate the recovery from metabolic changes induced by the acute inhibition of IR and IGF1R in adult mice, mice were treated with OSI-906 or a vehicle for 7 days and the results were analyzed on the last day of injection (Day 7) or after 7 or 21 days of withdrawal (Day 14 or Day 28). On day 7, the visceral white fat mass was significantly reduced in mice treated with OSI-906 accompanied by a reduced expression of leptin and an increased expression of the lipolysis-related genes Lpl and Atgl. Interestingly, the lipoatrophy and the observed changes in gene expression were completely reversed on day 14. Similarly, liver steatosis and β cell proliferation were transiently observed on day 7 but had disappeared by day 14. Taken together, these results suggest that this model for the acute inhibition of systemic IR/IGF1R signaling may be useful for investigating the recovery from metabolic disorders induced by impaired growth factor signaling.

Background: Fibroblast growth factor-21 (FGF21) has emerged as an important regulator of glucose, lipid, and body weight homeostasis. However, recent experimental studies have reported that increased FGF21 levels may lead to bone loss., Objective: To assess the relationship of serum FGF21 levels and altered bone homeostasis in HIV-1-infected patients., Design: Cross-sectional study of 137 HIV-1-infected patients and 35 healthy controls conducted at the Hospital de la Santa Creu i Sant Pau, Barcelona. Among HIV-1-infected patients, 35 were untreated (naïve), 43 were treated with antiretrovirals (HIV-1/ART) with no lipodystrophy, and 59 patients were HIV-1/ART and experienced lipodystrophy. Bone mineral density (BMD) and content (BMC) were assessed using dual-energy X-ray absorptiometry. Serum levels of FGF21, receptor activator of nuclear factor (NF)-KB ligand (RANKL), and C-telopeptide of type-I collagen (CTX-1) were measured by enzyme-linked immunosorbent assays. Serum levels of osteocalcin, osteoprotegerin, leptin, tumor necrosis factor-α, interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 were determined using an antibody-linked, fluorescently labeled microsphere bead-based multiplex analysis system., Results: Alterations in bone parameters and bone homeostasis marker levels were consistent with higher turnover and bone loss in HIV-1 infected patients. FGF21 correlated negatively with BMD and BMC. FGF21 correlated positively with serum levels of osteoprotegerin and CTX-1, as well as with the CTX-1/osteocalcin ratio., Conclusions: Elevated FGF21 levels are associated with poor bone homeostasis in HIV-1-infected patients. Increases in FGF21 serum level may be an indicator not only of metabolic derangement but it may also serve as a biomarker of altered bone homeostasis in HIV-1 infected patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin., Objective: Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin., Design: Prospective, single-arm, open-label studies with continuous enrollment since 2000., Setting: National Institutes of Health, Bethesda, Maryland., Patients: Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia)., Intervention: Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d)., Main Outcome Measures: Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment., Results: After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty., Conclusion: Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease., (Copyright © 2017 by the Endocrine Society)

Objective: Lipodystrophy (LD) syndromes are associated with diabetes mellitus, hypertriglyceridemia, and coronary artery disease. One pathogenetic factor of LD is dysregulation of several adipokines. However, the insulin resistance- and dyslipidemia-promoting adipokines adipocyte (AFABP) and epidermal (EFABP) fatty acid-binding protein have not been investigated in non-HIV-associated LD so far., Material and Methods: We performed a cross-sectional analysis of AFABP and EFABP serum concentrations in 37 LD patients and 37 age-, gender-, and body mass index-matched healthy controls. Moreover, AFABP and EFABP were correlated to clinical and biochemical parameters of inflammation, glucose control, and lipid metabolism., Results: There was no significant difference in median circulating AFABP and EFABP levels between LD patients (21.7μg/l and 7.5μg/l, respectively) and healthy controls (24.5μg/l and 8.6μg/l, respectively). Neither AFABP nor EFABP were related to markers of impaired glucose control or lipid metabolism. Multiple linear regression analysis showed a positive and independent association of AFABP with gender, serum leptin levels, and body mass index., Conclusions: Circulating levels of AFABP and EFABP are not decreased in LD despite adipose tissue loss in contrast to other adipokines including leptin and adiponectin., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Leptin, adiponectin, and resistin may play an important role in the development of lipodystrophy (LD) in HIV/AIDS patients. The aim of this study was to correlate levels of leptin, adiponectin, and resistin between HIV/AIDS patients with LD and without lipodystrophy (non-LD), as well as between subgroups of LD [lipoatrophy (LA), lipohypertrophy (LH), and mixed fat redistribution (MFR)] and non-LD patients., Methods: Cross-sectional study of 66 HIV/AIDS patients. Serum levels of leptin, adiponectin, and resistin were measured. The associations between adipocytokine levels and metabolic variables were estimated by Spearman correlation. Analysis of covariance with bootstrapping method was used to examine the relationship between adiponectin and leptin and lipodystrophy categories., Results: The LD was observed in 29 (44%) patients, while 15 (52%) of them had LA, 4 (14%) had LH, and 10 (34%) patients had MFR. No significant differences regarding leptin, adiponectin, and resistin levels, between LD and non-LD patients, were observed. LH patients had significantly higher levels of leptin and adiponectin in comparison with non-LD patients (P = 0.039, P = 0.011, respectively). Within the LD group, LA patients had significantly lower levels of leptin (LA vs. LH, P = 0.020; LA vs. MFR, P = 0.027), while LH patients had significantly higher levels of adiponectin (LH vs. LA, P = 0.027; LH vs. MFR, P = 0.028). Correlation of adiponectin with LD remains significant in the LH subgroup after adjustment for age, body mass index, cystatin-C, plasminogen activator inhibitor-1 (PAI-1), and interferon gamma (IFN-γ) (P = 0.001)., Conclusions: Adiponectin and leptin levels differ significantly between LH patients and non-LD patients, as well as between the LD subgroups. Adiponectin may be a more useful marker of LD in HIV/AIDS patients.

Background: The role of interleukins in the pathogenesis of lipodystrophy in HIV/AIDS-patients is still not understood. The aim of this study was to evaluate the relationship between serum levels of interleukins between HIV/AIDS-patients with or without lipodystrophy, as well as between different subgroups of lipodystrophy (lipoatrophy, lipohypertrophy, mixed-fat-redistribution) and patients without lipodystrophy., Methods: Cross-sectional study of 66 HIV/AIDS patients, all Caucasians. Serum levels of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10) were measured using Cytokine-Array-1 on Evidence Investigator, Biochip Array Technology. The associations between interleukins and anthropometric and metabolic variables were estimated by Spearman-correlation. Analysis of covariance with bootstrapping method (ACBM) was used to examine relationship between interleukins and lipodystrophy categories adjusted for confounding variables., Results: The lipodystrophy was observed in 29 (44%) patients, while 15 (52%) had lipoatrophy, 4 (14%) lipohypertrophy and 10 (34%) patients had mixed fat redistribution. There were 37 (56%) patients without lipodystrophy. Significantly lower levels of IL-4 and IL-10 were observed in lipodystrophy vs. non-lipodystrophy (p=0.008; p=0.027, respectively). No differences were found relating IL-1α, IL-1β, IL-2, IL-6 and IL-8 levels in lipodystrophy vs. non-lipodystrophy. In patient subgroup with lipoatrophy, significantly lower levels of IL-4 and IL-10 were found when compared to non-lipodystrophy (p=0.043; p=0.031, respectively). In lipohypertrophy subgroup significantly lower levels of IL-4 were found when compared to non-lipodystrophy (p=0.003). In order to estimate the correlation of IL-4 and IL-10 and the presence of lipodystrophy, ACBM showed that correlation of IL-4 levels in patients with lipodystrophy remains statistically significant (p=0.004) in all types of lipodystrophy: lipoatrophy, lipohypertrophy and mix-fat-redistribution (p=0.027; p=0.009; p=0.017, respectively) after adjustment for age, BMI., Conclusions: IL-4 and IL-10 levels were significantly lower in lipodystrophy vs. non-lipodystrophy. According to our knowledge, we showed for the first time significant correlation between IL-4 levels and lipodystrophy development in HIV/AIDS patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Lipohypertrophy (LH) is a complication of insulin therapy. We assessed LH prevalence, risk factors, insulin usage, and clinical and health economic effects in China., Methods: In four cities, 401 adult patients injecting insulin ≥1 year were surveyed for diabetes/insulin injection history and practices, pen needle reimbursement (PNR), and health resource utilization, followed by structured examination and HbA1c testing. Differences between those with and without LH were evaluated by Student's t-test or the Wilcoxon rank sum test. Insulin costs were calculated., Results: Patients were 59.6 ± 11.5 years old; 50% male; 93.5% type 2 diabetes. LH prevalence was 53.1%. Compared to those without LH, patients with LH had higher body mass index (BMI; 26 vs. 24.8 kg/m 2 ) and HbA1c (8.2% vs. 7.7% [66 vs. 61 mmol/mol]), took 11 IU (0.13 IU/kg or 31.7%) more insulin costing $1.4 versus $1.0 (RMB 9.5 vs. 6.8) daily, reused PNs more times, and had less PNR (all P ≤ 0.003). LH patients correctly rotated injection sites less often (67.6% vs. 92.3%, P < 0.0001). By stepwise logistic regression, BMI, needle reuse frequency, and PNR remained modestly associated with LH prevalence (odds ratios [OR] <1.9; P ≤ 0.03); weight-adjusted insulin dose and incorrect site rotation showed ORs of nearly 7 and 8.4, respectively (P ≤ 0.001). Extrapolated to 9 million insulin-injecting patients in China and adjusted for therapy adherence, LH-related excess annual insulin consumption cost is estimated at nearly $297 million (RMB 2 billion)., Conclusions: LH is common in China and associated with worse glycemic control, despite nearly one-third greater insulin consumption, with large cost implications. Proper injection technique education may reduce LH prevalence.

Aims: Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin. Progranulin, an adipokine with proinflammatory and insulin resistance-inducing characteristics, has not been investigated in LD so far., Methods: Circulating progranulin was determined in LD patients (N=37) and in age-, gender-, and body mass index-matched healthy control subjects (N=37). Additionally, we investigated progranulin expression in an LD mouse model as compared to wild-type mice. Moreover, we elucidated circulating progranulin before and during metreleptin supplementation in 10 patients with LD., Results: Median [interquartile range] circulating progranulin was increased in patients with LD (82.9 [25.9] μg/l) as compared to controls (73.6 [22.8] μg/l) (p=0.005). C-reactive protein (CRP) remained an independent and positive predictor of progranulin in multivariate analysis. Progranulin mRNA was significantly upregulated in all adipose tissue depots, i.e. visceral, subcutaneous, and brown adipose tissue, and in muscle of LD animals versus wild-type mice. Progranulin levels did not significantly change during metreleptin supplementation., Conclusions: Progranulin serum concentration is increased in patients with LD, and shows an independent and positive correlation with CRP. Different adipose tissue depots and muscle might be potential origins of elevated progranulin., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Partial lipodystrophy of the limbs (PLL) is a newly described form of lipodystrophy that is characterized by symmetrical distal lipoatrophy of the limbs and insulin resistant diabetes., Research Design and Methods: In this study, we prospectively screened our patients with type 2 diabetes for the presence of PLL phenotype. Metabolic parameters of PLL patients were compared to those with type 2 diabetes who applied to our diabetes clinic during the same period of time., Results: Between Sep 2013 and Mar 2015, 2020 patients with type 2 diabetes were evaluated for the presence of PLL. PLL was confirmed in 16 patients. The prevalence of PLL was calculated as 0.79% in our diabetes clinic. The most common phenotypic presentations were loss of subcutaneous fat in the forearms, calves and thighs, and loss of fat in forearms and calves. Patients with PLL had poor metabolic control and marked insulin resistance compared to subjects with type 2 diabetes. Diabetes had been diagnosed at a younger age in patients with PLL. Patients with PLL also had more atherogenic lipid profiles., Conclusions: Our data suggests that PLL is a relatively common form of lipodystrophy in diabetes clinics, which is associated with poor metabolic control and marked insulin resistance. The recognition of PLL in patients with type 2 diabetes can help better clinical management by alerting the physician to these associated co-morbidities., (Copyright © 2015 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Objective: Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD., Material and Methods: Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index. Moreover, FGF21 plasma levels and mRNA expression were measured in LD mice and control animals. Additionally, serum FGF21 levels were assessed in 10 LD patients before and during metreleptin therapy., Results: Median FGF21 serum concentrations were significantly higher in LD patients (381.2ng/l) as compared to the control group (231.2ng/l; p=0.023). There was an independent and positive association between circulating FGF21 and serum triglycerides (TG), as well as fibrate treatment, in multiple linear regression analysis. LD mice showed significantly upregulated FGF21 plasma levels (4.5-fold), as well as mRNA expression in various adipose tissue depots and liver as compared to controls (p<0.05). Metreleptin treatment did not significantly alter circulating FGF21 levels in human subjects., Conclusions: Serum concentrations of FGF21 are elevated in patients with non-HIV LD with adipose tissue and liver being potential sources of increased production. TG and fibrate treatment are independent positive predictors of circulating FGF21., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Lipodystrophy (LD) is characterized by loss of adipose tissue, dysregulation of adipokines and severe metabolic complications. Regulation of the insulin resistance-inducing and proinflammatory adipokine chemerin has not been assessed in LD. Therefore, we determined chemerin serum levels in LD, chemerin mRNA expression in insulin-sensitive tissues of LD mice, as well as the impact of metreleptin treatment on circulating chemerin in LD patients., Research Design and Methods: Serum chemerin, as well as clinical and biochemical parameters of glucose metabolism, lipid metabolism, and inflammation, was measured in 37 LD patients and 37 age-, gender- and body mass index-matched controls. Furthermore, chemerin mRNA expression was determined in LD mice and controls. Moreover, circulating chemerin was assessed at five different time points in 10 LD patients treated with metreleptin over 1 year., Results: Median serum chemerin levels were significantly higher in 37 subjects with LD (234·3 μg/l) as compared to controls (204·0 μg/l) (P = 0·002). Multiple linear regression analysis showed that circulating chemerin was independently and positively associated with glycosylated haemoglobin A1c (HbA1c) and C-reactive protein (CRP). Chemerin mRNA expression was significantly increased 2·5-fold in visceral adipose tissue (VAT) and 5·3-fold in brown adipose tissue (BAT) of LD mice as compared to controls (P < 0·01). Circulating chemerin was not significantly altered by metreleptin treatment., Conclusions: Circulating levels of the adipokine chemerin are elevated in LD, as well as independently and positively associated with HbA1c and CRP. Increased chemerin might originate from VAT and BAT., (© 2015 John Wiley & Sons Ltd.)

Context: Apolipoprotein CIII (apoCIII), an inhibitor of lipoprotein lipase, plays an important role in triglyceride metabolism. However, the role of apoCIII in hypertriglyceridemia in lipodystrophy and the effects of leptin replacement on apoCIII levels are unknown., Objective: The objective of the study was to test the hypotheses that apoCIII is elevated in hypertriglyceridemic patients with lipodystrophy and that leptin replacement in these patients lowers circulating apoCIII., Design, Setting, Study Participants, Intervention, and Outcome Measures: Using a post hoc cross-sectional case-control design, we compared serum apoCIII levels from patients with lipodystrophy not associated with HIV (n = 60) and age-, gender-, race-, and ethnicity-matched controls (n = 54) participating in ongoing studies at the National Institutes of Health. In a prospective, open-label, ongoing study, we studied the effects of 6–12 months of leptin replacement on apoCIII in lipodystrophy patients as an exploratory outcome., Results: ApoCIII was higher in lipodystrophy patients (geometric mean [25th and 75th percentiles]) (23.9 mg/dL [14.6, 40.3]) compared with controls (14.9 mg/dL [12.3, 17.7]) (P < .0001). ApoCIII and triglyceride levels were positively correlated in patients with lipodystrophy (R = 0.72, P < .0001) and healthy controls (R = 0.6, P < .0001). Leptin replacement (6–12 mo) did not significantly alter apoCIII (before leptin: 23.4 mg/dL [14.5, 40.1]; after leptin: 21.4 mg/dL [16.7, 28.3]; P = .34)., Conclusions: Leptin replacement in lipodystrophy did not alter serum apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement.

Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases low-density lipoprotein (LDL) clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for 4 days via sc osmotic pumps (∼24 μg/d). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes. In male mice, leptin suppressed PCSK9 but had no effect on plasma triglycerides or cholesterol. In female mice, leptin suppressed plasma triglycerides and cholesterol but had no effect on plasma PCSK9. In parallel, we treated female lipodystrophic patients (8 females, ages 5-23 y) with sc metreleptin injections (∼4.4 mg/d) for 4-6 months. In this case, leptin reduced plasma PCSK9 by 26% (298 ± 109 vs 221 ± 102 ng/mL; n = 8; P = .008), and the change in PCSK9 was correlated with a decrease in LDL cholesterol (r(2) = 0.564, P = .03). In summary, in leptin-deficient ob/ob mice, the effects of leptin on PCSK9 and plasma lipids appeared to be independent of one another and strongly modified by sex. On the other hand, in lipodystrophic females, leptin treatment reduced plasma PCSK9 in parallel with LDL cholesterol.

Objectives: The aim of this study was to examine the relationship between semicircular lipoatrophy (SL), inflammation marker (high sensibility C-reactive protein [hs-CRP]), adipokines (leptine, chemerine and vaspine) and autoimmune markers (rheumatoid factor [RF], C3 and C4 complement fractions, antinuclear antibodies [ANA], HLA DR3, and DR4). Chemerine is an adipokine, but also is an immunity marker., Methods: A case-control study was performed in May 2013; 21 cases were included. The closest healthy coworker to each case was used as a control. We calculated Kruskal-Wallis nonparametric test., Results: We found statistical significance (P<.05) between SL and raised hs-CRP, raised leptine and low chemerine., Conclusions: i) There seems to be an underlying inflammatory component (raised hs-CRP) in SL; ii) adipokine alteration (raised leptine and low chemerine) supports the idea that adipocytic differentiation is affected in SL, and iii) we have not found any immune marker associated with SL, except chemerine itself, which could explain a possible association between SL and immunity., (Copyright © 2015 Elsevier España, S.L.U. All rights reserved.)

Background: HIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa., Methods: Adult HIV-negative (n = 36), treatment naïve (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM-1, leptin and complete blood count were measured., Results: PWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naïve subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure., Conclusions: Current EFV- or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors.

Lipodystrophy is a common complication in HIV-infected patients taking highly active antiretroviral therapy. Its early diagnosis is crucial for timely modification of antiretroviral therapy. We hypothesize that mitochondrial DNA in plasma may be a potential marker of LD in HIV-infected individuals. In this study, we compared plasma mitochondrial DNA levels in HIV-infected individuals and non-HIV-infected individuals to investigate its potential diagnostic value. Total plasma DNA was extracted from 67 HIV-infected patients at baseline and 12, 24 and 30 months after initiating antiretroviral therapy. Real-time quantitative PCR was used to determine the mitochondrial DNA levels in plasma. Lipodystrophy was defined by the physician-assessed presence of lipoatrophy or lipohypertrophy in one or more body regions. The mitochondrial DNA levels in plasma were significantly higher at baseline in HIV-infected individuals than in non-HIV-infected individuals (p<0.05). At month 30, 33 out of 67 patients (49.2%) showed at least one sign of lipodystrophy. The mean plasma mitochondrial DNA levels in lipodystrophy patients were significantly higher compared to those without lipodystrophy at month 24 (p<0.001). The receiver operating curve analysis demonstrated that using plasma mitochondrial DNA level (with cut-off value <5.09 log10 copies/ml) as a molecular marker allowed identification of patients with lipodystrophy with a sensitivity of 64.2% and a specificity of 73.0%. Our data suggest that mitochondrial DNA levels may help to guide therapy selection with regards to HIV lipodystrophy risk.

The Barraquer-Simons syndrome or acquired parital lipodystrophy is a rare form of partial lipodystrophy characterized by gradual onset of bilaterally symmetrical subcutaneous fat loss from the face, neck, upper extremities, thorax, and abdomen but sparing the lower extremities. The patients gradually loose their subcutaneous fat in clearly demarcated, generally symmetric areas of the body over several years. Nephropathy, myopathy, deafness, epilepsy, and intellectual disability have also been described. Although the etiology is unknown, heterozygous mutations in the gene encoding one of the nuclear lamina proteins, lamin B2, have been reported in several patients. We here report on a young female patient affected by Barraquer-Simons syndrome, without accompanying renal or central nervous system involvement in whom DNA sequencing did not reveal any mutations in the genes LMNB2, LMNA, PPARG, AGPAT2, BSCL2, CAV1, PTRF, PLIN1, and CIDEC., (© 2014 Wiley Periodicals, Inc.)

Background: Few studies have investigated objective markers of lipodystrophy in African children. We compared body circumferences, skin-fold thickness (SFT) and lipids in antiretroviral therapy (ART)-naive and stavudine (d4T)-exposed children with HIV-uninfected controls., Methods: In the CHAPAS-3 trial, HIV-infected children (ART-naive or on d4T for ≥2 years without clinical lipodystrophy) were randomized to d4T, abacavir or zidovudine with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor. Mid-upper-arm circumference (MUAC) and calf circumference (CC), SFT (biceps, triceps, sub-scapular and supra-iliac) and fasting lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL] and triglycerides [TRIG]) were measured at randomization in all HIV-infected children, and in HIV-uninfected controls. Age- and sex-adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) using Dutch reference data were compared across groups using linear regression., Results: Of 496 children, 49% were male, 299 (median age 2.5 years [IQR 1.5-4.0]) were ART-naive, 109 (median age 6 years [IQR 5.5-7.0]) were ART-experienced and 88 (median age 2.2 years [IQR 1.5-3.0]) were control children. Overall, 100% and 95% of ART-experienced children had been on d4T plus 3TC and nevirapine, respectively, for a median 3.5 years (IQR 2.6-4.2). Mean (sd) weight-for-age z-scores and MUAC z-scores were -1.51 (1.29) versus -0.90 (0.88) versus -0.33 (1.15) and -1.56 (1.25) versus -1.24 (0.97) versus -0.65 (1.06) in ART-naive versus -experienced versus controls, respectively (all P<0.02). The mean (sd) of SSF was lower in the ART-experienced (-0.78 [1.28]) than in the ART-naive (-0.32 [1.09]; P<0.0001) children and controls (-0.29 [0.88]; P<0.002). ART-experienced children had higher mean fasting TC, LDL and HDL but lower TRIG compared to ART-naive children (P-values <0.0001), and higher TC and HDL but lower TRIG compared to controls (P-values <0.01)., Conclusions: In ART-experienced children on d4T-containing regimens, we observed lower SFT and higher TC and LDL values compared to ART-naive children and HIV-uninfected controls.

Background: Lipodystrophy characterized by adipose tissue redistribution and lipid and glucose metabolism abnormalities, is common among HIV-infected adults and children on highly-active-antiretroviral-therapy (HAART). In a previous study of HIV-infected children, we did not detect insulin resistance, despite a high percentage of body fat redistribution abnormalities., Aim of the Study: To investigate the non-traditional adipokines Retinol-binding-Protein-4 (RBP4), neutrophil-gelatinase-associated-lipocalin (NGAL), a-Fatty-Acid-Binding-Protein (a-FABP) and YKL-40 in HIV-infected children on highly-active-antiretroviral-therapy and evaluate their possible association to lipodystrophic changes or insulin resistance., Methods: Seventeen vertically HIV-infected children (mean age: 12.5 years, mean duration of HAART: 5.2 years) and 20 age- and BMI-matched controls were recruited. The HIV-children were re-evaluated after 12 months. RBP4, NGAL, a-FABP and YKL-40 were assessed at study entry and 12 months later and were correlated to body fat content and insulin resistance., Results: RBP4 values were similar at study entry and 12 months later in HIV-children and controls and showed no correlation to body fat or insulin resistance. NGAL was lower in HIV children at study entry but normalized after 12 months with no positive correlation to insulin resistance. a-FABP was positively correlated to body fat content, especially to trunk fat, both at initial evaluation and at follow-up in HIV children and, after prolonged highly-active-antiretroviral-therapy, it was also positively correlated to insulin resistance., Conclusions: This study is the first one to demonstrate that a-FABP could be a useful marker in unraveling central fat accumulation in HIV-infected children on highly-active-antiretroviral-therapy. Large prospective studies are needed to confirm these results.

Objective: Lipodystrophy syndrome is an unexpected clinical manifestation in patients infected with HIV and might be a clinical marker of increased risk for cardiovascular diseases (CVDs). Because hyperhomocysteinemia has been associated with CVD, the goal of the present study was to investigate homocysteine (Hcy) levels and their association with the factors of lipodystrophy syndrome in men with HIV., Methods: Hcy metabolism-related molecules were determined in 13 men infected with HIV with lipodystrophy (HIV+LIP), 10 men with HIV without lipodystrophy (HIV), and 10 healthy controls (C)., Results: Significant (P < 0.05) increased Hcy plasma levels were found in HIV (20.5%) and in HIV+LIP (35.2%) compared with the control group. Plasma levels of vitamin B12 (HIV, 26.5%; HIV+LIP, 28.8%) and folate (HIV, 39.1% and HIV+LIP, 49.4%) were significantly (P < 0.05) lower in the two groups of HIV patients compared with control. HIV+LIP men presented raised plasma total sulfur-containing amino acids (20.1%) and lower total plasma thiol (11.3%) than controls. The same was not observed in the HIV group. Spearman's correlation test revealed significant (P < 0.05) association between plasma Hcy and duration of highly active antiretroviral therapy (HAART) and plasma insulin, as well as plasma adiponectin levels., Conclusion: Our results demonstrated that HIV+LIP men were more susceptible to disturbances in Hcy metabolism compared with men infected with HIV without lipodystrophy characteristics. Duration of HAART treatment, elevated plasma insulin, and low levels of adiponectin seem to be relevant for the appearance of these Hcy metabolic disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Low-grade inflammation is a feature of chronic diseases such as type 2 diabetes and lipodystrophy. It is associated with abdominal adiposity, increased levels of NEFA, hyperinsulinaemia and low adiponectin levels. However, the causal relationship between impaired metabolism and inflammation is not understood. We explored the anti-lipolytic effect of acipimox and insulin on adiponectin and adipocyte-associated cytokines in patients with lipodystrophy., Methods: In a randomised placebo-controlled crossover design using nine patients with non-diabetic, HIV-associated lipodystrophy, we assessed whether (1) overnight administration of a low dose of acipimox and/or (2) insulin-induced suppression of NEFA flux altered circulating plasma levels of adiponectin, IL-18, TNF-α and IL-6 in the basal condition and in a two-stage euglycaemic-hyperinsulinaemic clamp combined with stable isotopes (insulin infusion rates 20 mU m(-2) min(-1) and 50 mU m(-2) min(-1))., Results: Insulin decreased plasma NEFA in a dose-dependent manner (p < 0.0001). Acipimox reduced basal plasma NEFAs and plasma NEFAs during the low-dose insulin infusion compared with placebo (p < 0.0001 for acipimox effect). Plasma adiponectin and plasma IL-18 were reduced during both situations where lipolysis was inhibited (p < 0.0001 for acipimox effect; p < 0.0001 and p < 0.05 for insulin effect on plasma adiponectin and plasma IL-18, respectively). In contrast, plasma IL-6 and plasma TNF-α did not change during low NEFA concentrations., Conclusions/interpretation: Using two different tools to manipulate lipolysis, the present study found that acute inhibition of lipolysis reduces levels of adiponectin and IL-18 in patients with HIV-associated lipodystrophy.

Body fat changes in HIV-infected persons are associated with increased systemic inflammation and increased mortality. It is unknown whether lipodystrophy is also associated with declines in physical function. Between 2001 and 2003, 33 HIV-infected men with evidence of lipodystrophy (LIPO⁺), 23 HIV-infected men without lipodystrophy (LIPO⁻), and 33 seronegative men were recruited from the Multicenter AIDS Cohort Study (MACS) for the Body Composition substudy. Visceral adipose tissue (VAT) was assessed by quantitative computed tomography. Lean body mass (LBM) and extremity fat were measured by dual-energy x-ray absorptiometry. Insulin resistance was estimated by Homeostatic Model Assessment (HOMA). Serum interleukin (IL)-6, soluble tumor necrosis factor (TNF)-α receptors I and II (sTNFRI and sTNFRII), and highly sensitive C-reactive protein (hs-CRP) concentrations were quantified from archived serum samples. These measurements were correlated with grip strength measured in 2007 using linear regression. At the substudy visit, the LIPO⁺ group had higher HOMA, sTNFRI, sTNFRII, and IL-6 levels than the LIPO⁻ group. In 2007, the LIPO⁺ group had lower median grip strength than the LIPO⁻ group (34.4 vs. 42.7 kg, p=0.002). Multivariable analysis of HIV⁺ men showed older age, lower LBM, higher sTNFRII concentrations, and LIPO⁺ status [adjusted mean difference -4.9 kg (p=0.045)] at the substudy visit were independently associated with lower subsequent grip strength. Inflammation, lower LBM, and lipodystrophy in HIV-infected men were associated with lower subsequent grip strength. These findings suggest that inflammation may contribute to declines in functional performance, independent of age.

Background: Fibroblast growth factor (FGF)-21 is a novel regulator of glucose and lipid metabolism. Recently, increased FGF-21 mRNA expression in muscle was found in patients with type 2 diabetes, but the role for FGF-21 in muscle is not well understood. Patients with HIV-infection and lipodystrophy are characterised by various degree of lipid-driven insulin resistance. We hypothesized that muscle FGF-21 mRNA would be altered in HIV patients with lipodystrophy., Design: Twenty-five HIV-infected men with lipodystrophy (LD) and 15 age-matched healthy controls, received an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp (50 mU/m2/min) combined with 6,6-H2 glucose infusion. Muscle biopsies were obtained and FGF-21 mRNA and glycogen synthase (GS) activity were measured., Results: Subjects with HIV were insulin resistant compared with non-HIV subjects. Compared to controls, HIV subjects demonstrated a twofold increase of plasma FGF-21 from 70.4±56.8 pg/ml vs 109.1±71.8 pg/ml, respectively (p = 0.04) and an eight-fold increase in muscular FGF-21 mRNA expression (p = 0.001). Muscle FGF-21 mRNA correlated inversely with the rate of disappearance of glucose during insulin clamp (r = -0.54, p = 0.0009), and the GS fractional velocity in muscle (r = -0.39, p = 0.03), and directly with fasting insulin (r = 0.50, p = 0.0022), HOMA-IR (r = 0.47, p = 0.004), triglycerides (r = 0.60. P = 0.0001), waist-to-hip ratio (r = 0.51, p = 0.0001) and limb fat mass (-0.46, p = 0.004), but not to plasma FGF-21., Conclusion: FGF-21 mRNA is increased in skeletal muscle in HIV patients and correlates to whole-body (primarily reflecting muscle) insulin resistance, but not to plasma FGF-21. Those findings add to the evidence that FGF-21 is a myokine and may suggest that muscle FGF-21 is working in a local manner.

Context: Glucocorticoid therapy may result in adipose tissue redistribution of unknown pathophysiology., Objectives: To evaluate the effects of glucocorticoids on adipokine levels and adipose tissue inflammation. To compare the results in patients with or without glucocorticoid-induced lipodystrophy (GIL) after 3 months of therapy., Design and Setting: Prospective monocentric study., Patients: Adult patients initiating systemic, high-dose prednisone therapy for at least 3 months. Blood samples and subcutaneous abdominal adipose tissue biopsies were collected at baseline and month 3. The presence of GIL after 3 months of therapy was assessed using standardized photography., Results: Thirty-two patients were enrolled. Blood samples and subcutaneous abdominal adipose tissue were available at baseline and month 3 for 30 patients [median age: 61 (38-79) years, 77% women]. Among those 30 patients, 15 were classified as GIL+ and 15 were GIL- at month 3. Between baseline and month 3, adiponectin and leptin levels increased in the overall population while the level of resistin remained unchanged. At baseline, leptin level was higher [19.3 (8.3-31.1) vs 4.5 (2.4-11.3) μg/l, P = 0.006] and resistin level lower [7.1 (6.3-12.4) vs 10.4 (8.0-21.7) μg/l, P = 0.05] in GIL+ than in GIL- patients. Baseline leptin level was predictive of GIL occurrence. Receiver operating characteristic curve analysis demonstrated that the best diagnostic accuracy was obtained with a baseline leptin cut-off of 5.9 μg/l (sensitivity: 93%, specificity: 60%). At month 3, leptin and adiponectin levels increased more in the GIL+ than in the GIL- group, as did the number of anti-inflammatory M2 macrophages in subcutaneous abdominal fat., Conclusion: Glucocorticoid-induced lipodystrophy is associated with a different adipokine profile both before and after glucocorticoid therapy. Serum leptin level prior to glucocorticoid therapy is highly predictive of GIL occurrence., (© 2012 Blackwell Publishing Ltd.)

Background: We describe an unplanned pregnancy in a 19-year-old with lipodystrophic diabetes caused by a mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. The pregnancy was complicated by poor compliance with treatment, severe hypertriglyceridaemia and pancreatitis., Case Report: The patient presented at 6 weeks' gestation with an HbA(1c) of 140 mmol/mol (15%), cholesterol 8.1 mmol/l and triglycerides 20.1 mmol/l. She wished to continue the pregnancy so lipid-lowering therapy was discontinued. She was severely insulin resistant and poorly compliant with diet and medication. A continuous subcutaneous insulin infusion was required for efficient delivery of large doses of basal insulin, alongside injected mealtime boluses, (up to 300 units insulin per day). At 17 weeks' gestation she developed acute pancreatitis secondary to hypertriglyceridaemia (triglycerides > 100 mmol/l) and required plasmapheresis. Lipid-lowering therapy was reinstated in the third trimester and plasmapheresis was required repeatedly to maintain triglycerides < 10 mmol/l. Delivery was arranged at 32 weeks, because of deteriorating glycaemic and lipid control (blood pressure was normal). Following betamethasone for fetal lung maturation, 20 units/h of intravenous insulin were required to maintain glycaemic control. A baby boy with significant subsequent developmental delay was delivered., Discussion: The features of PPARG mutations are discussed, with literature on lipodystrophy and pancreatitis in pregnancy reviewed. There are few documented cases of pregnancy in women with PPARG mutations. The notable features of this case include the consequences of non-concordance with treatment, the use of continuous subcutaneous insulin infusion to treat insulin-resistant diabetes and the need for repeated plasmapheresis during pregnancy to avert pancreatitis., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Objective: The excess cardiac risk, found in RA has been attributed to biological inflammation. Effective control of inflammation may be of benefit in reducing cardiovascular risk in RA patients. The aim of this study is to investigate the effects of 24 and 52 weeks of rituximab treatment on arterial stiffness and cardiovascular risk factors., Methods: Arterial stiffness was measured by augmentation index (AIx) and pulse wave velocity (PWV), and other cardiovascular risk factors (lipid profile, blood pressure) were collected in active RA patients., Results: Thirty-three patients, of whom 29 were females, with a mean age of 60.9 (12.0) years were included. Thirty patients had positive RFs, 27 had positive anti-CCP antibody and 93.9% (n = 31) were erosive. Nineteen patients were non-responders to anti-TNF-α treatments. After rituximab treatment, no change was observed in arterial stiffness, neither after 6 nor after 12 months [PWV 8.1 (3.1) m/s at baseline, 8.1 (2.8) at 6 months, 8.0 (2.7) at 1 year, P = 0.924; and AIx 30.4 (8.2)% at baseline, 28.6 (7.6) at 6 months, 29.4 (6.7) at 1 year, P = 0.216]. Total and low-density lipoprotein cholesterol levels increased significantly but high-density lipoprotein (HDL) and triglyceride levels were unchanged. The atherogenic index (total cholesterol/HDL cholesterol) was increased, but not to a level of significance. No change was found in other cardiovascular risk factors. DAS-28 according to levels of ESR and CRP and biologic inflammation were significantly improved., Conclusion: Arterial stiffness did not improve after 6 and 12 months of rituximab therapy. The treatment had a beneficial effect on biologic inflammation and disease activity, but caused a pro-atherogenic lipid profile.

Objective: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients., Methods: Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit β type 8). Cytokine levels were measured in sera from 3 patients. Skin biopsy samples were evaluated by immunohistochemistry, and blood microarray profile and STAT-1 phosphorylation were assessed in 4 patients and 3 patients, respectively., Results: One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A), suggesting a protein truncation; 4 patients were homozygous and 2 were heterozygous for a previously reported missense mutation (c.224C>T); and 1 patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the 4 patients with the same mutation, only 2 shared the same haplotype, indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high levels of interferon-γ (IFNγ)-inducible protein 10. Levels of monocyte chemotactic protein 1, interleukin-6 (IL-6), and IL-1 receptor antagonist were moderately elevated. Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders., Conclusion: CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause "JMP" syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target., (Copyright © 2012 by the American College of Rheumatology.)

Background: Congenital generalized lipodystrophy is a rare disorder characterized by scant adipose tissue, profound leptin deficiency, and severe insulin resistance, resulting in multiple metabolic derangements, including hyperandrogenism, anovulation, and impaired fecundity., Case: A young woman with congenital generalized lipodystrophy receiving leptin therapy experienced menarche, conceived spontaneously, and delivered a liveborn male neonate., Conclusion: Adipose tissue is important to normal female reproductive function. Leptin in particular appears to play a key role in adipose-mediated regulation of fertility.