Lipodystrophies in Children.

BACKGROUND: Lipodystrophy includes a wide group of diseases characterized by reduction, absence, or altered distribution of adipose tissue. Lipodystrophies are classified into generalized or partial, according to the fat distribution, and congenital or acquired, considering the etiology. SUMMARY: Impaired glucose and lipid metabolism are typically present, thus severe insulin resistance, diabetes mellitus, dyslipidemia, and hepatic steatosis are frequent complications. Because of the rarity and the diversification of lipodystrophies, diagnosis might be challenging, typically for partial forms that cannot be easily recognized, leading to progression of the several metabolic abnormalities associated. First management of lipodystrophy is diet and lifestyle changes, followed by the treatment of metabolic complications. Replacement therapy with metreleptin, currently available in the USA and Europe, has shown improvement of metabolic profile in a great number of patients with lipodystrophy. KEY MESSAGES: The purpose of this review was to describe the phenotypic characteristics of all the known lipodystrophic types and to present specific steps for obtaining an early diagnosis and assessing the best treatment of lipodystrophy.

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease.

Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.

Generalized lipoatrophy syndromes.

Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.

Autoimmunity in lipodystrophy syndromes.

Lipodystrophy syndromes are rare, heterogeneous disorders characterized by the complete or partial deficiency of adipose tissue and are classified according to the extent of fat loss in generalized or partial subtypes, or based on the pathogenic mechanisms in genetic or acquired. While in most cases of congenital forms of lipodystrophy a genetic alteration can be identified, the pathogenic mechanisms responsible for the acquired diseases are not fully clarified. Based on the evidence of a positive association between most acquired lipodystrophies and autoimmune disorders including immune mediated alterations in the adipose tissue of patients affected by acquired lipodystrophy, a reaction against white adipose tissue antigens is postulated. Recent acquisitions have shed new light on the possible pathogenic mechanisms and identified novel forms of acquired lipodystrophy which are possibly immune-mediated. The aim of this review is to give an update on acquired lipodystrophies describing pathogenic mechanisms involved and the relationships between acquired lipodystrophies and other autoimmune disorders. Larger studies based on international disease registries are needed to collect accurate information on the prevalence, risk factors, genetic predisposition, natural history, disease markers and treatment efficacy of these ultrarare disorders.

Cutaneous Manifestations of Diabetes.

Diabetes mellitus is a significant worldwide health concern and cutaneous manifestations are common. This review describes characteristic skin findings of diabetes, general skin findings related to diabetes, and findings related to diabetes treatment with a focus on clinical presentation, diagnosis, pathophysiology, epidemiology, and treatment. As the prevalence of diabetes continues to rise, cutaneous manifestations of diabetes mellitus likely will be encountered more frequently by physicians in all disciplines including dermatologists and primary care physicians. Accordingly, knowledge regarding the prevention, diagnosis, and management of cutaneous manifestations is an important aspect in the care of patients with diabetes.

Case Report: Metreleptin and SGLT2 Inhibitor Combination Therapy Is Effective for Acquired Incomplete Lipodystrophy.

Childhood cancer survivors (CCSs) who have undergone bone marrow transplantation with systemic chemotherapy and whole-body irradiation often experience impaired glucose tolerance with marked insulin resistance. Incomplete acquired diabetic lipodystrophy should be considered as a late complication of bone marrow transplantation. A 24-year-old Japanese female patient with incomplete acquired lipodystrophy, a CCS of acute lymphocytic leukemia at the age of 3 years, was treated for diabetes mellitus and dyslipidemia at our hospital. Administration of multiple daily insulin injections (70 units/day), and oral administration of 500 mg/day metformin, 15 mg/day pioglitazone, and 200 mg/day bezafibrate had proven ineffective for her metabolic disorders. Subcutaneous administration of metreleptin improved her insulin resistance and hypertriglyceridemia within a month; however, it failed to maintain adequate plasma glucose levels in the long term. When oral administration of 10 mg/day empagliflozin was added to the metreleptin supplementation, her HbA1c value (National Glycohemoglobin Standardization Program) improved from 11% to 8%, which was maintained for an additional 18 months. This is the first case report of incomplete lipodystrophy that shows efficacy of a combination therapy with metreleptin and a sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of diabetes and dyslipidemia. An SGLT2 inhibitor attenuates hyperglycemia through urinary glucose excretion and has been suggested to enhance lipid catabolism in the extra-adipose tissues, especially in the liver and skeletal muscles. Furthermore, metreleptin supplementation could enhance the action of the SGLT2 inhibitor by promoting satiety and lipolysis through the central nervous system. Combination therapy with metreleptin and an SGLT2 inhibitor was suggested to recover the volume of adipose tissue, possibly through improvement of insulin resistance in the adipose tissue. This report highlights the pathophysiological mechanism of an SGLT2 inhibitor in the improvement of glucose metabolism in non-healthy lean CCSs with insulin resistance. Administration of SGLT2 inhibitor, along with metreleptin supplementation, could be a good alternative therapy for diabetic lipodystrophy observed in CCSs.

Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies.

Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.

Circumferential Lipobrachioplasty Is a Safe Procedure.

BACKGROUND: Excess fat and skin in the upper arms have become troublesome with aging and especially after the advancement in methods of weight reduction. Arm contouring procedures can be divided into three groups: those dealing with skin redundancy, those dealing with the lipodystrophy, and a combination of both. This study tries to find an answer to the debate about the safety of simultaneous circumferential liposuction and brachioplasty. METHODS: Sixty-two patients (49 women and 13 men) were operated on by simultaneous circumferential suction-assisted lipectomy followed by brachioplasty. Preoperative and postoperative arm circumferences and outcomes (including complications and patient satisfaction) were evaluated starting at least 6 months after the procedure. RESULTS: Only two patients (3.2 percent) developed small areas of wound dehiscence that healed after repeated dressing and an extended period of compression garment use. One patient (1.6 percent) complained of hypertrophic scarring, which was managed by local compression and silicone sheets. The average reduction in mid arm circumference was 9 cm (range, 5 to 14 cm). Approximately 95.2 percent of the patients in the study are highly satisfied, and 4.8 percent reported a mild degree of satisfaction. CONCLUSIONS: Simultaneous circumferential arm liposuction followed by brachioplasty addresses both the lipodystrophy and arm ptosis in a single hospital admission. This combination does not increase the complication rate. The results are highly satisfactory to the patients. According to the results of this study, circumferential arm lipobrachioplasty is considered to be a safe, efficient, reliable, and feasible procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

Angiopoietin-like proteins, namely ANGPTL3-4-8, are known as regulators of lipid metabolism. However, recent evidence points towards their involvement in the regulation of adipose tissue function. Alteration of adipose tissue functions (also called adiposopathy) is considered the main inducer of metabolic syndrome (MS) and its related complications. In this review, we intended to analyze available evidence derived from experimental and human investigations highlighting the contribution of ANGPTLs in the regulation of adipocyte metabolism, as well as their potential role in common cardiometabolic alterations associated with adiposopathy. We finally propose a model of ANGPTLs-based adipose tissue dysfunction, possibly linking abnormalities in the angiopoietins to the induction of adiposopathy and its related disorders.

Molecular and Cellular Bases of Lipodystrophy Syndromes.

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

Metreleptin worked in a diabetic woman with a history of hematopoietic stem cell transplantation (HSCT) during infancy: further support for the concept of 'HSCT-associated lipodystrophy'.

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.

[Recognize rare diseases by the adipose tissue : Lipodystrophy-actually simple but nevertheless often overlooked]. / Seltene Erkrankungen am Fettgewebe erkennen : Lipodystrophie ­ eigentlich einfach und dennoch oft übersehen.

Lipodystrophy (LD) syndromes are a group of rare and heterogeneous diseases characterized by a congenital deficiency or acquired loss of adipose tissue. Due to the resulting disorder of metabolism, sometimes severe sequelae can develop, such as hypertriglyceridemia, marked insulin resistance and early manifestation of type 2 diabetes, recurrent pancreatitis, fatty liver disease and liver fibrosis. Lipodystrophies are clinically recognizable due to the complete lack of subcutaneous adipose tissue or a conspicuous pattern of the distribution of body fat. Acanthosis nigricans in slimly built persons, a high fasting triglyceride level and elevated concentrations of liver enzymes as well as a positive history of pancreatitis can be indications of LD.

Lipoatrophy in children, adolescents and adults with insulin pump treatment: Is there a beneficial effect of insulin glulisine?

AIM: To investigate whether zinc-free insulin is an effective treatment option for lipoatrophy. METHODS: Controlled, randomized, open-label parallel study in young people with type 1 diabetes, pump treatment and lipoatrophy at injection sites. Participants underwent dermatological examination and evaluation of affected areas using ultrasound and magnetic resonance imaging (MRI). After randomization, half of themswitched to insulin glulisine (intervention group) for 6 months. The control group continued their treatment with zinc-containing insulin and switched to insulin glulisine 6 months later. Both groups were followed-up until month 12. Primary endpoint was the increase of the relative thickness of the subcutaneous fat layer of the most atrophic site at 6 months as documented by MRI. RESULTS: Fourteen participants were included into the study. While relative thickness of subcutaneous fat tissue was comparable between intervention (-60% [-98.8 - -17.6], n = 7) and control group (-50% [-72.7 - -1.0], P = .511; median (range), n = 7)at baseline, it improved in the intervention (-14.3% [-85.7-83.3] vs -31.3% (-66.7-0), P = .031), but not in the control group (P = .125) after 6 months. At 12 months, relative fat thickness (P = .003), number (P = .015) and size of most atrophic sites (P = .001) were improved in the intervention group. Number (P = .018) and size of most atrophic sites (P = .008) were also reduced in the control group between 6 and 12 months. CONCLUSIONS: Although the present pilot study is based on a small sample, the data give first hint that the use of the zinc-free insulin glulisine may be beneficial in people with diabetes, pump and lipoatrophy.

The influence of hypertensive environment on adipose tissue remodeling measured by fluorescence lifetime imaging in spontaneously hypertensive rats.

There is a lack of information correlating low adiposity with hypertension experienced by Spontaneous Hypertensive Rats (SHR) or overweight and normotension in Wistar-Kyoto (WKY). We aimed to investigate this lipodystrophy phenomenon by measuring fluorescence lifetime (FLIM), optical redox ratio (ORR), serum levels of hypothalamic-pituitary-adrenal (HPA) and/or hypothalamic-pituitary-thyroid (HPT) hormones axes between Wistar, WKY and SHR before and after establishment of hypertension. Under high blood pressure, we evaluated serum adipokines. Brown adipose tissue was characterized as lower ORR and shorter FLIM compared to white adipose tissue. HPT axis showed a crucial role in the SHR adipose tissue configuration by attenuating whitening. The increased adiposity in WKY may act as a preventive agent for hypertension, since SHR, with low adiposity, establishes the disease. The hypertensive environment can highlight key adipokines that may result in new therapeutic approaches to the treatment of adiposity dysfunctions and hypertension.

Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome.

LMNA gene encodes for lamin A/C, attractive proteins linked to nuclear structure and functions. When mutated, it causes different rare diseases called laminopathies. In particular, an Arginine change in Histidine in position 527 (p.Arg527His) falling in the C-terminal domain of lamin A precursor form (prelamin A) causes mandibuloacral dysplasia Type A (MADA), a segmental progeroid syndrome characterized by skin, bone and metabolic anomalies. The well-characterized cellular models made difficult to assess the tissue-specific functions of 527His prelamin A. Here, we describe the generation and characterization of a MADA transgenic mouse overexpressing 527His LMNA gene, encoding mutated prelamin A. Bodyweight is slightly affected, while no difference in lifespan was observed in transgenic animals. Mild metabolic anomalies and thinning and loss of hairs from the back were the other observed phenotypic MADA manifestations. Histological analysis of tissues relevant for MADA syndrome revealed slight increase in adipose tissue inflammatory cells and a reduction of hypodermis due to a loss of subcutaneous adipose tissue. At cellular levels, transgenic cutaneous fibroblasts displayed nuclear envelope aberrations, presence of prelamin A, proliferation, and senescence rate defects. Gene transcriptional pattern was found differentially modulated between transgenic and wildtype animals, too. In conclusion, the presence of 527His Prelamin A accumulation is further linked to the appearance of mild progeroid features and metabolic disorder without lifespan reduction.

Surgical fat removal exacerbates metabolic disorders but not atherogenesis in LDLR-/- mice fed on high-fat diet.

Lipodystrophy is a severe adipose dysfunction that can be classified as congenital or acquired lipodystrophy, in term of the etiology. Previous knowledge about the metabolic disorders and cardiovascular consequences were mostly obtained from lipodystrophic mice with genetic defects. To completely rule out the genetic influence, we established a mouse model of acquired generalized lipodystrophy by surgical removal of multiple fat depots, including subcutaneous fat in the inguinal, visceral fat in the epididymis and brown fat in the scapula, in atherosclerosis-prone LDLR-/- mice which were fed with a high-fat diet (HFD). It was observed that fat removal increased diet-induced hyperlipidemia, especially hypercholesteremia, as early as 2 weeks after HFD and till the end of HFD feeding. After 12 weeks on the HFD, the residual fats of fat-removed mice were found expanded. Although fat removal aggravated diet-induced lipid deposition in the liver and systemic insulin resistance, there was no significant difference in atherogenesis in fat-removed mice compared with sham-operated control mice. Acquired generalized lipodystrophy by surgical fat removal promoted metabolic disorders but not atherogenesis in LDLR-/- mice fed on HFD.