Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice.

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.

Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity.

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant. In order to deepen the functional role of the in frame deletion affecting the polymerase catalytic site of the protein, cellular phenotype has been characterised. MDPL fibroblasts exhibit in vitro nuclear envelope anomalies, accumulation of prelamin A and presence of micronuclei. A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture. The evaluation of the genomic instability reveals a delayed recovery from DNA induced-damage. Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL. Our results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL. The understanding of the mechanisms linking these cellular characteristics to the accelerated aging and to the wide spectrum of affected tissues and clinical symptoms in the MDPL patients may provide opportunities to develop therapeutic treatments for progeroid syndromes.

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.

Adipose tissue is a critical regulator of osteoarthritis.

Osteoarthritis (OA), the leading cause of pain and disability worldwide, disproportionally affects individuals with obesity. The mechanisms by which obesity leads to the onset and progression of OA are unclear due to the complex interactions among the metabolic, biomechanical, and inflammatory factors that accompany increased adiposity. We used a murine preclinical model of lipodystrophy (LD) to examine the direct contribution of adipose tissue to OA. Knee joints of LD mice were protected from spontaneous or posttraumatic OA, on either a chow or high-fat diet, despite similar body weight and the presence of systemic inflammation. These findings indicate that adipose tissue itself plays a critical role in the pathophysiology of OA. Susceptibility to posttraumatic OA was reintroduced into LD mice using implantation of a small adipose tissue depot derived from wild-type animals or mouse embryonic fibroblasts that undergo spontaneous adipogenesis, implicating paracrine signaling from fat, rather than body weight, as a mediator of joint degeneration.

Nephrotic range proteinuria associated with focal segmental glomerulosclerosis reversed with pioglitazone therapy in a patient with Dunnigan type lipodystrophy.

Familial partiallipodystrophy (FPLD)is a rare disorder associated withsevere insulin resistance, hypertriglyceridemia, lowserumHDLcholesterol and proteinuricrenaldisease. Although proteinuric renal disease is not common among in patients with partial lipodystrophy, we report a patient with Dunnigan type FPLD complicated by nephrotic syndrome which resolved following treatment with thePPARγagonist pioglitazone, CPAP, diet, and exercise.

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.

Lessons from cavin-1 deficiency.

Caveolae have been implicated in a wide range of critical physiological functions. In the past decade, the dominant role of cavin-1 in caveolae formation has been established, and it has been recognized as another master regulator for caveolae biology. Human patients with cavin-1 mutations develop lipodystrophy and muscular dystrophy and have some major pathological dysfunctions in fat tissue, skeleton muscle, heart, lung and other organs. Cavin-1 deficiency animal models consistently show similar phenotypes. However, the underlying molecular mechanisms remain to be elucidated. Recent studies have suggested many possible pathways, including mechanosensing, stress response, signal transduction, exosome secretion, and potential functions in the nucleus. Many excellent and comprehensive review articles already exist on the topics of caveolae structure formation, caveolins, and their pathophysiological functions. We will focus on recent studies using cavin-1 deficiency models, to summarize the pathophysiological changes in adipose, muscle, and other organs, followed by a summary of mechanistic studies about the roles of cavin-1, which includes caveolae formation, ribosomal RNA transcription, mechanical sensing, stress response, and exosome secretion. Further studies may help to elucidate the exact underlying molecular mechanism to explain the pathological changes observed in cavin-1 deficient human patients and animal models, so potential new therapeutic strategies can be developed.

Altered adipose tissue and adipocyte function in the pathogenesis of metabolic syndrome.

Over the past decade, great progress has been made in understanding the complexity of adipose tissue biology and its role in metabolism. This includes new insights into the multiple layers of adipose tissue heterogeneity, not only differences between white and brown adipocytes, but also differences in white adipose tissue at the depot level and even heterogeneity of white adipocytes within a single depot. These inter- and intra-depot differences in adipocytes are developmentally programmed and contribute to the wide range of effects observed in disorders with fat excess (overweight/obesity) or fat loss (lipodystrophy). Recent studies also highlight the underappreciated dynamic nature of adipose tissue, including potential to undergo rapid turnover and dedifferentiation and as a source of stem cells. Finally, we explore the rapidly expanding field of adipose tissue as an endocrine organ, and how adipose tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes. Together these attributes and complexities create a robust, multidimensional signaling network that is central to metabolic homeostasis.

Turning over our fat stores: the key to metabolic health Blaxter Award Lecture 2018.

The present paper results from my receiving the Nutrition Society's first Blaxter Award, and describes briefly my academic history. My interest in human fat metabolism began in the Medical Research Council's Trauma Unit, studying metabolic changes in critically ill patients and their responses to nutrition. On moving to Oxford in 1986, I began to study pathways for depositing fat in adipose tissue. This involved the development of new methodologies, in particular, a technique for measurement of arterio-venous differences of metabolite concentrations across human adipose tissue beds, primarily the subcutaneous anterior abdominal depot. Our early studies showed that this tissue is dynamic in its metabolic behaviour, responding rapidly (within minutes) to changes in nutritional state. This led to an understanding of adipose tissue as playing an essential role in metabolic health, by capturing incoming dietary fatty acids, storing them as TAG and releasing them when needed, analogous to the role of the liver in glucose metabolism; we called this 'buffering' of fatty acid fluxes. In obesity, the mass of adipose tissue expands considerably, more than is often appreciated from BMI values. We confirmed other observations of a strong suppression of release of NEFA from adipose tissue in obesity, tending to normalise circulating NEFA concentrations. A corollary, however, is that fatty acid uptake must be equally suppressed, and this disrupts the 'buffering' capacity of adipose tissue, leading to fat deposition in other tissues; ectopic fat deposition. This, in turn, is associated with many metabolic abnormalities linked to obesity.

Bone matrix hypermineralization associated with low bone turnover in a case of Nasu-Hakola disease.

Analysis of tissue from a 34-years-old male patient from Austrian origin with a history of multiple fractures associated with painful episodes over the carpal, tarsal and at the end of the long bones respectively is presented. Radiographic images and axial 3DCT scans showed widespread defects in trabecular bone architecture and ill-defined cortices over these skeletal sites in the form of discrete cystic-like lesions. Family history indicated two sisters (one half and one full biological sisters) also with a history of fractures. Whole exome sequencing revealed two heterozygous missense mutations in TYROBP (MIM 604142; NM_003332.3) gene encoding for a cell-surface adaptor protein, which is part of a signaling complex triggering activation of immune responses. It is expressed in cells of the ectoderm cell linage such as NK and dendritic cells, macrophages, monocytes, myeloid cells, microglia cells and osteoclasts. The phenotype and genotype of the patient were consistent with the diagnosis of Nasu-Hakola disease (NHD) (OMIM 221770). Investigations at the bone material level of a transiliac bone biopsy sample from the patient using polarized light microscopy and backscatter electron imaging revealed disordered lamellar collagen fibril arrangement and extensively increased matrix mineralization. These findings are the first bone material data in a patient with NHD and point toward an osteoclast defect involvement in this genetic condition.

Beneficial effects of leptin substitution on impaired eating behavior in lipodystrophy are sustained beyond 150 weeks of treatment.

AIM: Metreleptin treatment in lipodystrophy patients improves eating behavior with increased satiety and reduced hunger. However, no data are available whether effects are maintained beyond 52 weeks of treatment. METHODS: A prospective study with measurements at baseline and at >150 weeks of metreleptin treatment was performed. Five female lipodystrophy patients with indication for metreleptin were included. Behavioral aspects of hunger- and satiety regulation were assessed by validated eating behavior questionnaires and visual analog scales assessing hunger and satiety feelings before and after a standardized meal. RESULTS: Hunger rated on visual analog scales at 120 min after the meal significantly decreased from 46 ±â€¯10 mm at baseline to 17 ±â€¯6 mm at long-term assessment. Furthermore, satiety at 5 and 120 min after the meal significantly increased from baseline to long-term assessment (5 min: 70 ±â€¯7 mm to 87 ±â€¯3 mm; 120 min: 43 ±â€¯10 mm to 79 ±â€¯8 mm). On the Three Factor Eating Questionnaire, the mean value of factor 3 (hunger) significantly decreased from 9.2 ±â€¯0.2 at baseline to 2.6 ±â€¯1.5 at long-term assessment. In the Inventory of Eating Behavior and Weight Problems Questionnaire, mean values for scale 2 (strength and triggering of desire to eat) and scale 7 (cognitive restraint of eating) significantly decreased from baseline (31.6 ±â€¯4.8 and 11.4 ±â€¯2.2, respectively) to long-term assessment (14.0 ±â€¯2.1 and 10.0 ±â€¯1.9). CONCLUSION: First evidence is presented that long-term metreleptin treatment of >150 weeks has sustained effects on eating behavior with increased satiety, as well as reduced hunger and hunger-related measures.

Phenotypic and Genetic Characteristics of Lipodystrophy: Pathophysiology, Metabolic Abnormalities, and Comorbidities.

PURPOSE OF REVIEW: This article focuses on recent progress in understanding the genetics of lipodystrophy syndromes, the pathophysiology of severe metabolic abnormalities caused by these syndromes, and causes of severe morbidity and a possible signal of increased mortality associated with lipodystrophy. An updated classification scheme is also presented. RECENT FINDINGS: Lipodystrophy encompasses a group of heterogeneous rare diseases characterized by generalized or partial lack of adipose tissue and associated metabolic abnormalities including altered lipid metabolism and insulin resistance. Recent advances in the field have led to the discovery of new genes associated with lipodystrophy and have also improved our understanding of adipose biology, including differentiation, lipid droplet assembly, and metabolism. Several registries have documented the natural history of the disease and the serious comorbidities that patients with lipodystrophy face. There is also evolving evidence for increased mortality rates associated with lipodystrophy. Lipodystrophy syndromes represent a challenging cluster of diseases that lead to severe insulin resistance, a myriad of metabolic abnormalities, and serious morbidity. The understanding of these syndromes is evolving in parallel with the identification of novel disease-causing mechanisms.

A case of diencephalic syndrome presenting with isolated lipodystrophy.

Diencephalic syndrome is a disorder characterized by severe emaciation during childhood. The rarity of the disorder coupled with nonspecific symptomology means that there is often a protracted diagnostic journey. Here, we report a child who was referred to a clinical genetics service for investigation of lipodystrophy and failure to thrive. A broad range of genetic differential diagnoses were considered and investigated before a mass lesion was identified in the hypothalamus, confirming diencephalic syndrome. In the context of this case, we consider the relevant differentials and appropriate workup of a child with lipodystrophy presenting to a genetics service. This report also highlights the importance of considering diencephalic syndrome in cases such as this.

Effect of combined training on body composition and metabolic variables in people living with HIV: A randomized clinical trial.

PURPOSE: The aim of this study was to conduct a randomized clinical trial to assess the effects of 16 weeks of combined training on body composition, lipid profile, adiponectin, C-reactive protein (CRP), and leptin levels in people living with HIV/AIDS (PLWHA). METHODS: Fifty-eight HIV-infected individuals were randomized into a training group (T) or a control group (C). Combined training consisted of aerobic and resistance exercises performed at the same training session, applied at a frequency of three times a week for a total of 16 weeks. Waist circumference, body mass, body fat percentage (%fat), fat mass, lipid profile, adiponectin, CRP, and leptin levels were measured pre- and post-training in both groups. RESULTS: Sixteen weeks of combined training decreased (P < 0.05) body fat in different body segments in PLWHA. Lipodystrophic PLWHA experienced greater reduction in body fat in the android region than non-lipodystrophic PLWHA after combined training. Lipid profile and circulating levels of adiponectin, leptin, and CRP remained unchanged. CONCLUSIONS: Sixteen weeks of combined training was effective to reduce body fat in different body segments, without altering plasma lipid and cytokine levels.

Surplus fat rapidly increases fat oxidation and insulin resistance in lipodystrophic mice.

OBJECTIVE: Surplus dietary fat cannot be converted into other macronutrient forms or excreted, so has to be stored or oxidized. Healthy mammals store excess energy in the form of triacylgycerol (TAG) in lipid droplets within adipocytes rather than oxidizing it, and thus ultimately gain weight. The 'overflow hypothesis' posits that the capacity to increase the size and number of adipocytes is finite and that when this limit is exceeded, fat accumulates in ectopic sites and leads to metabolic disease. METHODS: Here we studied the energetic and biochemical consequences of short-term (2-day) excess fat ingestion in a lipodystrophic (A-ZIP/F-1) mouse model in which adipose capacity is severely restricted. RESULTS: In wildtype littermates, this acute exposure to high fat diets resulted in excess energy intake and weight gain without any significant changes in macronutrient oxidation rates, glucose, TAG, or insulin levels. In contrast, hyperphagic lipodystrophic mice failed to gain weight; rather, they significantly increased hepatic steatosis and fat oxidation. This response was associated with a significant increase in hyperglycemia, hyperinsulinemia, glucosuria, hypertriglyceridemia, and worsening insulin tolerance. CONCLUSIONS: These data suggest that when adipose storage reserves are saturated, excess fat intake necessarily increases fat oxidation and induces oxidative substrate competition which exacerbates insulin resistance resolving any residual energy surplus through excretion of glucose.

Renal complications of lipodystrophy: A closer look at the natural history of kidney disease.

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

Lipodystrophy and obesity are associated with decreased number of T cells with regulatory function and pro-inflammatory macrophage phenotype.

BACKGROUND/OBJECTIVES: In lipodystrophy (LD) adipose tissue function to store lipids is impaired, leading to metabolic syndrome, similar to that found in obesity. Emerging evidence links dysmetabolism with disorders of the immune system. Our aim is to investigate whether T-cell populations with regulatory function and monocyte-derived macrophages (MDMs) are affected by LD and obesity. SUBJECTS/METHODS: Blood was collected from 16 LD, 16 obese (OB, BMI>30 kg m-2) and 16 healthy normal-weight women (CNT). Physical parameters, plasma lipid profile, glucose, HbA1c, leptin levels were determined. Flow cytometry was employed to assess the number of circulating CD4+/CD25hi regulatory T cells (Tregs) and invariant natural killer T (iNKT) cells. Characterization of MDMs included: 1. morphological/oil-Red-O staining analyses to define two morphotypes: lipid laden (LL) and spindle-like (sp) MDM; 2. gene expression studies; 3. use of conditioned medium from MDMs (MDMs CM) on human SGBS cells. RESULTS: As compared to CNT, LD and, to a lesser extent, obesity were associated with reduced Tregs and iNKTs (P<0.001 and P<0.01 for LD and OB, respectively), higher number of LL-MDMs (P<0.001 and P<0.01 for LD and OB, respectively), lower number of sp-MDMs (P<0.001 for both LD and OB), which correlated with increased paracrine stimulation of lipid accumulation in cells (P<0.001 and P<0.01 for LD and OB, respectively). LD MDMs showed decreased and increased expression for anti-inflammatory (IL10 and CD163) and pro-inflammatory (CD68 and CCL20) marker genes, respectively. Analysis of correlation indicated that Tregs are directly related with HDL (P<0.01) and inversely related with LL-MDM (P<0.001) and that LL-MDM are directly related with triglycerides (P<0.01) and oxidized LDL (P<0.01). CONCLUSIONS: LD and obesity are associated with changes in the immune system: a significant reduction in the number of T cells with regulatory function and a shift of MDM towards lipid accumulation. Lipid profile of the patients correlates with these changes.

Growth hormone deficiency and human immunodeficiency virus.

Treatment with highly active antiretroviral drugs (HAART) is associated with several endocrine and metabolic comorbidities. Pituitary growth hormone (GH) secretion seems to be altered in human immunodeficiency virus (HIV) infection, and about one-third of patients have biochemical GH deficiency (GHD). We undertake a historical review of the functioning of the GH/insulin-like growth factor-1 (IGF-1) axis in patients with acquired immunodeficiency syndrome, and provide an overview of the main changes of the GH/IGF-1 axis occurring today in patients with HIV. Both spontaneous GH secretion and GH response to provocative stimuli are reduced in patients with HIV infection, especially in those with HIV-related lipodystrophy. The role of fat accumulation on flattened GH secretion is discussed, together with all factors able to potentially interfere with the pituitary secretion of GH. Several factors contribute to the development of GHD, but the pathophysiologic mechanisms involved in the genesis of GHD are complex and not yet fully elucidated owing to the difficulty in separating the effects of HIV infection from those of HAART, comorbidities and body changes. An update on the putative mechanisms involved in the pathogenesis of altered GH secretion in these patients is provided, together with an overview on the therapeutic strategies targeting the GH/IGF-1 axis to counteract fat redistribution associated with HIV-related lipodystrophy. The clinical significance of GHD in the context of HIV infection is discussed. The administration of tesamorelin, a GH releasing hormone analogue, is effective in reducing visceral fat in HIV-infected patients with lipodystrophy. This treatment is promising and safer than treatment with high doses of recombinant human growth hormone, which has several side-effects.

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.

CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

Glucagon-like peptide-1 analogues - an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: two case reports.

BACKGROUND: Lipodystrophic syndromes are uncommon medical conditions which are normally associated with metabolic disorders, such as diabetes mellitus, dyslipidemia, and fatty liver disease. These complications are generally difficult to treat, particularly diabetes, due to severe insulin resistance. We present two case reports of successful treatment of diabetes with glucagon-like peptide-1 analogues in patients with clinical features of lipodystrophic syndromes. CASE PRESENTATION: Two white women aged 49 and 60 years manifested marked central body fat deposition with severe lipoatrophy of their limbs and buttocks and pronounced acanthosis nigricans. They had hypertension, dyslipidemia, fatty liver disease, and poorly controlled diabetes (glycated hemoglobin 8.3% and 10.2%, respectively) despite the use of three classes of oral antidiabetic drugs taken in combination in the first case, and high doses of insulin in the second case. Four months after the addition of glucagon-like peptide-1 analogue to their previous treatment they both showed a pronounced improvement in metabolic control (glycated hemoglobin 5.6% and 6.2%, respectively). In the first case, a weight loss of nearly 30 kg was recorded. CONCLUSIONS: We intend to demonstrate that glucagon-like peptide-1 analogues could be a valuable tool for patients with lipodystrophic disorders, probably by improving body fat distribution, with favorable results in insulin-sensitivity and glycemic control.