RARE DISEASE
Localized lipodystrophy
Localized lipodystrophy
Localized lipodystrophy
Drug discovery
0
drugs
With orphan designations
Overview
Localized lipodystrophy comprises rare acquired disorders characterized by focal adipose tissue loss, typically affecting small regions without significant metabolic complications. Etiologies include mechanical trauma (e.g., repeated injections), drug reactions (insulin, steroids), or panniculitis. Common subtypes are pressure-induced, drug-induced, and centrifugal lipodystrophy. Diagnosis requires differentiation from scleroderma and atrophoderma. While primarily cosmetic, lesions in weight-bearing areas may cause physical discomfort. Most cases resolve with trigger removal, though some require surgical intervention [1][6][7].
Categories: rare endocrine diseases, rare skin diseases
Research Papers
229 drug discovery papers about Localized lipodystrophy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
229 drug discovery papers about Localized lipodystrophy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-18 | Lamin A depletion and RSG influence PPARγ DNA binding and chromatin organization in murine adult fibroblast cells
Lamin A/C proteins, integral to the nuclear lamina and present throughout the nucleoplasm, contribute to the mechanical stability of the nucleus and influence transcription as seen in laminopathies like certain lipodystrophies and progeria. By using light-sheet FCS, earlier we proved that lamin A is an important determinant of chromatin viscoelasticity in murine adult fibroblasts (MAFs). Here, by using MAF WT and lamin A KO cells, we aimed to clarify the role of lamin A in chromatin organization and the DNA-binding of PPARγ, a key transcription factor in adipogenesis also implicated in lipodystrophies. We analyzed the distribution of chromatin marks by confocal microscopy and measured PPARγ mobility and DNA binding by FCS and FRAP. Conspicuous overall changes were detected upon lamin A depletion and PPARγ agonist (rosiglitazone) treatment. Confocal imaging showed a remarkable decrease in nuclear volume in the absence of lamin A and an increase upon rosiglitazone treatment indicating chromatin decondensation. Heterochromatin was enriched in a distinct peripheral rim, and the thickness of the constitutive heterochromatin rim diminished in the absence of lamin A. Colocalization analysis showed that the overlap between euchromatin and heterochromatin decreased in lamin A KO cells. PPARγ colocalized with euchromatin whereas its localization was anti-correlated with constitutive heterochromatin, especially in the absence of lamin A. FCS and FRAP indicated that PPARγ had a fast-diffusing fraction bound with short residence times on DNA and a slow, more stably bound fraction throughout the nucleus including the periphery. Rosiglitazone increased PPARγ’s colocalization with the euchromatin and enhanced its DNA binding, which was more pronounced in lamin A KO cells. Our results suggest that lamin A plays a primary role in determining nuclear volume and overall chromatin organization with likely functional consequences exemplified by regulating ligand-induced DNA binding of PPARγ, which may have epigenomic and transcriptional consequences.
2026-01-01 | Non-invasive and minimally invasive adipocyte apoptosis–inducing methods for the reduction of localized lipodystrophy in adults: a scoping review
Localized lipodystrophy, commonly known as localized fat, is a frequent aesthetic and clinical concern in adults and is associated with reduced self-esteem and quality of life. In recent years, there has been increasing demand for non-invasive and minimally invasive body-contouring procedures that are safer, more accessible, and capable of producing clinically meaningful reductions in subcutaneous fat. Many of these interventions act by inducing controlled adipocyte apoptosis, leading to a reduction in adipose tissue volume. Several technologies and agents based on this mechanism have been developed, including cryolipolysis, radiofrequency, high-intensity focused ultrasound (HIFU), high-intensity focused electromagnetic field (HIFEM), low-level laser therapy (LLLT), and injectable adipocytolytic agents such as CBL-514. Although primary studies report promising results, the evidence is heterogeneous, with variability in study design, treatment parameters, outcome measures, and populations. The aim of this scoping review is to systematically map and describe the scientific evidence on non-invasive and minimally invasive adipocyte apoptosis–inducing methods for the treatment of localized lipodystrophy in adults. The review will identify the types of interventions, populations, protocols, outcomes, and safety data reported in the literature, in order to summarize the current state of knowledge and identify gaps to guide future research in aesthetic and dermatofunctional physiotherapy.
2025-11-15 | Granulomas galore: Twin cases of insulin-induced granulomas
Suppurative granulomas at insulin injection sites are exceedingly rare. While localized reactions such as erythema, pruritus, and lipodystrophy are well documented, granulomatous inflammation features merit increased clinical awareness. We describe two young adults – a 27 year old male and a 20 year old female with type 1 diabetes – who developed firm, tender, nodular, and ulcerated lesions with occasional pus discharge at thigh, abdomen, and shoulder injection sites 1 month after switching from premixed to separate regular and neutral protamine hagedorn (NPH) insulin. Both reported improper mixing technique, syringe reuse, and suboptimal storage. Investigations ruled out infection, immunodeficiency, and retained foreign bodies. Histopathology revealed suppurative foreignbody type granulomas with central vacuolation in giant cells, without insulin crystals. Cultures and special stains for bacteria, fungi, and mycobacteria were negative. These presentations are highly unusual and likely represent insulin- or zinc-induced noninfective granulomatous inflammation exacerbated by improper handling and injection hygiene. Proper mixing technique, hygiene education, and use of premixed insulin resulted in rapid lesion resolution. Clinicians should recognize this rare complication, ensure patient education, and investigate potential contributing factors to minimize recurrence.
2024-12-18 | Lipodystrophy With an Uncommon Clinical Presentation in a Patient With Insulin-Requiring Type 2 Diabetes Mellitus.
We report the case of a patient with type 2 diabetes mellitus (T2DM) on insulin therapy with a history of recurrent and severe hypoglycemia related to lipodystrophy with an uncommon clinical presentation. This was the case of a 67-year-old female with type 2 diabetes hospitalized for the exploration and management of severe and recurrent hypoglycemia. Her diabetes has been evolving since the age of 40 years and was complicated by minimal retinopathy. She was on premixed human insulin, administered through an insulin syringe for the last 17 years. She presented a history of well-controlled diabetes until five months back when she started to show a fluctuating blood glucose concentration, with episodes of unpredictable hypoglycemia occurring at variable times, with values inferior to 0.3 g/l associated with neurological features. Clinical examination revealed a swelling localized in the hypogastric region of the abdomen. It was painless, firm, not fixed to the underlying plans, without local inflammatory signs, and had appeared in the patient's preferred insulin injection site. Thus, we retained the diagnosis of insulin-induced lipohypertrophy. The patient has reported reusing needles for up to one week for economic reasons, and not frequently rotating insulin injection sites. The patient found a less painful injection in the lipohypertrophic area, and she continued to inject insulin into that zone, leading to its progressive enlargement. Therapeutic management consisted of switching the patient to insulin analogs and resuming education concerning the correct injection techniques. The insulin injection technique continues to be suboptimal in many insulin-treated patients, and our case emphasizes the need for improved awareness and education.
2024-04-01 | Senp7 Deficiency Impairs Lipid Droplets Maturation in White Adipose Tissues via Plin4 DeSUMOylation
Lipid metabolism is important for the maintenance of physiological homeostasis. Several members of the SUMO-specific protease (SENP) family have been reported as the regulators of lipid homeostasis. However, the function of Senp7 in lipid metabolism remains unclear. In this study, we generated both conventional and adipocyte-specific Senp7 knockout mice to characterize the role of Senp7 in lipid metabolism homeostasis. Both Senp7-deficient mice displayed reduced white adipose tissue mass and decreased size of adipocytes. By analyzing the lipid droplet morphology, we demonstrated that the lipid droplet size was significantly smaller in Senp7-deficient adipocytes. Mechanistically, Senp7 could deSUMOylate the perilipin family protein Plin4 to promote the lipid droplet localization of Plin4. Our results reveal an important role of Senp7 in the maturation of lipid droplets via Plin4 deSUMOylation.
proteins
2026-03-23 | Lipodystrophies in Clinical Practice: A Case Series From a Local Health Unit in Portugal.
Background Lipodystrophies are rare disorders characterized by loss of adipose tissue, leading to severe metabolic and multisystem complications. Data on real-world management remain limited, particularly in Portugal. Objectives The objective of this study is to describe the clinical, metabolic, genetic, and therapeutic characteristics of patients with confirmed or suspected lipodystrophy followed at a Portuguese Endocrinology Outpatient Clinic. Methods We conducted a retrospective observational study including 21 patients with clinical suspicion or diagnosis of lipodystrophy. Demographic, clinical, laboratory, imaging, and genetic data were collected. Results The cohort was predominantly female (90.5%) with a median age at diagnosis of 49 years. Sixteen patients (76.2%) had familial partial lipodystrophy (FPLD), two (9.5%) had congenital generalized lipodystrophy, two (9.5%) had acquired generalized lipodystrophy, and one presented a complex syndromic form. Diabetes mellitus was present in 71.4% of patients and hypertriglyceridemia in 52.4%. Metabolic liver disease occurred in both generalized and partial forms. Autoimmune disorders affected 31.6% of patients, and cardiac involvement was observed in 23.8%. Genetic testing identified pathogenic or likely pathogenic variants in BSCL2 and PPARG in three patients, while most FPLD cases remained genetically unexplained. Metreleptin therapy in three patients with generalized lipodystrophy improved glycemic control, triglycerides, liver enzymes, and proteinuria. Dual-energy X-ray absorptiometry imaging supported the phenotypic characterization of adipose tissue loss. Conclusions Detailed physical examination, genetic testing, imaging, and early therapeutic interventions are critical for management. These findings align with European registry data and highlight the need for increased awareness and systematic evaluation in real-world clinical practice.
2025-12-10 | Lipid-induced Caveolin1-Lipid droplet trafficking is associated with lipid droplet growth
Abstract Caveolae are 50-100 nm sized plasma membrane invaginations involved in cellular lipid uptake and lipid accumulation. Several caveolin1 and cavin1 mutations are associated to human lipodystrophy. Interestingly, previous research identified caveolae proteins at lipid droplets although their specific cellular function at lipid droplets and in lipid trafficking is not understood. Here, we show that extracellular dietary lipids like oleic acid and cholesterol shift caveolae at the plasma membrane to highly spherical invaginations. Within 3 hours of lipid treatment caveolin1 accumulates specifically to lipid droplets. Correlative fluorescence FIB-SEM and split-APEX proteomics revealed no caveolar vesicles at the lipid droplet but caveolin1 alone. Mechanistically, caveolin1-lipid droplet trafficking is regulated by EHD2 at the plasma membrane level, followed by caveolin1 localization to EEA1- and Rab5-positive endosomes within 1 hour of oleic acid treatment, and subsequently lipid droplet accumulation. Caveolin1-lipid droplet trafficking does not depend on lysosomal activity. Surprisingly, the deletion of the central caveolin1 β-barrel (Cav1-F160X), a mutation found in lipodystrophy patients, abolished caveolin1-lipid droplet trafficking and lipid droplet growth. Taken together, our results show that dietary lipids induce caveolae uptake, caveolin1 accumulation to lipid droplets and a caveolin1-dependent lipid droplet growth.
2025-07-01 | The Impact of Neuregulin 4 on Metabolic Dysregulation in Lipodystrophy.
Lipodystrophies (LDs) are rare disorders characterized by the partial or complete loss of subcutaneous adipose tissue, leading to severe metabolic complications. Although metreleptin therapy has shown beneficial effects, its therapeutic efficacy is limited, particularly in patients with partial LD. Neuregulin 4 (NRG4), a batokine secreted by brown adipose tissue, regulates lipid metabolism and hepatic function, but its relevance in LD has not been investigated. In this study, we observed significantly reduced serum NRG4 levels in patients with LD compared to matched healthy controls. NRG4 levels declined further during metreleptin therapy, potentially reflecting fat mass reduction or limited treatment response. To explore functional relevance, we treated a transgenic LD mouse model with recombinant NRG4. While NRG4 enhanced thermogenic gene expression in brown and inguinal white adipose tissue, it did not improve systemic metabolic parameters or hepatic steatosis. In vitro, NRG4 failed to rescue impaired adipogenesis and thermogenesis in brown adipocytes from LD mice but increased insulin-stimulated fatty acid uptake in white adipocytes, indicating a preserved functional response despite differentiation defects. NRG4 also activated hepatic AMPK signaling without improving lipid accumulation. These findings suggest that NRG4 promotes adipose tissue remodeling but is insufficient to restore systemic metabolic homeostasis in LD. Together, our data indicate that NRG4's beneficial effects may depend on the presence of functional adipose tissue, which is profoundly impaired in LD. Consequently, while NRG4 may support local plasticity in adipose tissue, it is insufficient as a therapy for metabolic restoration in LD.
2023-08-28 | Forced Hepatic Expression of NRF2 or NQO1 Impedes Hepatocyte Lipid Accumulation in a Lipodystrophy Mouse Model
Lipodystrophy is a disorder featuring loss of normal adipose tissue depots due to impaired production of normal adipocytes. It leads to a gain of fat deposition in ectopic tissues such as liver and skeletal muscle that results in steatosis, dyslipidemia, and insulin resistance. Previously, we established a Rosa NIC/NIC::AdiCre lipodystrophy model mouse. The lipodystrophic phenotype that included hepatomegaly accompanied with hepatic damage due to higher lipid accumulation was attenuated substantially by amplified systemic NRF2 signaling in mice with hypomorphic expression of Keap1; whole-body Nrf2 deletion abrogated this protection. To determine whether hepatic-specific NRF2 signaling would be sufficient for protection against hepatomegaly and fatty liver development, direct, powerful, transient expression of Nrf2 or its target gene Nqo1 was achieved by administration through hydrodynamic tail vein injection of pCAG expression vectors of dominant-active Nrf2 and Nqo1 in Rosa NIC/NIC::AdiCre mice fed a 9% fat diet. Both vectors enabled protection from hepatic damage, with the pCAG-Nqo1 vector being the more effective as seen with a ~50% decrease in hepatic triglyceride levels. Therefore, activating NRF2 signaling or direct elevation of NQO1 in the liver provides new possibilities to partially reduce steatosis that accompanies lipodystrophy.
2023-08-10 | Protective effects of Mkl1/2 against lipodystrophy and muscle atrophy via PI3K/AKT-independent FoxO repression
ABSTRACT FoxO transcription factors are involved in the pathogenesis of lipodystrophy and muscle atrophy. FoxO proteins are phosphorylated and inactivated by PI3K/AKT signaling; however, little is known about FoxO repressors other than this pathway. Our study showed that the Srf cofactors Mkl1 and Mkl2 directly repressed FoxO transcriptional activity, independent of the PI3K/AKT pathway. Loss of Mkl1/2 led to the overactivation of FoxO, which impaired the maintenance of both white adipose tissue (WAT) and skeletal muscle. In Mkl2 -deficient preadipocytes, Pparγ was suppressed and white adipogenesis was severely impaired. In myotubes, Mkl1 and Mkl2 suppressed the expression of atrophy-related genes (atrogenes) induced by FoxO. Mkl1 expression was reduced at the onset of muscle atrophy in vivo , and exogenous supplementation of skeletal muscle Mkl1 suppressed atrogene expression and induced muscle hypertrophy. Finally, both Mkl2 nuclear localization and Mkl1/2 expression were upregulated by exercise, suggesting that Mkl1/2 is involved in the inhibitory effect of exercise on muscle atrophy. These findings indicate that Mkl1/2 act as PI3K/AKT signaling-independent repressors of FoxO and are essential for adipose and muscle tissue homeostasis.
gene therapies
2016-01-07 | Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations
Objective Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by marked scarcity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early-onset diabetes. Mutation of the BSCL2/SEIPIN gene causes the most severe form of CGL. The aim of this study was to generate induced pluripotent stem (iPS) cells from patients with CGL harboring BSCL2/SEIPIN mutations. Methods Skin biopsies were obtained from two Japanese patients with CGL harboring different nonsense mutations (E189X and R275X) in BSCL2/SEIPIN. The fibroblasts thus obtained were infected with retroviruses encoding OCT4, SOX2, c-MYC, and KLF4. The generated iPS cells were evaluated for pluripotency by examining the expression of pluripotency markers (alkaline phosphatase, SSEA-4, TRA-1-60, and NANOG) and their ability to differentiate to three germ layers in vitro by forming embryoid bodies, and to form teratomas in vivo. Adipogenic capacity of differentiated BSCL2-iPS cells was determined by oil red O and adipose differentiation-related protein (ADRP) staining. Rescue experiments were also performed using stable expression of wild-type BSCL2. A coimmunoprecipitation assay was conducted to investigate the interaction of SEIPIN with ADRP. Results iPS cells were generated from fibroblasts of the two patients with CGL. Each of the patient-derived iPS (BSCL2-iPS) clones showed all of the hallmarks of pluripotency and could differentiate into derivatives of all three germ layers in vitro by forming embryoid bodies, and form teratomas after injection into mouse testes. BSCL2-iPS cells maintained the mutations in BSCL2 and lacked intact BSCL2. Upon adipogenic differentiation, BSCL2-iPS cells exhibited marked reduction of lipid droplet formation concomitant with diffuse cytoplasmic distribution of ADRP, compared with iPS cells from healthy individuals. Forced expression of BSCL2 not only rescued the lipid accumulation defects, but also restored cytoplasmic punctate localization of ADRP in BSCL2-iPS cells. Coimmunoprecipitation indicated SEIPIN interacted with ADRP. Conclusion BSCL2-iPS cells that recapitulate the lipodystrophic phenotypes in vitro could provide valuable models with which to study the physiology of lipid accumulation and the pathology of human lipodystrophy. We found that BSCL2 defines the localization of ADRP, which has a role in lipid accumulation and adipogenic differentiation.
2015-02-19 | Defective Differentiation of Adipose Precursor Cells from Lipodystrophic Mice Lacking Perilipin 1
Perilipin 1 (Plin1) localizes at the surface of lipid droplets to regulate triglyceride storage and hydrolysis in adipocytes. Plin1 defect leads to low adiposity in mice and partial lipodystrophy in human. This study investigated the roles of Plin1 in adipocyte differentiation. Plin1 null (-/-) mice showed plenty of multilocular adipocytes and small unilocular adipocytes in adipose tissue, along with lack of a subpopulation of adipose progenitor cells capable of in vivo adipogenesis and along with downregulation of adipogenic pathway. Before initiation of differentiation, adipose stromal-vascular cells (SVCs) from Plin1-/- mice already accumulated numerous tiny lipid droplets, which increased in number and size during the first 12-h induction but thereafter became disappeared at day 1 of differentiation. The adipogenic signaling was dysregulated despite protein level of PPARγ was near normal in Plin1-/- SVCs like in Plin1-/- adipose tissue. Heterozygous Plin1+/- SVCs were able to develop lipid droplets, with both the number and size more than in Plin1-/- SVCs but less than in Plin1+/+ SVCs, indicating that Plin1 haploinsufficiency accounts for attenuated adipogenesis. Aberrant lipid droplet growth and differentiation of Plin1-/- SVCs were rescued by adenoviral Plin1 expression and were ameliorated by enhanced or prolonged adipogenic stimulation. Our finding suggests that Plin1 plays an important role in adipocyte differentiation and provides an insight into the pathology of partial lipodystrophy in patients with Plin1 mutation.
2013-09-10 | BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling
Seipin regulates lipid homeostasis by preventing lipid droplet (LD) formation in non-adipocytes but promoting it in developing adipocytes. Here, we report that seipin interacts with 14-3-3β through its N- and C-termini. Expression of 14-3-3β is upregulated during adipogenesis, and its deletion results in defective adipogenesis without affecting key adipogenic transcription factors. We further identified the actin-severing protein cofilin-1 as an interacting partner to 14-3-3β. Cofilin-1 was spatiotemporally recruited by 14-3-3β in the cytoplasm during adipocyte differentiation. Extensive actin cytoskeleton remodelling, from stress fibres to cortical structures, was apparent during adipogenesis, but not under lipogenic conditions, indicating that actin cytoskeleton remodelling is only required for adipocyte development. Similar to seipin and 14-3-3β, cofilin-1 knockdown led to impaired adipocyte development. At the cellular level, differentiated cells with knockdown of cofilin-1, 14-3-3β or seipin continued to maintain relatively intact stress fibres, in contrast to cortical actin structure in control cells. Finally, 3T3-L1 cells expressing a severing-resistant actin mutant exhibited impaired adipogenesis. We propose that seipin regulates adipogenesis by recruiting cofilin-1 to remodel actin cytoskeleton through the 14-3-3β protein.
2011-04-14 | Tissue-Autonomous Function of Drosophila Seipin in Preventing Ectopic Lipid Droplet Formation
Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy.
cell therapies
2026-04-15 | Dilute Hyaluronic Acid for Lipoatrophy: Three Cases and Literature Review.
Localized lipoatrophy, characterized by subcutaneous fat loss, can result from trauma, injectable drugs, panniculitis, or idiopathic causes, leading to outcomes ranging from self-resolution to permanent disfigurement. This case series presents a novel approach using dilute hyaluronic acid (HA) for three cases of lipoatrophy (trauma-induced, radiation-induced, and steroid-induced), with all cases showing notable improvement after one session. This approach represents a promising, low-risk alternative for managing lipoatrophy of various etiologies, with potential benefits for patient quality of life.
2025-07-02 | Preliminary high-dose irradiation of the recipient and associated damage of bone marrow stromal compartment enables bone marrow stroma transplantation.
Transplantability of allogeneic mesenchymal stem cells (MSCs) as a stable engraftment and participation in physiological renewal of bone marrow (BM) stroma remains an open question. We hypothesized that a necessary condition for successful MSCs transplantation is the prior significant damage to the recipient's BM stroma. To test this, BM derived from male B10 mice was injected intravenously into syngeneic female mice irradiated with 6.5 Gy and 13 Gy, and unirradiated individuals. We measured donor chimerism 30 days after irradiation in recipients' bones by RQ-PCR and in BM CFU-Fs by ddPCR. The ratio of PCR signals from single-copy Y chromosome-linked Prssly gene and autosomal Gapdh gene was used to determine donor chimerism. None of the non-irradiated recipients had donor cells in the BM subpopulation under study. In the group of recipients irradiated at a dose of 6.5 Gy, donor cells were detected at 0.16% in BM of only one animal. Increasing the radiation dose resulted in a significant increase in donor chimerism among BM stromal cells: it was 11% and 14% in two survived animals of this group. Donor chimerism in the bones of unirradiated recipients was not observed in any of the 15 samples. It was detected in only 2/18 bones of recipients irradiated with 6.5 Gy (0.8% and 1%). The median donor chimerism in bones of recipients irradiated with 13 Gy was 15%. We conclude that the condition for successful engraftment of donor stromal progenitor cells is prior damage to the recipient's BM stroma. Development of protocols of MSCs and HSCs co-transplantation, when full donor chimerism of hematopoietic and stromal tissue will be observed in recipient BM, is feasible. It will allow to increase the efficiency of therapy of malignant and other diseases of blood system, for which allogeneic BM transplantation is indicated, as well as patients with impaired stroma function such as osteogenesis imperfecta and congenital generalized lipodystrophy.
2024-09-27 | Successful fat transplant in a rare acquired lipodystrophy Barraquer–Simons syndrome
Lipodystrophies can be generalized and partial/localized lack of subcutaneous tissue, which are uncommon heterogeneous illnesses that can be hereditary or acquired. Acquired partial lipodystrophy’ (APL) is the new name for lipodystrophia progressiva, also known as Barraquer–Simons syndrome (BSS). It could come after a severe viral infection like the measles. Young people and children both experience it. Typically, BSS or APL starts between the ages of 5 and 15. The principal feature of BSS is cephalothoracic lipodystrophy, which affects the face, neck, arms, thorax, and upper abdomen in a cephalocaudal pattern. Alternate complement pathway activation and C3 hypocomplementemia with adipocyte lysis brought on by complement 3 nephritic factor (C3NeF) have been suggested as potential causes of fat loss in individuals with APL, even though the precise process is still mostly understood. Therapeutic options for lipodystrophy include fat fillers. Different types of autologous fat transplants are possible. Autologous free fat graft where a mass of tissue harvested from any discrete subcutaneous location and implanted at a recipient site. Dermofat grafts are made from tissue that has been removed from a region, allowing for the removal of full-thickness skin grafts and the primary closure of defects. The dermofat graft can be employed as a spacer between gliding tissues or as a filler. Omental flaps, which are revascularized fat flaps, can be utilized for microvascular transfer, soft-tissue filler for hemifacial atrophy, or to cover any significant skin defects. When fat is extracted, processed, and transplanted in liquid injectable form for a variety of purposes, it is known as free fat injection.
2020-02-14 | Safety and Localization of Mesenchymal Stromal Cells Derived from Human Adipose Tissue-Associated Hyaluronic Acid: A Preclinical Study
Millions of plastic surgeries are performed worldwide every year with the objective of correcting lipodystrophies stemming from lesions, tumor resections, birth defects, and AIDS-associated antiretroviral therapy. Besides that, a large number of clinical research have assessed the outcome of procedures that rely on combinations of dermal fillers and autologous cells. However, little is known about the safety of these combinations and the localization of the injected cells. The aim of this study was to test the toxicity of a solution containing 1% hyaluronic acid (HA) and adipose-derived stromal cells (ASCs) from the human adipose tissue and to assess the localization of the injected cells, with and without HA, labeled with technetium-99m. Rats received subcutaneous and intraperitoneal injections of a solution containing 1% HA/adipose-derived stromal cells isolated from the human fat tissue. The animals were then observed for up to forty-two days. The solution tested in this study did not result in systemic, biochemical, or anatomic alterations that could represent toxicity symptoms. The association of HA and ASCs labeled with technetium-99m remained at the site of the injection within a period of twenty-four hours, as demonstrated by a whole-body imaging software fusion of SPECT and CT. In conclusion, our study shows that the subcutaneous and intraperitoneal injection of HA associated with adipose-derived stromal cells (ASCs) is safe. The association of HA and ASCs did not induce local or systemic toxicity. Thus, the administration of volume equal to or less than 0.2 mL of the agent filler (1 × 106 ASC+HA 1%) should be considered for subsequent studies and may be an alternative to dermal fillers due to the expected lasting effects.
2018-08-30 | Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome): Early Cosmetic Intervention with Autologous Fat
Barraquer-Simons syndrome is a rare acquired lipodystrophy characterized by gradually symmetric subcutaneous fat loss in a craniocaudal distribution, often associated with hypocomplementemia and nephropathies. Facial cosmetic treatment in this disorder has not been fully described in the literature. We present a patient with Barraquer-Simons syndrome with emphasis on early cosmetic intervention with autologous fat grafting and its long-term efficacy. At the follow-up 37 months after the last fat grafting, preservation of the grafted fat was noted while lipodystrophy progressed in the trunk regions. Autologous fat grafting is suggested for the correction of facial dysmorphism in this type of lipodystrophy.
other
2025-11-29 | Mechanisms of Glucagon-Like Peptide 1 Receptor Agonist-Induced Facial Lipodystrophy and a Path Toward Prevention.
The emergence of a distinct facial appearance characterized by pronounced hollowing of the cheeks, temples, chin, and periorbital region has become a noteworthy side effect of treatment with glucagon-like peptide 1 receptor agonists (GLP-1RAs). This phenomenon presents a growing concern in both dermatology and aesthetic medicine. The reduction of facial adipose tissue in patients receiving GLP-1RAs often exceeds the overall weight and fat loss typically associated with these agents, suggesting that the effect cannot be fully attributed to systemic metabolic changes alone. Instead, it raises the possibility of localized, tissue-specific mechanisms of GLP-1RA action within facial fat depots. In this article, we explore the underlying pathophysiology of this selective facial fat loss and discuss potential strategies for mitigating or reversing the aesthetic impact of GLP-1RAs. Since the local effects of GLP-1RAs are realized through internalization of GLP-1 receptors (canonical pathway) or IGF-1R (non-canonical pathway), the suppression of mechanisms responsible for this internalization can be used to prevent the development of partial lipodystrophy after the application of GLP-1RAs. One encouraging possibility for such a preventive intervention can be the local modulation of CAV1 in the facial adipose tissue during the GLP-1RAs treatment course.
2002-04-01 | Exclusive Action of Transmembrane TNFα in Adipose Tissue Leads to Reduced Adipose Mass and Local But Not Systemic Insulin Resistance
Aberrant TNFα expression in adipocytes is a molecular mechanism by which insulin action is modulated in adipose tissue. While this might be a compensatory response to limit adipose expansion, neither the mechanisms underlying this local effect nor its systemic biological consequences have been studied. It is also not clear whether TNFα-induced insulin resistance in adipocyte alone is responsible for systemic insulin resistance in the absence of obesity. In a transgenic mouse model deficient in endogenous TNFα, we demonstrate that specific expression of the transmembrane TNFα (mTNFα) in adipocytes leads to decreased whole body adipose mass, and local, but not systemic insulin resistance. These data demonstrate that exclusive action of TNFα in adipose tissue strongly inhibits insulin action at this site and leads to reduced adiposity in mice. However, this isolated adipocyte insulin resistance in the context of reduced fat mass and/or the absence of obesity is insufficient to alter systemic glucose homeostasis.
small molecules
2026-05-18 | Lamin A depletion and RSG influence PPARγ DNA binding and chromatin organization in murine adult fibroblast cells
Lamin A/C proteins, integral to the nuclear lamina and present throughout the nucleoplasm, contribute to the mechanical stability of the nucleus and influence transcription as seen in laminopathies like certain lipodystrophies and progeria. By using light-sheet FCS, earlier we proved that lamin A is an important determinant of chromatin viscoelasticity in murine adult fibroblasts (MAFs). Here, by using MAF WT and lamin A KO cells, we aimed to clarify the role of lamin A in chromatin organization and the DNA-binding of PPARγ, a key transcription factor in adipogenesis also implicated in lipodystrophies. We analyzed the distribution of chromatin marks by confocal microscopy and measured PPARγ mobility and DNA binding by FCS and FRAP. Conspicuous overall changes were detected upon lamin A depletion and PPARγ agonist (rosiglitazone) treatment. Confocal imaging showed a remarkable decrease in nuclear volume in the absence of lamin A and an increase upon rosiglitazone treatment indicating chromatin decondensation. Heterochromatin was enriched in a distinct peripheral rim, and the thickness of the constitutive heterochromatin rim diminished in the absence of lamin A. Colocalization analysis showed that the overlap between euchromatin and heterochromatin decreased in lamin A KO cells. PPARγ colocalized with euchromatin whereas its localization was anti-correlated with constitutive heterochromatin, especially in the absence of lamin A. FCS and FRAP indicated that PPARγ had a fast-diffusing fraction bound with short residence times on DNA and a slow, more stably bound fraction throughout the nucleus including the periphery. Rosiglitazone increased PPARγ’s colocalization with the euchromatin and enhanced its DNA binding, which was more pronounced in lamin A KO cells. Our results suggest that lamin A plays a primary role in determining nuclear volume and overall chromatin organization with likely functional consequences exemplified by regulating ligand-induced DNA binding of PPARγ, which may have epigenomic and transcriptional consequences.
2026-01-01 | Non-invasive and minimally invasive adipocyte apoptosis–inducing methods for the reduction of localized lipodystrophy in adults: a scoping review
Localized lipodystrophy, commonly known as localized fat, is a frequent aesthetic and clinical concern in adults and is associated with reduced self-esteem and quality of life. In recent years, there has been increasing demand for non-invasive and minimally invasive body-contouring procedures that are safer, more accessible, and capable of producing clinically meaningful reductions in subcutaneous fat. Many of these interventions act by inducing controlled adipocyte apoptosis, leading to a reduction in adipose tissue volume. Several technologies and agents based on this mechanism have been developed, including cryolipolysis, radiofrequency, high-intensity focused ultrasound (HIFU), high-intensity focused electromagnetic field (HIFEM), low-level laser therapy (LLLT), and injectable adipocytolytic agents such as CBL-514. Although primary studies report promising results, the evidence is heterogeneous, with variability in study design, treatment parameters, outcome measures, and populations. The aim of this scoping review is to systematically map and describe the scientific evidence on non-invasive and minimally invasive adipocyte apoptosis–inducing methods for the treatment of localized lipodystrophy in adults. The review will identify the types of interventions, populations, protocols, outcomes, and safety data reported in the literature, in order to summarize the current state of knowledge and identify gaps to guide future research in aesthetic and dermatofunctional physiotherapy.
2025-11-15 | Granulomas galore: Twin cases of insulin-induced granulomas
Suppurative granulomas at insulin injection sites are exceedingly rare. While localized reactions such as erythema, pruritus, and lipodystrophy are well documented, granulomatous inflammation features merit increased clinical awareness. We describe two young adults – a 27 year old male and a 20 year old female with type 1 diabetes – who developed firm, tender, nodular, and ulcerated lesions with occasional pus discharge at thigh, abdomen, and shoulder injection sites 1 month after switching from premixed to separate regular and neutral protamine hagedorn (NPH) insulin. Both reported improper mixing technique, syringe reuse, and suboptimal storage. Investigations ruled out infection, immunodeficiency, and retained foreign bodies. Histopathology revealed suppurative foreignbody type granulomas with central vacuolation in giant cells, without insulin crystals. Cultures and special stains for bacteria, fungi, and mycobacteria were negative. These presentations are highly unusual and likely represent insulin- or zinc-induced noninfective granulomatous inflammation exacerbated by improper handling and injection hygiene. Proper mixing technique, hygiene education, and use of premixed insulin resulted in rapid lesion resolution. Clinicians should recognize this rare complication, ensure patient education, and investigate potential contributing factors to minimize recurrence.
2024-12-18 | Lipodystrophy With an Uncommon Clinical Presentation in a Patient With Insulin-Requiring Type 2 Diabetes Mellitus.
We report the case of a patient with type 2 diabetes mellitus (T2DM) on insulin therapy with a history of recurrent and severe hypoglycemia related to lipodystrophy with an uncommon clinical presentation. This was the case of a 67-year-old female with type 2 diabetes hospitalized for the exploration and management of severe and recurrent hypoglycemia. Her diabetes has been evolving since the age of 40 years and was complicated by minimal retinopathy. She was on premixed human insulin, administered through an insulin syringe for the last 17 years. She presented a history of well-controlled diabetes until five months back when she started to show a fluctuating blood glucose concentration, with episodes of unpredictable hypoglycemia occurring at variable times, with values inferior to 0.3 g/l associated with neurological features. Clinical examination revealed a swelling localized in the hypogastric region of the abdomen. It was painless, firm, not fixed to the underlying plans, without local inflammatory signs, and had appeared in the patient's preferred insulin injection site. Thus, we retained the diagnosis of insulin-induced lipohypertrophy. The patient has reported reusing needles for up to one week for economic reasons, and not frequently rotating insulin injection sites. The patient found a less painful injection in the lipohypertrophic area, and she continued to inject insulin into that zone, leading to its progressive enlargement. Therapeutic management consisted of switching the patient to insulin analogs and resuming education concerning the correct injection techniques. The insulin injection technique continues to be suboptimal in many insulin-treated patients, and our case emphasizes the need for improved awareness and education.
2024-04-01 | Senp7 Deficiency Impairs Lipid Droplets Maturation in White Adipose Tissues via Plin4 DeSUMOylation
Lipid metabolism is important for the maintenance of physiological homeostasis. Several members of the SUMO-specific protease (SENP) family have been reported as the regulators of lipid homeostasis. However, the function of Senp7 in lipid metabolism remains unclear. In this study, we generated both conventional and adipocyte-specific Senp7 knockout mice to characterize the role of Senp7 in lipid metabolism homeostasis. Both Senp7-deficient mice displayed reduced white adipose tissue mass and decreased size of adipocytes. By analyzing the lipid droplet morphology, we demonstrated that the lipid droplet size was significantly smaller in Senp7-deficient adipocytes. Mechanistically, Senp7 could deSUMOylate the perilipin family protein Plin4 to promote the lipid droplet localization of Plin4. Our results reveal an important role of Senp7 in the maturation of lipid droplets via Plin4 deSUMOylation.
proteins
2026-03-23 | Lipodystrophies in Clinical Practice: A Case Series From a Local Health Unit in Portugal.
Background Lipodystrophies are rare disorders characterized by loss of adipose tissue, leading to severe metabolic and multisystem complications. Data on real-world management remain limited, particularly in Portugal. Objectives The objective of this study is to describe the clinical, metabolic, genetic, and therapeutic characteristics of patients with confirmed or suspected lipodystrophy followed at a Portuguese Endocrinology Outpatient Clinic. Methods We conducted a retrospective observational study including 21 patients with clinical suspicion or diagnosis of lipodystrophy. Demographic, clinical, laboratory, imaging, and genetic data were collected. Results The cohort was predominantly female (90.5%) with a median age at diagnosis of 49 years. Sixteen patients (76.2%) had familial partial lipodystrophy (FPLD), two (9.5%) had congenital generalized lipodystrophy, two (9.5%) had acquired generalized lipodystrophy, and one presented a complex syndromic form. Diabetes mellitus was present in 71.4% of patients and hypertriglyceridemia in 52.4%. Metabolic liver disease occurred in both generalized and partial forms. Autoimmune disorders affected 31.6% of patients, and cardiac involvement was observed in 23.8%. Genetic testing identified pathogenic or likely pathogenic variants in BSCL2 and PPARG in three patients, while most FPLD cases remained genetically unexplained. Metreleptin therapy in three patients with generalized lipodystrophy improved glycemic control, triglycerides, liver enzymes, and proteinuria. Dual-energy X-ray absorptiometry imaging supported the phenotypic characterization of adipose tissue loss. Conclusions Detailed physical examination, genetic testing, imaging, and early therapeutic interventions are critical for management. These findings align with European registry data and highlight the need for increased awareness and systematic evaluation in real-world clinical practice.
2025-12-10 | Lipid-induced Caveolin1-Lipid droplet trafficking is associated with lipid droplet growth
Abstract Caveolae are 50-100 nm sized plasma membrane invaginations involved in cellular lipid uptake and lipid accumulation. Several caveolin1 and cavin1 mutations are associated to human lipodystrophy. Interestingly, previous research identified caveolae proteins at lipid droplets although their specific cellular function at lipid droplets and in lipid trafficking is not understood. Here, we show that extracellular dietary lipids like oleic acid and cholesterol shift caveolae at the plasma membrane to highly spherical invaginations. Within 3 hours of lipid treatment caveolin1 accumulates specifically to lipid droplets. Correlative fluorescence FIB-SEM and split-APEX proteomics revealed no caveolar vesicles at the lipid droplet but caveolin1 alone. Mechanistically, caveolin1-lipid droplet trafficking is regulated by EHD2 at the plasma membrane level, followed by caveolin1 localization to EEA1- and Rab5-positive endosomes within 1 hour of oleic acid treatment, and subsequently lipid droplet accumulation. Caveolin1-lipid droplet trafficking does not depend on lysosomal activity. Surprisingly, the deletion of the central caveolin1 β-barrel (Cav1-F160X), a mutation found in lipodystrophy patients, abolished caveolin1-lipid droplet trafficking and lipid droplet growth. Taken together, our results show that dietary lipids induce caveolae uptake, caveolin1 accumulation to lipid droplets and a caveolin1-dependent lipid droplet growth.
2025-07-01 | The Impact of Neuregulin 4 on Metabolic Dysregulation in Lipodystrophy.
Lipodystrophies (LDs) are rare disorders characterized by the partial or complete loss of subcutaneous adipose tissue, leading to severe metabolic complications. Although metreleptin therapy has shown beneficial effects, its therapeutic efficacy is limited, particularly in patients with partial LD. Neuregulin 4 (NRG4), a batokine secreted by brown adipose tissue, regulates lipid metabolism and hepatic function, but its relevance in LD has not been investigated. In this study, we observed significantly reduced serum NRG4 levels in patients with LD compared to matched healthy controls. NRG4 levels declined further during metreleptin therapy, potentially reflecting fat mass reduction or limited treatment response. To explore functional relevance, we treated a transgenic LD mouse model with recombinant NRG4. While NRG4 enhanced thermogenic gene expression in brown and inguinal white adipose tissue, it did not improve systemic metabolic parameters or hepatic steatosis. In vitro, NRG4 failed to rescue impaired adipogenesis and thermogenesis in brown adipocytes from LD mice but increased insulin-stimulated fatty acid uptake in white adipocytes, indicating a preserved functional response despite differentiation defects. NRG4 also activated hepatic AMPK signaling without improving lipid accumulation. These findings suggest that NRG4 promotes adipose tissue remodeling but is insufficient to restore systemic metabolic homeostasis in LD. Together, our data indicate that NRG4's beneficial effects may depend on the presence of functional adipose tissue, which is profoundly impaired in LD. Consequently, while NRG4 may support local plasticity in adipose tissue, it is insufficient as a therapy for metabolic restoration in LD.
2023-08-28 | Forced Hepatic Expression of NRF2 or NQO1 Impedes Hepatocyte Lipid Accumulation in a Lipodystrophy Mouse Model
Lipodystrophy is a disorder featuring loss of normal adipose tissue depots due to impaired production of normal adipocytes. It leads to a gain of fat deposition in ectopic tissues such as liver and skeletal muscle that results in steatosis, dyslipidemia, and insulin resistance. Previously, we established a Rosa NIC/NIC::AdiCre lipodystrophy model mouse. The lipodystrophic phenotype that included hepatomegaly accompanied with hepatic damage due to higher lipid accumulation was attenuated substantially by amplified systemic NRF2 signaling in mice with hypomorphic expression of Keap1; whole-body Nrf2 deletion abrogated this protection. To determine whether hepatic-specific NRF2 signaling would be sufficient for protection against hepatomegaly and fatty liver development, direct, powerful, transient expression of Nrf2 or its target gene Nqo1 was achieved by administration through hydrodynamic tail vein injection of pCAG expression vectors of dominant-active Nrf2 and Nqo1 in Rosa NIC/NIC::AdiCre mice fed a 9% fat diet. Both vectors enabled protection from hepatic damage, with the pCAG-Nqo1 vector being the more effective as seen with a ~50% decrease in hepatic triglyceride levels. Therefore, activating NRF2 signaling or direct elevation of NQO1 in the liver provides new possibilities to partially reduce steatosis that accompanies lipodystrophy.
2023-08-10 | Protective effects of Mkl1/2 against lipodystrophy and muscle atrophy via PI3K/AKT-independent FoxO repression
ABSTRACT FoxO transcription factors are involved in the pathogenesis of lipodystrophy and muscle atrophy. FoxO proteins are phosphorylated and inactivated by PI3K/AKT signaling; however, little is known about FoxO repressors other than this pathway. Our study showed that the Srf cofactors Mkl1 and Mkl2 directly repressed FoxO transcriptional activity, independent of the PI3K/AKT pathway. Loss of Mkl1/2 led to the overactivation of FoxO, which impaired the maintenance of both white adipose tissue (WAT) and skeletal muscle. In Mkl2 -deficient preadipocytes, Pparγ was suppressed and white adipogenesis was severely impaired. In myotubes, Mkl1 and Mkl2 suppressed the expression of atrophy-related genes (atrogenes) induced by FoxO. Mkl1 expression was reduced at the onset of muscle atrophy in vivo , and exogenous supplementation of skeletal muscle Mkl1 suppressed atrogene expression and induced muscle hypertrophy. Finally, both Mkl2 nuclear localization and Mkl1/2 expression were upregulated by exercise, suggesting that Mkl1/2 is involved in the inhibitory effect of exercise on muscle atrophy. These findings indicate that Mkl1/2 act as PI3K/AKT signaling-independent repressors of FoxO and are essential for adipose and muscle tissue homeostasis.
gene therapies
2016-01-07 | Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations
Objective Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by marked scarcity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early-onset diabetes. Mutation of the BSCL2/SEIPIN gene causes the most severe form of CGL. The aim of this study was to generate induced pluripotent stem (iPS) cells from patients with CGL harboring BSCL2/SEIPIN mutations. Methods Skin biopsies were obtained from two Japanese patients with CGL harboring different nonsense mutations (E189X and R275X) in BSCL2/SEIPIN. The fibroblasts thus obtained were infected with retroviruses encoding OCT4, SOX2, c-MYC, and KLF4. The generated iPS cells were evaluated for pluripotency by examining the expression of pluripotency markers (alkaline phosphatase, SSEA-4, TRA-1-60, and NANOG) and their ability to differentiate to three germ layers in vitro by forming embryoid bodies, and to form teratomas in vivo. Adipogenic capacity of differentiated BSCL2-iPS cells was determined by oil red O and adipose differentiation-related protein (ADRP) staining. Rescue experiments were also performed using stable expression of wild-type BSCL2. A coimmunoprecipitation assay was conducted to investigate the interaction of SEIPIN with ADRP. Results iPS cells were generated from fibroblasts of the two patients with CGL. Each of the patient-derived iPS (BSCL2-iPS) clones showed all of the hallmarks of pluripotency and could differentiate into derivatives of all three germ layers in vitro by forming embryoid bodies, and form teratomas after injection into mouse testes. BSCL2-iPS cells maintained the mutations in BSCL2 and lacked intact BSCL2. Upon adipogenic differentiation, BSCL2-iPS cells exhibited marked reduction of lipid droplet formation concomitant with diffuse cytoplasmic distribution of ADRP, compared with iPS cells from healthy individuals. Forced expression of BSCL2 not only rescued the lipid accumulation defects, but also restored cytoplasmic punctate localization of ADRP in BSCL2-iPS cells. Coimmunoprecipitation indicated SEIPIN interacted with ADRP. Conclusion BSCL2-iPS cells that recapitulate the lipodystrophic phenotypes in vitro could provide valuable models with which to study the physiology of lipid accumulation and the pathology of human lipodystrophy. We found that BSCL2 defines the localization of ADRP, which has a role in lipid accumulation and adipogenic differentiation.
2015-02-19 | Defective Differentiation of Adipose Precursor Cells from Lipodystrophic Mice Lacking Perilipin 1
Perilipin 1 (Plin1) localizes at the surface of lipid droplets to regulate triglyceride storage and hydrolysis in adipocytes. Plin1 defect leads to low adiposity in mice and partial lipodystrophy in human. This study investigated the roles of Plin1 in adipocyte differentiation. Plin1 null (-/-) mice showed plenty of multilocular adipocytes and small unilocular adipocytes in adipose tissue, along with lack of a subpopulation of adipose progenitor cells capable of in vivo adipogenesis and along with downregulation of adipogenic pathway. Before initiation of differentiation, adipose stromal-vascular cells (SVCs) from Plin1-/- mice already accumulated numerous tiny lipid droplets, which increased in number and size during the first 12-h induction but thereafter became disappeared at day 1 of differentiation. The adipogenic signaling was dysregulated despite protein level of PPARγ was near normal in Plin1-/- SVCs like in Plin1-/- adipose tissue. Heterozygous Plin1+/- SVCs were able to develop lipid droplets, with both the number and size more than in Plin1-/- SVCs but less than in Plin1+/+ SVCs, indicating that Plin1 haploinsufficiency accounts for attenuated adipogenesis. Aberrant lipid droplet growth and differentiation of Plin1-/- SVCs were rescued by adenoviral Plin1 expression and were ameliorated by enhanced or prolonged adipogenic stimulation. Our finding suggests that Plin1 plays an important role in adipocyte differentiation and provides an insight into the pathology of partial lipodystrophy in patients with Plin1 mutation.
2013-09-10 | BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling
Seipin regulates lipid homeostasis by preventing lipid droplet (LD) formation in non-adipocytes but promoting it in developing adipocytes. Here, we report that seipin interacts with 14-3-3β through its N- and C-termini. Expression of 14-3-3β is upregulated during adipogenesis, and its deletion results in defective adipogenesis without affecting key adipogenic transcription factors. We further identified the actin-severing protein cofilin-1 as an interacting partner to 14-3-3β. Cofilin-1 was spatiotemporally recruited by 14-3-3β in the cytoplasm during adipocyte differentiation. Extensive actin cytoskeleton remodelling, from stress fibres to cortical structures, was apparent during adipogenesis, but not under lipogenic conditions, indicating that actin cytoskeleton remodelling is only required for adipocyte development. Similar to seipin and 14-3-3β, cofilin-1 knockdown led to impaired adipocyte development. At the cellular level, differentiated cells with knockdown of cofilin-1, 14-3-3β or seipin continued to maintain relatively intact stress fibres, in contrast to cortical actin structure in control cells. Finally, 3T3-L1 cells expressing a severing-resistant actin mutant exhibited impaired adipogenesis. We propose that seipin regulates adipogenesis by recruiting cofilin-1 to remodel actin cytoskeleton through the 14-3-3β protein.
2011-04-14 | Tissue-Autonomous Function of Drosophila Seipin in Preventing Ectopic Lipid Droplet Formation
Obesity is characterized by accumulation of excess body fat, while lipodystrophy is characterized by loss or absence of body fat. Despite their opposite phenotypes, these two conditions both cause ectopic lipid storage in non-adipose tissues, leading to lipotoxicity, which has health-threatening consequences. The exact mechanisms underlying ectopic lipid storage remain elusive. Here we report the analysis of a Drosophila model of the most severe form of human lipodystrophy, Berardinelli-Seip Congenital Lipodystrophy 2, which is caused by mutations in the BSCL2/Seipin gene. In addition to reduced lipid storage in the fat body, dSeipin mutant flies accumulate ectopic lipid droplets in the salivary gland, a non-adipose tissue. This phenotype was suppressed by expressing dSeipin specifically within the salivary gland. dSeipin mutants display synergistic genetic interactions with lipogenic genes in the formation of ectopic lipid droplets. Our data suggest that dSeipin may participate in phosphatidic acid metabolism and subsequently down-regulate lipogenesis to prevent ectopic lipid droplet formation. In summary, we have demonstrated a tissue-autonomous role of dSeipin in ectopic lipid storage in lipodystrophy.
cell therapies
2026-04-15 | Dilute Hyaluronic Acid for Lipoatrophy: Three Cases and Literature Review.
Localized lipoatrophy, characterized by subcutaneous fat loss, can result from trauma, injectable drugs, panniculitis, or idiopathic causes, leading to outcomes ranging from self-resolution to permanent disfigurement. This case series presents a novel approach using dilute hyaluronic acid (HA) for three cases of lipoatrophy (trauma-induced, radiation-induced, and steroid-induced), with all cases showing notable improvement after one session. This approach represents a promising, low-risk alternative for managing lipoatrophy of various etiologies, with potential benefits for patient quality of life.
2025-07-02 | Preliminary high-dose irradiation of the recipient and associated damage of bone marrow stromal compartment enables bone marrow stroma transplantation.
Transplantability of allogeneic mesenchymal stem cells (MSCs) as a stable engraftment and participation in physiological renewal of bone marrow (BM) stroma remains an open question. We hypothesized that a necessary condition for successful MSCs transplantation is the prior significant damage to the recipient's BM stroma. To test this, BM derived from male B10 mice was injected intravenously into syngeneic female mice irradiated with 6.5 Gy and 13 Gy, and unirradiated individuals. We measured donor chimerism 30 days after irradiation in recipients' bones by RQ-PCR and in BM CFU-Fs by ddPCR. The ratio of PCR signals from single-copy Y chromosome-linked Prssly gene and autosomal Gapdh gene was used to determine donor chimerism. None of the non-irradiated recipients had donor cells in the BM subpopulation under study. In the group of recipients irradiated at a dose of 6.5 Gy, donor cells were detected at 0.16% in BM of only one animal. Increasing the radiation dose resulted in a significant increase in donor chimerism among BM stromal cells: it was 11% and 14% in two survived animals of this group. Donor chimerism in the bones of unirradiated recipients was not observed in any of the 15 samples. It was detected in only 2/18 bones of recipients irradiated with 6.5 Gy (0.8% and 1%). The median donor chimerism in bones of recipients irradiated with 13 Gy was 15%. We conclude that the condition for successful engraftment of donor stromal progenitor cells is prior damage to the recipient's BM stroma. Development of protocols of MSCs and HSCs co-transplantation, when full donor chimerism of hematopoietic and stromal tissue will be observed in recipient BM, is feasible. It will allow to increase the efficiency of therapy of malignant and other diseases of blood system, for which allogeneic BM transplantation is indicated, as well as patients with impaired stroma function such as osteogenesis imperfecta and congenital generalized lipodystrophy.
2024-09-27 | Successful fat transplant in a rare acquired lipodystrophy Barraquer–Simons syndrome
Lipodystrophies can be generalized and partial/localized lack of subcutaneous tissue, which are uncommon heterogeneous illnesses that can be hereditary or acquired. Acquired partial lipodystrophy’ (APL) is the new name for lipodystrophia progressiva, also known as Barraquer–Simons syndrome (BSS). It could come after a severe viral infection like the measles. Young people and children both experience it. Typically, BSS or APL starts between the ages of 5 and 15. The principal feature of BSS is cephalothoracic lipodystrophy, which affects the face, neck, arms, thorax, and upper abdomen in a cephalocaudal pattern. Alternate complement pathway activation and C3 hypocomplementemia with adipocyte lysis brought on by complement 3 nephritic factor (C3NeF) have been suggested as potential causes of fat loss in individuals with APL, even though the precise process is still mostly understood. Therapeutic options for lipodystrophy include fat fillers. Different types of autologous fat transplants are possible. Autologous free fat graft where a mass of tissue harvested from any discrete subcutaneous location and implanted at a recipient site. Dermofat grafts are made from tissue that has been removed from a region, allowing for the removal of full-thickness skin grafts and the primary closure of defects. The dermofat graft can be employed as a spacer between gliding tissues or as a filler. Omental flaps, which are revascularized fat flaps, can be utilized for microvascular transfer, soft-tissue filler for hemifacial atrophy, or to cover any significant skin defects. When fat is extracted, processed, and transplanted in liquid injectable form for a variety of purposes, it is known as free fat injection.
2020-02-14 | Safety and Localization of Mesenchymal Stromal Cells Derived from Human Adipose Tissue-Associated Hyaluronic Acid: A Preclinical Study
Millions of plastic surgeries are performed worldwide every year with the objective of correcting lipodystrophies stemming from lesions, tumor resections, birth defects, and AIDS-associated antiretroviral therapy. Besides that, a large number of clinical research have assessed the outcome of procedures that rely on combinations of dermal fillers and autologous cells. However, little is known about the safety of these combinations and the localization of the injected cells. The aim of this study was to test the toxicity of a solution containing 1% hyaluronic acid (HA) and adipose-derived stromal cells (ASCs) from the human adipose tissue and to assess the localization of the injected cells, with and without HA, labeled with technetium-99m. Rats received subcutaneous and intraperitoneal injections of a solution containing 1% HA/adipose-derived stromal cells isolated from the human fat tissue. The animals were then observed for up to forty-two days. The solution tested in this study did not result in systemic, biochemical, or anatomic alterations that could represent toxicity symptoms. The association of HA and ASCs labeled with technetium-99m remained at the site of the injection within a period of twenty-four hours, as demonstrated by a whole-body imaging software fusion of SPECT and CT. In conclusion, our study shows that the subcutaneous and intraperitoneal injection of HA associated with adipose-derived stromal cells (ASCs) is safe. The association of HA and ASCs did not induce local or systemic toxicity. Thus, the administration of volume equal to or less than 0.2 mL of the agent filler (1 × 106 ASC+HA 1%) should be considered for subsequent studies and may be an alternative to dermal fillers due to the expected lasting effects.
2018-08-30 | Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome): Early Cosmetic Intervention with Autologous Fat
Barraquer-Simons syndrome is a rare acquired lipodystrophy characterized by gradually symmetric subcutaneous fat loss in a craniocaudal distribution, often associated with hypocomplementemia and nephropathies. Facial cosmetic treatment in this disorder has not been fully described in the literature. We present a patient with Barraquer-Simons syndrome with emphasis on early cosmetic intervention with autologous fat grafting and its long-term efficacy. At the follow-up 37 months after the last fat grafting, preservation of the grafted fat was noted while lipodystrophy progressed in the trunk regions. Autologous fat grafting is suggested for the correction of facial dysmorphism in this type of lipodystrophy.
other
2025-11-29 | Mechanisms of Glucagon-Like Peptide 1 Receptor Agonist-Induced Facial Lipodystrophy and a Path Toward Prevention.
The emergence of a distinct facial appearance characterized by pronounced hollowing of the cheeks, temples, chin, and periorbital region has become a noteworthy side effect of treatment with glucagon-like peptide 1 receptor agonists (GLP-1RAs). This phenomenon presents a growing concern in both dermatology and aesthetic medicine. The reduction of facial adipose tissue in patients receiving GLP-1RAs often exceeds the overall weight and fat loss typically associated with these agents, suggesting that the effect cannot be fully attributed to systemic metabolic changes alone. Instead, it raises the possibility of localized, tissue-specific mechanisms of GLP-1RA action within facial fat depots. In this article, we explore the underlying pathophysiology of this selective facial fat loss and discuss potential strategies for mitigating or reversing the aesthetic impact of GLP-1RAs. Since the local effects of GLP-1RAs are realized through internalization of GLP-1 receptors (canonical pathway) or IGF-1R (non-canonical pathway), the suppression of mechanisms responsible for this internalization can be used to prevent the development of partial lipodystrophy after the application of GLP-1RAs. One encouraging possibility for such a preventive intervention can be the local modulation of CAV1 in the facial adipose tissue during the GLP-1RAs treatment course.
2002-04-01 | Exclusive Action of Transmembrane TNFα in Adipose Tissue Leads to Reduced Adipose Mass and Local But Not Systemic Insulin Resistance
Aberrant TNFα expression in adipocytes is a molecular mechanism by which insulin action is modulated in adipose tissue. While this might be a compensatory response to limit adipose expansion, neither the mechanisms underlying this local effect nor its systemic biological consequences have been studied. It is also not clear whether TNFα-induced insulin resistance in adipocyte alone is responsible for systemic insulin resistance in the absence of obesity. In a transgenic mouse model deficient in endogenous TNFα, we demonstrate that specific expression of the transmembrane TNFα (mTNFα) in adipocytes leads to decreased whole body adipose mass, and local, but not systemic insulin resistance. These data demonstrate that exclusive action of TNFα in adipose tissue strongly inhibits insulin action at this site and leads to reduced adiposity in mice. However, this isolated adipocyte insulin resistance in the context of reduced fat mass and/or the absence of obesity is insufficient to alter systemic glucose homeostasis.
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