Absence Of Adipose Tissue Research Articles

Biological Depiction of Lipodystrophy and Its Associated Challenges Among HIV AIDS Patients: Literature Review.

Lipodystrophy syndrome is a medical condition characterized by the absence of adipose tissue without any underlying starvation or macromolecule breakdown. In HIV AIDS patients, the use of highly active antiretroviral therapy (HAART) can lead to an acquired form of lipodystrophy, with a prevalence ranging from 10% to 83% among HIV AIDS patients. It was aimed to review the current understanding of biological depiction and challenges related to lipodystrophy in AIDS patients.Relevant articles published in the English language were searched in PubMed, Google Scholar, and Google. Keywords used for the search were: lipodystrophy, lipodystrophy and HIV, ART and lipodystrophy, HIV treatment, metabolic syndrome and HIV. Articles with full abstract information were read for those that met the objective criteria of the review, then full text of the articles was accessed and used. It was revealed by the literature that patients who developed lipodystrophy are characterized by insulin abnormality, obesity, diabetes mellitus, dyslipidemia, fatty liver disease, and ovarian dysfunction. Anthropometric measurements have been known to change significantly with lipodystrophy. HIV patients suffering from hepatitis C virus, hepatitis B virus, who take a protease inhibitor, are changing treatment or duration of treatment, and are womenare the common risk factors for lipodystrophy. The metabolic syndrome seen in HIV patients associated with lipodystrophy can further be complicated to different adverse health effects and can result in increased morbidity and mortality rate if not treated. Existing studies have successfully identified several challenges faced by HIV AIDS patients due to lipodystrophy, including low self-esteem, compromised quality of life, and poor treatment adherence. However, it is crucial to acknowledge that there may be numerous other challenges that have yet to be discovered, emphasizing the need for further studies. It is recommended that managing dyslipidemia, treating diabetes mellitus, modifying lifestyle, and improving the anthropometric measurements have crucial roles to halt further complications associated with lipodystrophy.

The neonatal onset diabetes mellitus of Chinese neonate with congenital generalized lipodystrophy 2: a case report

BackgroundCongenital generalized lipodystrophy (CGL) is a clinically heterogeneous disorder characterized by near total absence of adipose tissue along with metabolic complications. Diabetes mellitus developed from CGL usually present between ages 15 and 20 years, and there are few reports in neonate.Case presentationIn this report, we described a rare clinical presentation of CGL in a 12-day-old Chinese female neonates with hyperglycemia, hyperlipidemia, and subsequently appeared diabetes, hepatomegaly and fatty liver. The two clinical-exome sequencing identified heterozygous null mutations (c.793C > T and c.565G > T) in BSCL2 gene which was inherited from father and mother respectively. To date, it was the firstly reported CGL patient with neonatal onset diabetes. The neonate was treated with antibiotic, insulin and deeply hydrolyzed formula milk to significantly decrease FBG and serum trigylcerides levels. ConclusionsOur case report analyzes the causes of early onset diabetes may relate with the locus of BSCL2 gene mutations and infection induction. It also suggests the importance of early identification, genetic analysis, and symptomatic treatment in the CGL, which are essential for improving the prognosis of children.

BSCL2/Seipin in Lipid metabolism and Lipodystrophy

Adipose tissue is the body's largest endocrine organ that plays a major role in systemic energy homeostasis and thermoregulation. Mutations in BSCL2 (a.k.a. Seipin) gene underlie human type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease with near absence of adipose tissue at birth and severe metabolic diseases. Global Bscl2−/− mice largely recapitulate human BSCL2 lipodystrophy. Seipin is known for its critical role in controlling lipid droplet (LD) assembly at the LD-forming subdomain of the endoplasmic reticulum (ER), but its exact functional role has been enigmatic. Our laboratory has focused on elucidating the mechanisms through which Seipin regulates adipocyte differentiation, lipodystrophy and its associated metabolic diseases. This presentation will focus on the physiological role of Seipin in mediating cAMP/PKA signaling to regulate lipid catabolism in mature white adipose tissue (WAT) and brown adipose tissue (BAT) which exerts profound impact on metabolic homeostasis and thermogenesis. We will also explore the role of Seipin as a key node that links ATGL-mediated lipolysis to mitochondrial function in WAT, BAT and heart. These findings will provide novel insights into Seipin's role in cellular and organismal biology and its importance in human health.

Perivascular adipose tissue (PVAT)‐derived leptin improves aortic endothelial function via attenuating endothelial glycolysis in a mouse model of lipodystrophy

Endothelial dysfunction, characterized by impaired endothelial-dependent relaxation (EDR), is a hallmark and first step in the chain of events leading to cardiovascular disorders. Several vascular pathologies have been associated with aberrant increases in endothelial glycolysis and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) expression/activity, however, whether endothelial glycolysis contributes to EDR regulation remains unknown. Additionally, endothelial dysfunction is present in conditions associated with severe alterations in body fat content including obesity (excess) and lipodystrophy (absence of adipose tissue). However, the exact link between endothelial function and adipose tissue, particularly the one surrounding blood vessels (perivascular adipose tissue, PVAT) remains ill-defined. As leptin, the adipokine highly involved in the regulation of cardiovascular function, has also been shown to modulate cellular bioenergetics in immune and cancer cells, we hypothesized that leptin derived from PVAT controls EDR via endothelial leptin receptor activation and attenuation of PFKFB3-mediated glycolysis. To determine the role of PFKFB3 in endothelial function, we overexpressed PFKFB3 in mouse endothelial cells via adenovirus transduction (Ad-PFKFB3), and reported impaired aorta EDR. Additionally, using seahorse analyzer and glycolysis stress test we found that human aortic endothelial cells (HAEC) transduced with Ad-PFKFB3 showed a significant increase in basal glycolysis (p<0.05) which was blunted by exposure to leptin (10µg/ml, 2h). To determine the role of PVAT-derived leptin in EDR, we used a mouse model of lipodystrophy, with total deficiency in adipose tissue and leptin (Bscl2-/-) characterized by vascular and metabolic dysfunctions as evidenced by impaired EDR and glucose intolerance. We also found that aortas from Bscl2-/- mice exhibited a marked increase in basal and maximum glycolysis measured using seahorse analyzer and glycolysis stress test. This is in line with the PCR data showing increased expression of PFKFB3 mRNA compared to WT mice. Interestingly, inhibition of PFKFB3 using 3 PO or PFK158 (20uM) restored EDR in Bscl2-/- mice. Additionally, we transplanted 25 mg PVAT from WT mice to the abdominal aorta of Bscl2-/-. After 4 weeks, PVAT significantly reduced aortic expression of PFKFB3 and corrected systemic glycemia as well as EDR in Bscl2-/- vs sham (P<0.05). However, leptin receptor blockade (Allo-Aca, 0.05 mg/kg/day) blunted PVAT-mediated restoration of EDR in PVAT-transplanted Bscl2-/- mice. In conclusion, these data demonstrate that PVAT releases a vasodilatory factor, potentially, leptin that acts via activation of endothelial leptin receptor to improve endothelial function via a mechanism that involves regulation of PFKFB3-mediated endothelial glycolysis.

Culturing Articular Cartilage Explants in the Presence of Autologous Adipose Tissue Modifies Their Inflammatory Response to Lipopolysaccharide.

The purpose of the current study was to explore the effect of autologous adipose tissue on cartilage responses to lipopolysaccharide (LPS). We hypothesized that LPS elicits an inflammatory response in cartilage, and that response is augmented in the presence of adipose tissue. Furthermore, we hypothesized that this augmented inflammatory response is due, at least in part, to increased exposure of cartilage to adipose tissue-derived c3a. Porcine cartilage explants from market-weight pigs were cultured in the presence or absence of autologous adipose tissue for 96 hours, the final 48 hours of which they were stimulated with LPS (0 or 10 μg/mL). Adipose tissue explants were also cultured alone, in the presence or absence of LPS. Media from all cartilage treatments was assayed for c3a/c3a des Arg, PGE2, GAG, and NO, and the viability of cartilage tissue was determined by differential fluorescent staining. Media from adipose tissue explants was assayed for c3a/c3a des Arg and PGE2. LPS produced a significant increase in PGE2, GAG, and NO production when cartilage was cultured in the absence of adipose tissue. Coculture of adipose tissue prevented a significant increase in PGE2 in cartilage explants. There was no effect of adipose tissue on LPS-induced GAG or NO, but the presence of adipose tissue significantly reduced cell viability in LPS-stimulated cartilage explants. Adipose tissue explants from lean animals reduced inflammatory responses of cartilage to LPS via a c3a/c3a des Arg-independent mechanism and were associated with a significant decline in cell viability. Thus, contrary to our hypothesis, adipose tissue from lean animals does not augment the inflammatory response of cartilage to stimulation by LPS. The mechanism of modulatory effects of adipose tissue on LPS-induced increase in PGE2 and decline in chondrocyte viability requires further research but appears to have occurred via a mechanism that is independent of adipocentric c3a/c3a des Arg.

Presence of adipose tissue in aortic valves from aortic regurgitation patients: pathophysiological role and clinical implications

Abstract Introduction Adipose tissue is a common constituent of the heart and it is located, without great clinical relevance, frequently in the pericardium. The presence of adipose tissue in the aortic valve is rare, with unknown significance on valve structural properties and function. Aortic regurgitation (AR) is the third most prevalent valve disease, although it is uncommon to find it in isolation. Myxoid degeneration may be the cause or result of AR, although the pathophysiology remains poorly understood. Purpose To describe and characterize the presence of adipose tissue in the aortic valves from a cohort of AR patients. Methods 116 patients undergoing aortic valve replacement due to severe AR were enrolled. We classified them in two groups according to the histological results showing presence or absence of adipose tissue in the aortic valves. In the valve tissue molecular analysis were performed by RT-PCR, Western Blot and ELISA to analyze markers of adipocytes (leptin, adiponectin, resistin), inflammation (Rantes, interleukin-6, interleukin-1β), extracellular matrix remodeling (metalloproteinases-1, -2 and -9), proteoglycans (aggrecan, hyaluronan, lumican, syndecan-1, decorin) and fibrosis (collagens, fibronectin). Results Adipose tissue was found in 63% of the aortic valves analyzed. Baseline characteristics (age, hypertension, dyslipidemia, diabetes, smoking, left ventricular telediastolic diameter, left ventricular systolic function, ascending aorta) were similar in patients presenting valve adipose tissue as compared with patients without valve adipose tissue. Valves containing adipocytes exhibited a higher leptin content (p&amp;lt;0.001), fibronectin (p&amp;lt;0.01), decorin (p&amp;lt;0,0001), hyaluronan (p=0.03), aggrecan (p=0.04) and metalloproteinase 1 (p=0.03). Interestingly, the presence of adipocytes in the valve was positively correlated with valve thickness measured by echocardiogram (Pearson chi2 statistical significance = 26.3345 p&amp;lt;0.001). Conclusion To our knowledge, this is the first study that describes the presence of adipose cells in aortic valves from a cohort of AR patients. Aortic valves containing adipocytes were thicker and exhibited significant higher levels of proteoglycans, suggesting that adipocytes could contribute to the myxomatous degeneration process. Our results propose that the valve adipose tissue could play a role in the pathophysiology of AR. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Gobierno de Navarra

SAT-588 Role of Adipose Tissue in Reproduction, Mammary Gland Development, Function and Cancer

To investigate the role of adipose tissue in the function of the mammary gland (MG) and reproductive system, we have examined lipodystrophic (LD) mice. LD mice of both sexes are sterile, but fertility was restored in both sexes with leptin injections. In addition, leptin was only needed for initial stages of pregnancy and not for parturition. A transplant of mouse embryonic fibroblasts (MEFs) led to the formation of an ectopic fat pad which also rescued the fertility in both sexes. However, pups born to rescued LD mothers died shortly after birth. We therefore examined the mammary glands of these mothers. MGs from LD mice were rudimentary and lacked terminal end buds. Leptin-injected and MEF rescued LD mice were able to become pregnant, showed normal pregnancy-associated glandular proliferation despite a smaller glandular area, were able to produce a small amount of milk that had grossly normal content of milk proteins and neutral lipids, but could not sustain pups to weaning. In order to separate the individual requirements for 1) adipokines such as leptin, 2) estradiol, and 3) epithelial-adipocyte interactions, we performed a series of experiments with both LD and ob (leptin-deficient) mice that received either estradiol or preadipocyte transplant. The resulting fat pad did not rescue the defect in MG development in LD mice. The defect also was not rescued with estradiol pellets. Ob/ob mice, like LD mice, lack leptin and estradiol, but retain adipose tissue. Ob mice have defective MG development. However, in striking contrast to LD mice, reconstitution of a WT fat pad in ob mice rescued the defect in MG development. Estradiol treatment did not rescue MG development in ob mice. Therefore direct interaction between mammary gland epithelia and adipocytes is a requirement for full invasion and expansion of the gland during puberty, but is not required for glandular proliferation during pregnancy and milk production.Given that excess adipose tissue is a risk factor for breast cancer we wanted to determine if breast cancer was affected by the absence of adipose tissue. LD mice were bred to MMTV-PyMT mice that develop spontaneous breast cancer. Remarkably, LD PyMT+ mice had accelerated growth of primary tumors compared to WT PyMT+ mice. Using our MEF transplant model future studies will be directed to understanding whether the accelerated breast cancer growth is due to loss of adipokines or altered epithelial-stromal interactions.

Transformation gélatineuse de la moelle osseuse au cours d’une leucémie aiguë

Serous degeneration of bone marrow is a rare hematological complication, of multiple etiologies, which physiopathology is yet to be fully understood. It is described as a focal hypoplasia of the bone marrow and atrophy of its adipocytes coupled with an extracellular deposit of an eosinophilic substance that corresponds to "hyaluronic acid". The prognosis of these lesions depends on the etiological diagnosis. We report the case of a 19-year-old female patient without no notable pathological history, hospitalized in a regional hospital for mucocutaneous pallor with an impaired general condition. The biological assessment revealed a pancytopenia, and the presence of 60% blast cells on the blood smear, which was in favor of acute leukemia. As part of the etiological assessment, a bone marrow biopsy was performed, revealing a typical aspect of serous degeneration. The bone marrow cellularity was reduced, made of rare hematopoietic cells, dissociated by pale extracellular deposits that were colored by PAS and alcian blue, with no individualized blasts. Serous transformation of the hematopoietic marrow is a rare condition, described at the end of the 19th century. The most severe forms are observed in young patients with hypoplasia. It most often manifests as pancytopenia at the beginning, if not then by an isolated cytopenia, anemia or thrombocytopenia. It is interesting to underline the contribution of MRI in diagnosis. The foci of bone marrow serous degeneration are characterized in the long bones by a fluid signal with a T1hypo-signal and a T2hyper-signal with no enhancement after injection of gadolinium, unlike bone metastases. The histology of bone marrow biopsy finds focal marrow hypoplasia of the hematopoietic lines associated with a depletion of adipocytes and an eosinophilic gelatinous interstitial infiltration alcian blue and PAS positive. The histological differential diagnosis is amyloidosis due to red Congo positivity, a previous biopsy (the absence of adipose tissue or hematopoietic tissue with granulation tissue and bone formation) and interstitial edema. Bone marrow necrosis can also be observed. Serous degeneration of bone marrow can be a symptom of a chronic systemic illness. In most cases, it is found in cases of severe chronic malnutrition, such as anorexia nervosa, certain cancers (acute leukemia), systemic diseases (lupus) or severe infection. Though there is no specific treatment for this complication, the treatment of the cause most often allows for the complete regression of the peripheral and spinal anomalies. In rare cases, as is the case in our observation, the serous degeneration of bone marrow can reveal underlying solid tumors or hemopathies, knowledge of it can help guide the investigations towards these etiologies.

BSCL2/Seipin in Lipid Catabolism and Lipodystrophy

Adipose tissue is the body’s largest endocrine organ that plays a major role in systemic energy homeostasis and thermoregulation. Mutations in BSCL2 (a.k.a. Seipin) gene underlie human type 2 Berardinelli‐Seip Congenital Lipodystrophy (BSCL2) disease with near absence of adipose tissue at birth and severe metabolic diseases. Global Bscl2−/− mice largely recapitulate human BSCL2 lipodystrophy with severe insulin resistance and organomegly. Seipin is known for its critical role in controlling lipid droplet (LD) assembly at the LD‐forming subdomain of the endoplasmic reticulum (ER), but its exact functional role has been enigmatic. Our laboratory has focused on elucidating the mechanisms through which Seipin regulates adipocyte differentiation thus lipodystrophy and its associated metabolic diseases. This presentation will focus on the role of Seipin in mediating cAMP/PKA signaling to regulate lipid catabolism in mature white adipose tissue (WAT) and during perinatal brown adipose tissue (BAT) development which exert profound effect on metabolic homeostasis and thermogenesis. We will also explore the role of Seipin as a key node that links ATGL‐mediated lipolysis to govern mitochondrial dynamics and function in WAT, BAT and heart. These findings will highlight novel roles for Seipin in cellular and organismal biology and its importance in human health.Support or Funding InformationThis work was supported by NIH grant 1R01HL132182‐01.

MON-104 Defining the Contribution of Weight to the Extent of Metabolic Disease in FPLD: Insights from a Retrospective "Matched" Case-Control Study

Familial partial lipodystrophy (FPLD) presents with an absence of adipose tissue in the extremities, with accumulation in the upper body. Metabolic abnormalities associated with FPLD include diabetes mellitus and/or severe insulin resistance, hypertriglyceridemia, and non-alcoholic steatohepatitis. FPLD patients have a disproportionately lower BMI compared to individuals with common obesity and similar metabolic derangements. However, the extent and degree of metabolic disease at comparable truncal mass, or the “equivalent” BMI between the groups with similar metabolic disease are not known. To determine a BMI reference or “equivalence”, we performed a retrospective case control study comparing “cases” of FPLD against “controls” with severe obesity while matching for co-morbidities or total trunk mass. Baseline data were gathered to perform two k:1 nearest neighbor case-control matches using matchControls function of R’s e1071 package. MATCH1 included matching of age, sex, and total trunk mass with the hypothesis that FPLD with similar trunk mass had worse metabolic parameters. MATCH2 was performed using age, sex, and presence of comorbidities (hypertension, hypertriglyceridemia (>300mg/dL), diabetes, fatty liver, heart disease, arthritis, depression and anxiety, smoking history) with the hypothesis that there would be a significant difference in weight or BMI between the two populations. Our populations consisted of 55 FPLD cases (46F/9M, Age = 47±12 years, Total trunk mass=45.3±11.6 Kg) and a pool of 549 non-FPLD controls (338F/211M, Age = 48±10 years). MATCH1 allowed for a 2:1 nearest neighbor match with 110 obese controls (92F/18M, p=1.00, Age=48±11 years, p=0.72; Total Trunk Mass= 46.8±10.9 Kg, p=0.36). FPLD had worse glycemic control (HbA1c= 8.2±1.6%, 5.9±0.9%, respectively, p=<0.001), higher triglycerides (884±1190 mg/dL, 139±79 mg/dL, respectively, p<0.001), and lower leptin compared to obese controls (20.5±15.8 ng/mL, 41.9±29.4 ng/mL, p<0.001). MATCH2 allowed for a 1:1 nearest neighbor match with 55 controls (38F/17M, Age=53±9 years). The two groups had similar glycemic control (HbA1c = 8.2±1.6%, 7.8±1.6%, respectively, p=0.15), but the FPLD group had markedly higher triglycerides (884±1190 mg/dL, 224±123 mg/dL, respectively, p<0.001). Average BMI was 9.1 kg/m2 lower in the FPLD group compared to controls (BMI = 29.5±5.7 kg/m2, 38.6±5.2 kg/m2, respectively, p<0.001). In conclusion, FPLD patients with a similar truncal mass will have a worse metabolic profile than that of a non-FPLD obese patients despite having a lower BMI. This supports the understanding that lack of healthy fat depots drives metabolic disease in FPLD. The metabolic disease burden of the FPLD patients is equivalent to non-FPLD obesity that is at on average 9.1kg/m2 heavier than the observed BMI. This can be taken into account while defining weight goals for these patients.

Abstract P140: Leptin Supplementation Restores Endothelial Function and Vascular Adrenergic Tone via Direct Endothelial Mechanisms and Sympato-Activation, Respectively, in a Mouse Model of Congenital Lipodystrophy

Absence of adipose tissue in congenital generalized lipodystrophy (CGL) leads to metabolic and cardiovascular disease and reduced leptin levels. We tested the hypothesis that leptin supplementation restores endothelial function and reduces vascular adrenergic response respectively via acting directly on endothelial cells (EC) and desensitizing vascular adrenergic response, in CGL mice. Deletion of Berardinelli-Seip gene (Bscl2) was used to mimic the human pathology in mice. Bscl2-/- mice showed reduced adipose mass [% of fat: wild-type (WT): 8.6 ± 0.3 vs Bscl2-/-: 2.4 ± 0.1, P&lt;0.05], leptin levels [ng/mL: WT: 4.0 ± 0.3 vs Bscl2-/-: 0.3 ± 0.1, *P&lt;0.05], impaired aortic endothelium-dependent relaxation to acetylcholine (Ach): [% relaxation: WT: 71.9 ± 1 vs Bscl2-/-: 49.9 ± 2*, *P&lt;0.05], increased vascular contractility to phenylephrine (Phe), associated with upregulation of α-adrenergic receptors, high mean arterial pressure (MAP) and reduced heart rate (HR): [(mmHg: WT: 100.7 ± 5 vs Bscl2-/-: 109.5 ± 6*), (bpm: WT: 592.7 ± 9 vs Bscl2-/-: 542.9 ± 15*) *P&lt;0.05]. Moreover, Bscl2-/- mice shown increase in Nox1 gene expression and increases in vascular - O 2 and H 2 O 2 levels. Both chronic (in vivo) and acute (organ bath) leptin supplementation or NOX 1 inhibition (GKT771, 10μM) restored endothelial function in addition to reducing endothelial Nox1 expression and ROS production, which suggest a direct role for leptin in endothelial cells. EC leptin receptor deficiency induced an endothelial dysfunction in mice, which was restored by Nox1 inhibition, further supporting a direct role of leptin in endothelial cells. In parallel, leptin supplementation reduced vascular adrenergic tone and aortic α-adrenergic receptors and increased in HR without changing MAP. Our data show that leptin replacement restores endothelial function and reduces vascular adrenergic tone in mouse model of congenital lipodystrophy by acting directly in EC and desensitizing vascular adrenergic response, respectively. This highlight the importance of leptin in the maintenance of vascular homeostasis and presents leptin as a potential therapeutic avenue for the treatment of vascular diseases associated with low leptin levels.

High prevalence of Berardinelli-Seip Congenital Lipodystrophy in Rio Grande do Norte State, Northeast Brazil

BackgroundBerardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare disease characterized by the almost complete absence of adipose tissue. Although a large number of BSCL cases was previously identified in Rio Grande do Norte (RN), a state in Northeast Brazil, its prevalence in RN regions and municipalities remains unknown. The purpose of this study was to better characterize the prevalence of BSCL in RN.MethodsA descriptive study was conducted using secondary data obtained from the Association of Parents and People with BSCL of RN to determine its prevalence. The patients’ socio-demographic characteristics and geolocalization were analyzed.ResultsWe estimated a total of 103 BSCL cases in RN, resulting in a prevalence of 3.23 per 100,000 people. The Central Potiguar mesoregion, Seridó territory, Carnaúba dos Dantas and Timbaúba dos Batistas municipalities had a much higher prevalence of BSCL, with 20.56, 20.66, 498.05 and 217.85 per 100,000 people, respectively.ConclusionsTogether, our results showed that BSCL is highly prevalent in RN and confirmed that our state has one of the highest prevalences of this lipodystrophy worldwide. More studies are still needed to better estimate the prevalence and incidence of BSCL in RN as well as in other states in Brazil.Trial registration Study Number 31809314.0.0000.5568

Pathological findings in explanted vaginal mesh

In light of the legal issues and the shortage of data on histopathological findings, we summarized our experience on how explanted vaginal mesh specimens were managed in a surgical pathology practice during the last 5 years. Clinical history and pathology reports were collected from 155 women undergoing transvaginal tape excision. The degree of chronic inflammation, fibrosis, foreign-body giant cell reactions, the number of capillary vessels and nerve fibers, and the presence or absence of adipose tissue were recorded. Among the 155 patients, 65 (41.9%) were active medicolegal cases, with a significant increase in recent years. The main medical indications for mesh excision were pelvic pain, mesh erosion, voiding dysfunction, genital organ prolapse, and vaginal bleeding. In most cases, mild to moderate chronic inflammation with a mild degree of foreign-body giant cell reaction and minimal to mild fibrosis were found in explanted mesh specimens. The specimens were well vascularized without any evidence of nerve abnormality. Patient age correlated negatively with vaginal pain (P = .007) but positively with erosion (P = .005). In addition, the presence of adipose tissue within the explanted mesh correlated significantly with pelvic pain (P = .016). Overall, there was good tissue integration in all specimens. Considering the significant increase in the number of lawsuits in recent years, we recommend that all explanted vaginal mesh specimens be examined microscopically as well as grossly. A list of microscopic findings, including the presence or absence of adipose tissue, is suggested.

Delayed Hair Follicle Morphogenesis and Hair Follicle Dystrophy in a Lipoatrophy Mouse Model of Pparg Total Deletion

PPARγ regulates multiple aspects of skin physiology, including sebocyte differentiation, keratinocyte proliferation, epithelial stem cell survival, adipocyte biology, and inflammatory skin responses. However, the effects of its global deletion, namely of nonredundant key functions of PPARγ signaling in mammalian skin, are yet unknown because of embryonic lethality. Here, we describe the skin and hair phenotype of a whole-body PPARγ-null mouse (PpargΔ/Δ), obtained by preserving PPARγ expression in the placenta. PpargΔ/Δ mice exhibited total lipoatrophy and complete absence of sebaceous glands. Right after birth, hair follicle (HF) morphogenesis was transiently delayed, along with reduced expression of HF differentiation markers and of transcriptional regulators necessary for HF development. Later, adult PpargΔ/Δ mice developed scarring alopecia and severe perifollicular inflammation. Skin analyses in other models of lipodystrophy, AZIPtg/+ and Adipoq-Cretg/+Ppargfl/fl mice, coupled with skin graft experiments, showed that the early defects observed in hair morphogenesis were caused by the absence of adipose tissue. In contrast, the late alteration of HF cycleand appearance of inflammation were observed only in PpargΔ/Δ mice and likely were due to the lack sebaceous glands. Our findings underscore the increasing appreciation for the importance of adipose tissue-mediated signals in HF development and function.

Abstract 128: Leptin: A Regulator of Aldosterone Synthase Expression &amp; Aldosterone Secretion in Visceral Adipocytes, in Mice

Obesity is associated with inappropriately high aldosterone levels, which contribute to the development of metabolic and cardiovascular disorders. The origin of these high aldosterone levels is incompletely understood. We recently demonstrated that the adipocyte-derived hormone leptin regulates aldosterone synthase (CYP11B2) expression and stimulates aldosterone release from adrenal zona glomerulosa cells. Recent studies demonstrate that adipocytes express CYP11B2 and secrete aldosterone. However, the mechanisms regulating aldosterone release from adipocytes remain unclear. Likewise, whether visceral (Visc) and subcutaneous (SubQ) adipose tissue contribute to a similar extent to aldosterone production is unknown. We tested the hypothesis that leptin increases adipocyte CYP11B2 expression and aldosterone production and investigated whether Visc and SubQ adipose tissues respond similarly to leptin. Immunostaining of mouse adipose tissue cross-sections and isolated mature adipocytes revealed that Visc and SubQ adipose tissue express leptin receptors. Treatment of mouse freshly isolated mature adipocytes, non-differenciated (stromal fraction) and differentiated adipocytes revealed that leptin dose-dependently increased CYP11B2 expression and aldosterone production in Visc adipose tissue only. Although leptin receptor and CYP11B2 levels were similar in SubQ and Visc adipocytes, SubQ adipocytes were unresponsive to leptin. The physiological relevance of these in vitro data was tested by measuring plasma aldosterone levels in mice deprived of adipose tissue (lipodystrophic mice) treated with leptin. Absence of adipose tissue in lipodystrophic mice blunted leptin-induced increases in aldosterone levels (WT-vehicle: 471±82 vs. WT-Leptin: 1699±396, p&lt;0.05; KO-vehicle: 539±71 vs. KO+leptin: 787±156, NS). The human relevance of these data was determined by reporting that CYP11B2 expression gradually increased with body mass index in human mediastinal and omental fat depots. In summary these data strongly suggest that leptin regulates CYP11B2 levels and aldosterone release in visceral adipose tissue and that leptin-induced, adipocyte-derived aldosterone may contribute to obesity-associated hyperaldosteronism.

Berardinelli-Seip syndrome in a Chinese boy with Seipin gene mutation: a case study and literature review of genotype-phenotype

Objective Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare and heterogeneous disease of autosomal recessive inheritance characterized by the generalized absence of adipose tissue at birth and severe adverse metabolic consequences. The identified causative genes for CGL include 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin), Caveolin-1 (CAV1) and polymerase I and transcript release factor (PTRF). Although more than 60 cases of CGL with different gene mutations have been found in Asian patients, only 7 patients were Chinese. Data are also limited regarding genotype-phenotype analysis in Asian CGL patients. Therefore, we aimed to analyze variations of two identified major causative genes, Seipin and AGPAT2, involved in CGL etiology in a mainland Chinese affected family and explore the genotype-phenotype of Berardinelli-Seip syndrome in Asian populations.

A mutation in the c-fos gene associated with congenital generalized lipodystrophy.

BackgroundCongenital generalized lipodystrophy (CGL) or Berardinelli–Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes.Methods and resultsIn a patient with CGL and insulin resistance we investigated the known candidate genes but the patient did not carry a relevant mutation. Analyses of the insulin activated signal transduction pathways in isolated fibroblasts of the patient revealed a postreceptor defect altering expression of the immediate early gene c-fos. Sequence analyses revealed a novel homozygous point mutation (c.–439, T→A) in the patients’ c-fos promoter. The point mutation was located upstream of the well characterized promoter elements in a region with no homology to any known cis-elements. The identified mutation was not detected in a total of n=319 non lipodystrophic probands. In vitro analyses revealed that the mutation facilitates the formation of a novel and specific protein/DNA complex. Using mass spectrometry we identified the proteins of this novel complex. Cellular investigations demonstrate that the wild type c-fos promoter can reconstitute the signaling defect in the patient, excluding further upstream signaling alterations, and vice versa the investigations with the c-fos promoter containing the identified mutation generally reduce basal and inducible c-fos transcription activity. As a consequence of the identified point mutation gene expression including c-Fos targeted genes is significantly altered, shown exemplified in cells of the patient.ConclusionThe immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. According to the role of c-fos in adipocyte differentiation our findings of a mutation that initiates a repression mechanism at c-fos promoter features the hypothesis that diminished c-fos expression might play a role in CGL by interfering with adipocyte development.

Function of seipin: New insights from Bscl2/seipin knockout mouse models

Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterized by near absence of adipose tissue and severe insulin resistance. Since the discovery of the gene in 2001, several cellular studies intended to unravel the biological function of seipin and revealed that seipin-deficiency alters adipocyte differentiation and lipid droplet morphology. However, the exact function of the protein remains unclear and the pathophysiology of BSCL in patients carrying BSCL2/seipin mutations is poorly understood. A major breakthrough in the field of seipin came recently, with the demonstration by three independent groups that Bscl2-deficient mice (Bscl2(-/-)) developed severe lipodystrophy with only residual white and brown fat pads, validating a critical role for seipin in adipose tissue homeostasis. Using in vivo, ex vivo and in vitro methods, these studies demonstrate that seipin plays a key role in adipogenesis, lipid droplet homeostasis and cellular triglyceride lipolysis. In addition to adipose tissue impairment, Bscl2(-/-) mice are diabetic and display severe hepatic steatosis. Treatment with thiazolidinediones (TZD) in Bscl2(-/-) mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype. Except an unexpected hypotriglyceridemia, Bscl2(-/-) mice phenotype represents an almost perfect picture of the human disease. This review analyses how these studies using Bscl2(-/-) mice brought new insights into seipin function and the mechanisms involved in the pathophysiology of BSCL. We also analyse some of the human data in the light of the mouse phenotyping and discuss the validity of Bscl2(-/-) mice model to test pharmaceutical approaches for treating BSCL and its associated metabolic complications.

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice. Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.

Congenital generalized lipodystrophy of Berardinelli-Seip type: A rare case

Congenital generalized lipodystrophy of Berardinelli-Seip type is a rare autosomal recessive disorder characterized by nearly complete absence of adipose tissue and a consequent generalized muscular appearance, which is recognized easily at birth. The condition is associated with various dermatological and systemic manifestations. We report a case of this form of lipodystrophy. The patient had several cutaneous manifestations, including severe acanthosis nigricans, generalized hyperpigmentation, curly scalp hair, prominent subcutaneous veins, and enlarged clitoris. She also had associated celiac disease.