The Molecular Signature of HIV-1-Associated Lipomatosis Reveals Differential Involvement of Brown and Beige/Brite Adipocyte Cell Lineages

Highly active antiretroviral therapy has remarkably improved quality of life of HIV-1-infected patients. However, this treatment has been associated with the so-called lipodystrophic syndrome, which conveys a number of adverse metabolic effects and morphological alterations. Among them, lipoatrophy of subcutaneous fat in certain anatomical areas and hypertrophy of visceral depots are the most common. Less frequently, lipomatous enlargements of subcutaneous fat at distinct anatomic areas occur. Lipomatous adipose tissue in the dorso-cervical area (“buffalo hump”) has been associated with a partial white-to-brown phenotype transition and with increased cell proliferation, but, to date, lipomatous enlargements arising in other parts of the body have not been characterized. In order to establish the main molecular events associated with the appearance of lipomatosis in HIV-1 patients, we analyzed biopsies of lipomatous tissue from “buffalo hump” and from other anatomical areas in patients, in comparison with healthy subcutaneous adipose tissue, using a marker gene expression approach. Both buffalo-hump and non-buffalo-hump lipomatous adipose tissues exhibited similar patterns of non-compromised adipogenesis, unaltered inflammation, non-fibrotic phenotype and proliferative activity. Shorter telomere length, prelamin A accumulation and SA-β-Gal induction, reminiscent of adipocyte senescence, were also common to both types of lipomatous tissues. Buffalo hump biopsies showed expression of marker genes of brown adipose tissue (e.g. UCP1) and, specifically, of “classical” brown adipocytes (e.g. ZIC1) but not of beige/brite adipocytes. No such brown fat-related gene expression occurred in lipomatous tissues at other anatomical sites. In conclusion, buffalo hump and other subcutaneous adipose tissue enlargements from HIV-1-infected patients share a similar lipomatous character. However, a distorted induction of white-to-“classical brown adipocyte” phenotype appears unique of dorso-cervical lipomatosis. Thus, the insults caused by HIV-1 viral infection and/or antiretroviral therapy leading to lipomatosis are acting in a location- and adipocyte lineage-dependent manner.     

Adenylate cyclase of multiple lipomata. Regional differences in adrenaline-responsiveness

Multiple symmetric lipomatosis has been proposed to be associated with impaired catecholamine-responsiveness of hypertrophic adipose tissue at the level of beta-adrenergic receptors or adenylate cyclase respectively. We have studied the regulation of the adenylate cyclase by guanine nucleotides and adrenaline in 5 subjects suffering from multiple encapsulated lipomata. In the presence of GTP (0.1 mmol/l) basal adenylate cyclase activity averaged 0.5 +/- 0.3 nmol cAMP/mg protein/10 minutes in normal adipose tissue and 1.0 +/- 0.4 nmol cAMP/mg protein/10 minutes in hypertrophic adipose tissue respectively. The synthetic GTP-analogue GMP(PNP) (0.1 mmol/l) increased non-stimulated activity by about 100% in both tissues. Adrenaline (1 mumol/l-1 mmol/l) caused a dose-dependent increase of enzymic activity in both tissues which had a maximum of 130% above basal levels in the presence of GTP and of 300% in the presence of GMP(PNP) respectively. In one of the six subjects suffering from gluteal lipomata normal adipose tissue was obtained from the gluteal as well as the abdominal region on two occasions. Maximally effective concentrations of adrenaline (1 mmol/l) induced a 3-fold increase of enzymic activity in abdominal membranes compared with about a 1.7- and 1.75-fold increase in normal and lipomatous tissue from the gluteal region. The results show that encapsulated lipomata contain a normally reactive adenylate cyclase system.     

Fine needle aspiration diagnosis of lipoblastoma of the parotid region. A case report

BACKGROUND: Lipoblastomas are rare tumors of embryonal fat that occur in infants and children. They are usually located in the extremities and trunk. Two cases in the parotid region have been described. A diagnosis on fine needle aspiration (FNA) specimens has been reported in six cases. CASE: Lipoblastoma of the parotid region occurred in a 6-year-old boy and was diagnosed by FNA. Cytology showed rare lipoblasts and hibernomalike cells in a myxoid background with spindle and stellate mesenchymal cells, mature adipose cells and plexiform capillaries. A 7.0-cm, well-circumscribed mass with lobulated adipose tissue and delicate fibrous bands was resected. Microscopically, it showed a lobulated myxoid stroma, many capillaries, mesenchymal cells, lipoblasts and mature adipose cells. CONCLUSION: Lipoblastoma has to be differentiated from myxoid and lipomatous soft tissue tumors, especially from myxoid liposarcoma, a malignancy that classically affects older individuals and shows pleomorphism, atypical lipoblasts and chromosome-12 translocation. A lipoblastoma diagnosis must be established only after careful consideration of all available clinical, radiologic, cytogenetic and morphologic data.     

Diagnosis of thymolipoma with fine needle aspiration biopsy. Report of a case initially misdiagnosed as liposarcoma

BACKGROUND: Thymolipomas are the most outstanding mesenchymal mediastinal tumors although they represent only a small percentage of thymic neoplasms. Their histogenesis remains unsolved, and they are usually benign. Fine needle aspiration biopsy (FNAB) has become the method of choice for the study of mediastinal tumors, including thymolipomas. Making the correct diagnosis depends on the availability of all thymic and lipomatous components as well as on the correct application of a differential diagnosis with other lipomatous tumors. CASE: A 24-year-old woman had a 3-month history of coughing with sputum, fever, asthenia, adynamia, headaches and anemia. Physical examination revealed a bilateral pulmonary condensation syndrome. Imaging studies showed a well-defined, large mass occupying both hemithoraxes and the mediastinum. FNAB revealed an admixture of atypical adipocytes, nonneoplasic lymphoid tissue and capillaries with prominent endothelium. An initial diagnosis of well-differentiated liposarcoma was made. A 2.8-kg, encapsulated, yellowish gray mediastinal tumor was surgically removed. Mature adipose tissue intermingled with abundant thymic tissue containing numerous Hassall's corpuscles were seen histologically. Immunohistochemical markers for thymic epithelium, lymphoid tissue and adipocytes were all positive. Thymolipoma was the final diagnosis. The anemia subsided with resection of the tumor, and the patient was disease free 2.5 years after surgery. CONCLUSION: To the best of our knowledge, this is the second report of a thymolipoma studied with FNAB. The criteria for the differential diagnosis between thymolipomas and other lipomatous tumours should be kept in mind.     

Fine needle aspiration biopsy of well-differentiated liposarcoma of the neck in a young female. A case report.

BACKGROUND: Well-differentiated liposarcomas are low grade, nonmetastasizing, malignant neoplasms composed primarily of mature adipose tissue. They are uncommon in the head and neck. CASE: A 24-year-old female presented to the ears, nose and throat clinic for evaluation of a recent, rapidly growing neck mass on the right side. Fine needle aspiration (FNA) biopsy of the mass showed that the smears had fragments of connective tissue with a mixture of mature-appearing fat traversed by bands of fibrous collagen and vessels. Nuclei within the fat and fibrous bands were mildly irregular, hyperchromatic and enlarged, with one or two small nucleoli. Infrequently present but readily identified, lipoblasts were scattered throughout the aspirate smears. A diagnosis of "atypical lipomatous neoplasm" was rendered. Subsequently, the mass was surgically removed. On histologic examination, the tumor was a well-differentiated liposarcoma. CONCLUSION: FNA biopsy of well-differentiated liposarcomas in the head and neck can present difficulties in the classification and diagnosis of this neoplasm.     

Adrenocortical Neoplasms With Myelolipomatous and Lipomatous Metaplasia: Report of 3 Cases

ObjectiveTo present pathologic and radiographic features of 3 patients with adrenocortical neoplasms—2 with uncertain malignant potential and 1 adenoma with areas of myelolipomatous and lipomatous metaplasia.MethodsWe describe 3 patients who had adrenocortical neoplasms with foci of myelolipomatous and lipomatous metaplasia. For each patient, the clinical and pathologic data are reviewed.ResultsAll 3 patients were women, with a mean age at presentation of 58 years. The lesion size averaged 6.8 cm (range, 3.9 to 11.0), and the mean gland weight was 128.8 g (range, 32.5 to 249). Two patients showed imaging findings compatible with adrenal myelolipoma. Pathologically, 2 of the lesions were classified as adrenocortical neoplasms of uncertain malignant potential, and 1 lesion was classified as an adrenocortical adenoma. All 3 lesions contained myelolipomatous foci throughout the neoplasm, and 2 of the tumors contained several pure lipomatous foci.ConclusionAdrenocortical neoplasms, including those associated with an uncertain malignant potential, may be associated with areas of myelolipomatous and lipomatous metaplasia. Imaging studies may result in a false diagnosis of a benign adrenal myelolipoma and potential undertreatment in such patients. (Endocr Pract. 2009;15:128-133)     

京尼平对小鼠棕色和白色脂肪组织UCP1表达的影响

目的:棕色脂肪组织活化和白色脂肪组织棕化是改善减肥的良好策略。本研究利用冷刺激作为阳性对照,观察京尼平对小鼠脂肪组织活化与棕化的作用。方法:8周龄雄性C57BL/6J小鼠30只,随机分为正常对照组、京尼平组、冷刺激组, 每组10只。京尼平组小鼠腹腔注射给予京尼平处理(15 mg/(kg·d),连续9 d),对照组用生理盐水处理,冷刺激组小鼠在室温(22℃±2℃)下处理4 d后,置于4℃环境中进行冷刺激处理5 d(24 h/d)。检测各组小鼠每天摄食量、体重和体温变化,取肩胛下区、腹股沟区及附睾周围部分脂肪组织观察形态学的变化,测定棕色脂肪组织、皮下白色脂肪组织以及内脏白色脂肪组织解偶联蛋白1(UCP1)的表达。结果:与正常对照组相比,京尼平组小鼠白色脂肪湿重下降16%,冷刺激组下降28%,均有明显差异(P＜0.05);京尼平组和冷刺激组白色脂肪组织颜色变深,HE染色显示脂肪细胞内的脂滴变小,数量增加;京尼平组小鼠的皮下、内脏白色脂肪组织和棕色3种脂肪组织中的UCP1表达量均明显增加(P＜0.05)。结论:京尼平通过上调UCP1的表达促进棕色脂肪组织活化和白色脂肪组织棕化,此效应是京尼平降脂减轻体重的作用机制之一。     

Relation of lipoprotein lipase activity in adipose tissue to adipocyte volume and its influence in hypertriglyceridemia pathogenesis

In the subcutaneous adipose tissue of 20 normal weight and overweight subjects with normo- or hypertriglyceridemia, the relation is examined between the lipoprotein lipase activity (LPLA) per gram adipose tissue and adipocyte volume. The following findings were obtained: 1. Significant positive correlations between the LPLA per gram adipose tissue and the adipocyte volume were ascertained in the groups of subjects having normal triglyceridemia or exhibiting hypertriglyceridemia. 2. The negative relation between the LPLA in the adipose tissue and the triglyceride level in serum described in literature could not be verified. Across a glyceride span of 76 to 600 mg% in serum we found a correlation coefficient of +0.34. 3. It can therefore be assumed that the LPLA per gram adipose tissue with increasing adipocyte volume does not represent an inhibiting factor to the triglyceride in serum breakdown in the development of hypertriglyceridemia.     

Localized early mesenteric Castleman's disease presenting as recurrent intestinal obstruction: a case report

Introduction

Pleomorphic adenoma is the most common benign neoplasm of the salivary glands. Extensive lipomatous involvement of the tumor is, however, a very rare finding.

Case report

Herein, a rare case of lipomatous pleomorphic adenoma arising in the parotid gland of a 14-year-old Japanese woman is presented.

Conclusion

This is the sixth case of lipomatous pleomorphic adenoma in the English literature. Recognition of this rare subtype of pleomorphic adenoma is important for clinical diagnosis and management. On CT scan, it may not be detected possibly due to the extensive fatty component.     

Effects of hypophysectomy and acute growth hormone treatment upon glucose metabolism in adipose tissues and isolated adipocytes of rats.

Glucose oxidation and incorporation into lipid were measured in epididymal adipose tissues and isolated adipose cells of normal and hypophysectomized rats in an effort to determine whether the acute hypoglycemic effect of a systemic growth hormone (GH) injection was related to alterations in the glucose metabolism of adipose tissue. The rats were fed rat chow or a high sucrose diet and received 100 mug GH intraperitoneally 30 minutes or three and one-half hours before sacrifice. Hypophysectomized rats showed a lower plasma glucose as compared with normal rats on both diets. Thirty minutes after a GH injection there was a further decrease of the plasma glucose which, however, was not present in those rats receiving GH three and one-half hours before sacrifice. Adipose tissues from hypophysectomized rats fed the high sucrose diet showed a blunted insulin sensitivity as compared with normal rats on a similar diet. The insulin sensitivity of these tissues was further decreased 30 minutes after a GH injection. Basal glucose metabolism of isolated adipocytes from hypophysectomized rats, as compared with normal rats, was depressed if they were fed rat chow, was at normal levels if they were fed the high sucrose diet and was increased if they were fed the sucrose diet and received triiodothyronine and cortisone supplements. No manipulations of diet or hormonal treatments made the isolated adipocyte from hypophysectomized rats sensitive to insulin either 30 minutes or three and one-half hours after a GH injection. Since basal glucose utilization is not enhanced by GH injection and both the blunted insulin sensitivity of adipose tissue and the absent insulin sensitivity of adipopocytes would be expected to produce hyperglycemia rather than hypoglycemia, it is concluded that immediate systemic effects of a GH injection on carbohydrate metabolism are not related to changes in glucose metabolism of the peripheral adipose tissues.     

Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency

Glucocorticoids are pivotal for adipose tissue development. Rodent studies suggest that corticosteroid-binding globulin (CBG) modulates glucocorticoid action in adipose tissue. In humans, both genetic CBG deficiency and suppressed CBG concentrations in hyperinsulinemic states are associated with obesity. We hypothesized that CBG deficiency in humans modulates the response of human preadipocytes to glucocorticoids, predisposing them to obesity. We compared normal preadipocytes with subcultured preadipocytes from an individual with the first ever described complete deficiency of CBG due to a homozygous null mutation. CBG-negative preadipocytes proliferated more rapidly and showed greater peroxisome proliferator-activated receptor-gamma-mediated differentiation than normal preadipocytes. CBG was not expressed in normal human preadipocytes. Glucocorticoid receptor number and binding characteristics and 11beta-hydroxysteroid dehydrogenase activity were similar for CBG-negative and normal preadipocytes. We propose that the increased proliferation and enhanced differentiation of CBG-negative preadipocytes may promote adipose tissue deposition and explain the obesity seen in individuals with genetic CBG deficiency. Furthermore, these observations may be relevant to obesity occurring with suppressed CBG concentrations associated with hyperinsulinemia.     

Regulation of cytoplasmic acetyl-CoA and acetoacetyl-CoA synthetases by dexamethasone phosphate in rat liver and adipose tissue.

The activity of cytoplasmic acetyl-CoA synthetase and acetoacetyl-CoA synthetase in both liver and adipose tissue was measured in five groups of rats : fed, fasted, fasted and re-fed, fasted, re-fed and injected with dexamethasone during the re-feeding period, fed and injected with dexamethasone. Fasting was found to have a strong inhibitory effect on the activity of the two enzymes in both adipose tissue and liver, which could be abolished by re-feeding. In adipose tissue, dexamethasone prevented this re-establishment of normal enzyme activity but was without effect in the liver. It can therefore be concluded that dexamethasone inhibits the synthesis of acetyl-CoA and acetoacetyl-CoA synthetases in adipose tissue.     

FGF21 promotes metabolic homeostasis via white adipose and leptin in mice

Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.     

Changes in lipogenesis and lipolysis associated with recovery from reversible obesity in mature female rats

Reversible obesity provides a model for demonstration of weight regulation in mature animals. Changes in body composition and in vitro adipose and hepatic lipid synthesis and adipose lipolysis of rats recovering from enforced weight gain were examined to determine whether correction of weight was facilitated by metabolic changes independent of those resulting from hypophagia and negative energy balance. Female Sprague-Dawley rats (200 g) were divided into three groups. Controls ate ad libitum, tube-fed control rats were weight matched to controls. Two-hundred percent-fed rats were tube-fed twice control intake. After 26 days tube feeding stopped and a subgroup from each treatment was killed for determination of body composition and in vitro tissue metabolism. Further subgroups were examined 5, 10, 15, and 36 days later. At the end of overfeeding 200%-fed rats were hypophagic and had high rates of adipose and hepatic lipid synthesis, which soon returned to normal. Gross changes in body fat mass were corrected by hypophagia and increased adipose lipolysis. The remaining small excess in body fat appeared to be corrected by decreased basal and insulin-stimulated adipose fatty acid synthesis when food intake had returned to normal.     

Fatty acid synthesis in liver and adipose tissue of normal and genetically obese (ob/ob) mice during the 24-hour cycle.

1. The synthesis of long-chain fatty acids de novo was measured in the liver and in regions of adipose tissue in intact normal and genetically obses mice throughout the daily 24h cycle. 2. The total rate of synthesis, as measured by the rate of incorporation of 3H from 3H2O into fatty acid, was highest during the dark period, in liver and adipose tissue of lean or obese mice. 3. The rate of incorporation of 14C from [U-14C]glucose into fatty acid was also followed (in the same mice). The 14C/3H ratios were higher by a factor of 5-20 in parametrial and scapular fat than that in liver. This difference was less marked during the dark period (of maximum fatty acid synthesis). 4. In normal mice, the total rate of fatty acid synthesis in the liver was about twofold greater than that in all adipose tissue regions combined. 5. In obese mice, the rate of fatty acid synthesis was more rapid than in lean mice, in both liver and adipose tissue. Most of the extra lipogenesis occurred in adipose tissue. The extra hepatic fatty acids synthesized in obese mice were located in triglyceride rather than phospholipid. 6. In adipose tissue of normal mice, the rate of fatty acid synthesis was most rapid in the intra-abdominal areas and in brown fat. In obese mice, all regions exhibited rapid rates of fatty acid synthesis. 7. These results shed light on the relative significance of liver and adipose tissue (i.e. the adipose 'organ') in fatty acid synthesis in mice, on the mino importance of glucose in hepatic lipogenesis, and on the alterations in the rate of fatty acid synthesis in genetically obese mice.     

Characterization and assessment of hyperelastic and elastic properties of decellularized human adipose tissues

Decellularized adipose tissue (DAT) has shown potential as a regenerative scaffold for plastic and reconstructive surgery to augment or replace damaged or missing adipose tissue (e.g. following lumpectomy or mastectomy). The mechanical properties of soft tissue substitutes are of paramount importance in restoring the natural shape and appearance of the affected tissues, and mechanical mismatching can lead to unpredictable scar tissue formation and poor implant integration. The goal of this work was to assess the linear elastic and hyperelastic properties of decellularized human adipose tissue and compare them to those of normal breast adipose tissue. To assess the influence of the adipose depot source on the mechanical properties of the resultant decellularized scaffolds, we performed indentation tests on DAT samples sourced from adipose tissue isolated from the breast, subcutaneous abdominal region, omentum, pericardial depot and thymic remnant, and their corresponding force–displacement data were acquired. Elastic and hyperelastic parameters were estimated using inverse finite element algorithms. Subsequently, a simulation was conducted in which the estimated hyperelastic parameters were tested in a real human breast model under gravity loading in order to assess the suitability of the scaffolds for implantation. Results of these tests showed that in the human breast, the DAT would show similar deformability to that of native normal tissue. Using the measured hyperelastic parameters, we were able to assess whether DAT derived from different depots exhibited different intrinsic nonlinearities. Results showed that DAT sourced from varying regions of the body exhibited little intrinsic nonlinearity, with no statistically significant differences between the groups.     

Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes

Obesity with enlarged fat cells is associated with high local concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) in the adipose tissue. We examined the effects of this inflammatory state on 3T3-L1 preadipocyte development and differentiation to mature adipose cells. Both IL-6 and TNFalpha impaired the normal differentiation pattern and lipid accumulation. However, IL-6 allowed a normal early induction of differentiation with inhibition of Wnt10b and Pref-1, whereas expression of CCAAT/enhancer-binding protein alpha, in contrast to peroxisome proliferator-activated receptor gamma, was markedly reduced. TNFalpha also allowed a normal early induction of differentiation, whereas the terminal differentiation to adipose cells was completely prevented. However, both cytokines induced an inflammatory phenotype of the cells but with different profiles. Remarkably, both IL-6 and TNFalpha maintained and augmented the canonical Wnt signaling associated with low axin and high low density lipoprotein receptor-related protein (LRD), Dishevelled, and beta-catenin levels. TNFalpha, but not IL-6, activated Wnt10b expression, whereas IL-6 increased the apparent phosphorylation of Dishevelled. Thus, both IL-6 and TNFalpha prevent the normal development of preadipocytes to fully differentiated adipose cells and, instead, promote an inflammatory phenotype of the adipocytes. These results provide an explanation as to why obesity and diabetes are associated with both local and systemic inflammation, insulin resistance, and ectopic lipid accumulation.     

Effect of thyroid status and cold stress on tyrosine hydroxylase activity in adrenal gland and brown adipose tissue.

A tyrosine hydroxylase activity (THa) of 1.4 nanomoles DOPA formed per hour per mg of protein has been found in brown adipose tissue homogenate; a value of 30.3 nanomoles was found in the corresponding adrenal homogenate. The THa of brown adipose tissue of normal rat increases markedly upon intermittent exposure to cold temperature and is greatly increased in the thyroidectomized rat. In adrenal gland there is, upon intermittent cold stress, an increase in the THa of normal and of thyroidectomized rats, but no increase in the THa of animal receiving triiodothyronine.     

Dehydroepiandrosterone concentration in adipose tissue of normal and overweight subjects.

Unconjugated dehydroepiandrosterone has been isolated from human abdominal adipose tissue and identified by double isotope derivatization and recrystallization to constant isotope ratio. Gas chromatography with electron capture detection revealed an actual dehydroepiandrosterone concentration between 0.32 to 2.82 mug/g in adipose tissue of normal and overweight subjects. The approximate dehydroepiandrosterone content of the total adipose tissue mass varied between 30 and 173 mg in subjects with severe obesity.     

Effects of high-carbohydrate diets on lipogenesis in rat interscapular brown adipose tissue

Cycloplasmic preparations from brown and white adipose tissues were assayed for three lipogenic enzymes throughout a programme of starvation followed by refeeding on either a normal or a white-bread diet. In the brown adipose tissue of rats fed on a white-bread diet the three enzymes were elevated to levels significantly higher than those in white adipose tissue.