Gender-specific effects of capsiate supplementation on body weight and bone mineral density: a randomized, double-blind, placebo-controlled study in slightly overweight women.

INTRODUCTION: Overweight and obesity are highly prevalent conditions associated with premature morbidity and mortality worldwide. Capsiate, a nonpungent analogue of capsaicin, binds to TRP vanilloid 1 (TRPV1) receptor, which is involved in adipogenesis, and could be effective as a weight-lowering agent. METHODS: Eighteen slightly overweight women were enrolled in this randomized, double-blind, placebo-controlled study. Nine patients were included in the capsiate intervention group and received 9 mg/day of capsinoids and 9 patients received placebo for 8 weeks. All patients underwent weight and waist circumference assessment before and after treatment. Body composition and bone mineral density (BMD) were also detected by dual-energy X-ray absorptiometry (DXA). RESULTS: Fourteen patients completed the study. The treatment with capsiate or placebo for 8 weeks was not associated with significant changes in weight or waist circumference. After treatment, there was a significant improvement in BMD values measured at the spine in the capsiate group (1.158 vs 1.106 g/cm2, + 4.7%; p = 0.04), but not in the group treated with placebo. Similarly, the capsiate group showed a 9.1% increase (p = 0.05) in the adipose tissue and an 8.5% decrease in lean mass measured at the supraclavicular level, whereas these changes were not statistically significant in the placebo group. CONCLUSIONS: Treatment with capsiate for 8 weeks led to negligible changes in body weight in a small sample of slightly overweight women, but our findings suggest a potential effect of capsaicin on bone metabolism in humans.

Crosstalk Between Muscle and Bone Via the Muscle-Myokine Irisin.

Several lines of evidence have recently established that skeletal muscle is an endocrine organ producing and releasing myokines acting in a paracrine or endocrine fashion. Among these, the newly identified myokine Irisin, produced by skeletal muscle after physical exercise, was originally described as molecule able to promote energy expenditure in white adipose tissue. Recently, it has been shown that the myokine Irisin affects skeletal metabolism in vivo. Thus, mice treated with a micro-dose of r-Irisin displayed improved cortical bone mass, geometry and strength, resembling the effect of physical activity in developing an efficient load-bearing skeleton. Further studies highlighted the autocrine effect of Irisin on skeletal muscle, and research performed in humans has definitively established that Irisin is a circulating hormone-like myokine, increased by physical activity. Albeit there are still few, since Irisin has been very recently discovered, herein are summarized the most relevant research findings published on this topic.

Multiple symmetric lipomatosis: a rare disease and its possible links to brown adipose tissue.

AIM: Aim of this study is an updated review of our case series (72 patients) as well as available literature on the Multiple Symmetric Lipomatosis (MSL), a rare disease primarily involving adipose tissue, characterized by the presence of not encapsulated fat masses, symmetrically disposed at characteristic body sites (neck, trunk, proximal parts of upper and lower limbs). DATA SYNTHESIS: The disease is more frequent in males, associated to an elevated chronic alcohol consumption, mainly in form of red wine. Familiarity has been reported and MSL is considered an autosomic dominant inherited disease. MSL is associated to severe clinical complications, represented by occupation of the mediastinum by lipomatous tissue with a mediastinal syndrome and by the presence of a somatic and autonomic neuropathies. Hyper-alphalipoproteinemia with an increased adipose tissue lipoprotein-lipase activity, a defect of adrenergic stimulated lipolysis and a reduction of mitochondrial enzymes have been described. The localization of lipomatous masses suggests that MSL lipomas could originate from brown adipose tissue (BAT). Moreover, studies on cultured pre-adipocytes demonstrate that these cells synthetize the mitochondrial inner membrane protein UCP-1, the selective marker of BAT. Surgical removal of lipomatous tissue is to date the only validated therapeutic approach. CONCLUSIONS: MSL is supposed to be the result of a disorder of the proliferation and differentiation of human BAT cells.

Increased density of inhibitory noradrenergic parenchymal nerve fibers in hypertrophic islets of Langerhans of obese mice.

BACKGROUND AND AIM: We sought to identify mechanisms of beta cell failure in genetically obese mice. Little is known about the role of pancreatic innervation in the progression of beta cell failure. In this work we studied adrenergic innervation, in view of its potent inhibitory effect on insulin secretion. We analyzed genetically obese ob/ob and db/db mice at different ages (6- and 15-week-old), corresponding to different compensatory stages in the course of beta cell dysfunction. 15 week-old HFD mice were also studied. METHODS AND RESULTS: All mice were characterized by measures of plasma glucose, insulin, and HOMA. After perfusion, pancreata were dissected and studied by light microscopy, electron microscopy, and morphometry. Insulin, Tyrosine Hydroxylase-positive fibers and cells and Neuropeptide Y-positive cells were scored by immunohistochemistry. Islets of obese mice showed increased noradrenergic fiber innervation, with significant increases of synaptoid structures contacting beta cells compared to controls. Noradrenergic innervation of the endocrine area in obese db/db mice tended to increase with age, as diabetes progressed. In ob/ob mice, we also detected an age-dependent trend toward increased noradrenergic innervation that, unlike in db/db mice, was unrelated to glucose levels. We also observed a progressive increase in Neuropeptide Y-immunoreactive elements localized to the islet core. CONCLUSIONS: Our data show increased numbers of sympathetic nerve fibers with a potential to convey inhibitory signals on insulin secretion in pancreatic islets of genetically obese animals, regardless of their diabetic state. The findings suggest an alternative interpretation of the pathogenesis of beta cell failure, as well as novel strategies to reverse abnormalities in insulin secretion.

Time course of histomorphological changes in adipose tissue upon acute lipoatrophy.

BACKGROUND AND AIMS: Crown-like structures (CLS) are characteristic histopathology features of inflamed adipose tissues in obese mice and humans. In previous work, we suggested that these cells derived from macrophages primarily involved in the reabsorption of dead adipocytes. Here, we used a well-characterized transgenic mouse model in which the death of adipocytes in adult mice is inducible and highly synchronized. In this "FAT ATTAC" model, apoptosis is induced through forced dimerization of a caspase-8 fusion protein. METHODS AND RESULTS: 0, 0.5, 1, 2, 3 and 10 days post induction of adipocyte cell death, we analyzed mesenteric and epididymal adipose depots by histology, immunohistochemistry and electron microscopy. Upon induction of caspase-8 dimerization, numerous adipocytes lost immunoreactivity for perilipin, a marker for live adipocytes. In the same areas, we found adipocytes with hypertrophic mitochondria and signs of organelle degeneration. Neutrophils and lymphocytes were the main inflammatory cells present in the tissue, and the macrophages were predominantly Mac-2 negative. Over the course of ablation, Mac-2 positive macrophages substituted for Mac-2 negative macrophages, followed by CLS formation. All perilipin negative, dead adipocytes were surrounded by CLS structures. The time course of histopathology was similar in both fat pads studied, but occurred at earlier stages and was more gradual in mesenteric fat. CONCLUSION: Our data demonstrate that CLS formation results as a direct consequence of adipocyte death, and that infiltrating macrophages actively uptake remnant lipids of dead adipocytes. Upon induction of adipocyte apoptosis, inflammatory cells infiltrate adipose tissue initially consisting of neutrophils followed by macrophages that are involved in CLS formation.

Exercise as a new physiological stimulus for brown adipose tissue activity.

BACKGROUND AND AIM: Brown adipose tissue (BAT) plays a major role in body energy expenditure counteracting obesity and obesity-associated morbidities. BAT activity is sustained by the sympathetic nervous system (SNS). Since a massive activation of the SNS was described during physical activity, we investigated the effect of endurance running training on BAT of young rats to clarify the role of exercise training on the activity and recruitment state of brown cells. METHODS AND RESULTS: Male, 10-week-old Sprague Dawley rats were trained on a motor treadmill (approximately 60% of VO2max), 5 days/week, both for 1 and 6 weeks. The effect of endurance training was valuated using morphological and molecular approaches. Running training affected on the morphology, sympathetic tone and vascularization of BAT, independently of the duration of the stimulus. Functionally, the weak increase in the thermogenesis (no difference in UCP-1), the increased expression of PGC-1α and the membrane localization of MCT-1 suggest a new function of BAT. Visceral fat increased the expression of the FOXC2, 48 h after last training session and some clusters of UCP-1 paucilocular and multilocular adipocytes appeared. CONCLUSION: Exercise seemed a weakly effective stimulus for BAT thermogenesis, but surprisingly, without the supposed metabolically hypoactive effects. The observed browning of the visceral fat, by a supposed white-to-brown transdifferentiation phenomena suggested that exercise could be a new physiological stimulus to counteract obesity by an adrenergic-regulated brown recruitment of adipocytes.

The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes.

White and brown adipocytes are believed to occupy different sites in the body. We studied the anatomical features and quantitative histology of the fat depots in obesity and type 2 diabetes-prone C57BL/6J mice acclimated to warm or cold temperatures. Most of the fat tissue was contained in depots with discrete anatomical features, and most depots contained both white and brown adipocytes. Quantitative analysis showed that cold acclimation induced an increase in brown adipocytes and an almost equal reduction in white adipocytes; however, there were no significant differences in total adipocyte count or any signs of apoptosis or mitosis, in line with the hypothesis of the direct transformation of white into brown adipocytes. The brown adipocyte increase was accompanied by enhanced density of noradrenergic parenchymal nerve fibers, with a significant correlation between the density of these fibers and the number of brown adipocytes. Comparison with data from obesity-resistant Sv129 mice disclosed a significantly different brown adipocyte content in C57BL/6J mice, suggesting that this feature could underpin the propensity of the latter strain to develop obesity. However, the greater C57BL/6J browning capacity can hopefully be harnessed to curb obesity and type 2 diabetes in patients with constitutively low amounts of brown adipose tissue.

The Adipose Organ Is a Unitary Structure in Mice and Humans.

Obesity is the fifth leading cause of death worldwide. In mice and humans with obesity, the adipose organ undergoes remarkable morpho-functional alterations. The comprehension of the adipose organ function and organization is of paramount importance to understand its pathology and formulate future therapeutic strategies. In the present study, we performed anatomical dissections, magnetic resonance imaging, computed axial tomography and histological and immunohistochemical assessments of humans and mouse adipose tissues. We demonstrate that most of the two types of adipose tissues (white, WAT and brown, BAT) form a large unitary structure fulfilling all the requirements necessary to be considered as a true organ in both species. A detailed analysis of the gross anatomy of mouse adipose organs in different pathophysiological conditions (normal, cold, pregnancy, obesity) shows that the organ consists of a unitary structure composed of different tissues: WAT, BAT, and glands (pregnancy). Data from autoptic dissection of 8 cadavers, 2 females and 6 males (Age: 37.5 ± 9.7, BMI: 23 ± 2.7 kg/m2) and from detailed digital dissection of 4 digitalized cadavers, 2 females and 2 males (Age: 39 ± 14.2 years, BMI: 22.8 ± 4.3 kg/m2) confirmed the mixed (WAT and BAT) composition and the unitary structure of the adipose organ also in humans. Considering the remarkable endocrine roles of WAT and BAT, the definition of the endocrine adipose organ would be even more appropriate in mice and humans.

Noradrenergic fibers are associated with beta-cell dedifferentiation and impaired beta-cell function in humans.

AIMS/HYPOTHESIS: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the "disappearance" of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. METHODS: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. RESULTS: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ±â€¯0.21 vs 0.32 ±â€¯0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = -0.84; p = 0.01), incremental second-phase insulin secretion (r = -0.84, p = 0.03) and arginine-stimulated insulin secretion (r = -0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). CONCLUSIONS/INTERPRETATION: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation.

The origin of brown adipocytes arising in white adipose tissue (WAT) after cold acclimatization is unclear. Here, we demonstrate that several UCP1-immunoreactive brown adipocytes occurring in WAT after cold acclimatization have a mixed morphology (paucilocular adipocytes). These cells also had a mixed mitochondrioma with classic "brown" and "white" mitochondria, suggesting intermediate steps in the process of direct transformation of white into brown adipocytes (transdifferentiation). Quantitative electron microscopy disclosed that cold exposure (6 degrees C for 10 days) did not induce an increase in WAT preadipocytes. beta(3)-adrenoceptor-knockout mice had a blunted brown adipocyte occurrence upon cold acclimatization. Administration of the beta(3)-adrenoceptor agonist CL316,243 induced the occurrence of brown adipocytes, with the typical morphological features found after cold acclimatization. In contrast, administration of the beta(1)-adrenoceptor agonist xamoterol increased only the number of preadipocytes. These findings indicate that transdifferentiation depends on beta(3)-adrenoceptor activation, whereas preadipocyte recruitment is mediated by beta(1)-adrenoceptor. RT-qPCR experiments disclosed that cold exposure induced enhanced expression of the thermogenic genes and of genes expressed selectively in brown adipose tissue (iBAT) and in both interscapular BAT and WAT. beta(3)-adrenoceptor suppression blunted their expression only in WAT. Furthermore, cold acclimatization induced an increased WAT expression of the gene coding for C/EBPalpha (an antimitotic protein), whereas Ccna1 expression (related to cell proliferation) was unchanged. Overall, our data strongly suggest that the cold-induced emergence of brown adipocytes in WAT predominantly reflects beta(3)-adrenoceptor-mediated transdifferentiation.

Morphological and immunohistochemical features of brown adipocytes and preadipocytes in a case of human hibernoma.

BACKGROUND AND AIM: The role of brown adipose tissue physiology and pathology in humans is debated. A greater knowledge of its developmental aspects could play a pivotal role in devising treatments for obesity and diabetes. METHODS AND RESULTS: Tissue from a rare case of hibernoma, removed from a 17-year-old boy, was examined by light and electron microscopy, morphometry and immunohistochemistry. The tumour was well vascularised and innervated and contained mature adipocytes with the characteristics of both brown and white adipocytes. Numerous, poorly differentiated cells resembling brown adipocyte precursors were seen in a pericytic position in close association with the capillary wall. On immunohistochemistry mature brown adipocytes were seen to express the marker protein UCP1. On morphometry the intensity of uncoupling protein 1 (UCP1) immunostaining varied in relation to the morphological features of adipocytes: the "whiter" their appearance, the weaker their UCP1 immunoreactivity. CONCLUSIONS: Our data suggest that in humans, as in rodents, brown adipocyte precursors arise in close association with vessel walls and that intermediate forms between white and brown adipocytes can also be documented in human adults.

n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet.

AIMS/HYPOTHESIS: Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity. METHODS: Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). RESULTS: DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT. CONCLUSIONS/INTERPRETATION: DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.

Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ.

The mammalian adipose organ is composed of subcutaneous and visceral depots containing white and brown adipocytes. Cold acclimatisation induces an increase in the brown component without affecting the overall number of adipocytes; this form of plasticity is associated to obesity and diabetes resistance in experimental models. Cold activates the drive of the sympathetic nervous system to the adipose organ, where the vast majority of nerve fibers are in fact noradrenergic. However, it is unclear whether and how such fibers are involved in the plastic changes of the adipose organ. We thus conducted a systematic study of the distribution and number of sympathetic noradrenergic nerve fibers in the adipose organ of mice kept at different environmental temperatures. Adult Sv129 female mice were kept at 28 degrees C or 6 degrees C for 10 days. The density of tyrosine hydroxylase (noradrenergic)-positive nerve fibers (no. of fibers per 100 adipocytes) was calculated in the subcutaneous and visceral depots of the adipose organ, and a correlation was sought between fiber density and proportion of brown adipocytes. Tyrosine hydroxylase-positive parenchymal fibers were detected in all subcutaneous and visceral depots among white as well as brown adipocytes, the mediastinal depot displaying the densest innervation. Cold acclimatisation induced a threefold increase in the total number of TH fibers in the whole organ. The proportion of brown adipocytes positively correlated with noradrenergic fiber density in the organ. Taken together, these data suggest that cold acclimatisation induces noradrenergic fiber branching in the adipose organ of adult mice, and that such changes may be a precondition for its plastic transformation into a brown phenotype.

Origami multiple paper-based electrochemical biosensors for pesticide detection.

Herein, we propose the first three-dimensional origami paper-based device for the detection of several classes of pesticides by combining different enzyme-inhibition biosensors. This device was developed by integrating two different office paper-based screen-printed electrodes and multiple filter paper-based pads to load enzymes and enzymatic substrates. The versatile analysis of different pesticides was carried by folding and unfolding the filter paper-based structure, without any addition of reagents and any sample treatment (i.e. dilution, filtration, pH adjustment). The paper-based platform was employed to detect paraoxon, 2,4-dichlorophenoxyacetic acid, and atrazine by exploiting the capability of these different types of pesticides (i.e. organophosphorus insecticides, phenoxy-acid herbicides, and triazine herbicide) to inhibit butyrylcholinesterase, alkaline phosphatase, and tyrosinase, respectively. The degree of inhibition correlating to the quantity of pesticides was evaluated by chronoamperometrically monitoring the enzymatic activity in the absence and in the presence of pesticides by using a portable potentiostat. To improve the sensitivity, the paper-based electrodes were modified with carbon black alone in the case of platforms for 2,4-dichlorophenoxyacetic acid and atrazine detection, or decorated with Prussian blue nanoparticles for the detection of paraoxon. The paper-based device was applied for the detection of paraoxon, 2,4-dichlorophenoxyacetic acid, and atrazine at ppb level in both standard solutions and river water sample. The accuracy of this origami multiple paper-based electrochemical biosensor was evaluated in river water by recovery studies, obtaining satisfactory values (e.g. for paraoxon 90 ±â€¯1% and 88 ±â€¯2%, for 10 and 20 ppb, respectively). The proposed three-dimensional origami paper device allows for rapid, cost-effective and accurate pesticide detection in surface water as a result of combining filter and office papers, screen-printing, wax-printing and nanomaterial technology.

The solitary chemosensory cells and the diffuse chemosensory system of the airway.

Solitary chemosensory cells (SCCs), which resemble taste bud cells, are present in the epidermis and oropharynx of most primary aquatic vertebrates. Recent studies have led to the description of SCCs also in mammals too. In the airway and digestive apparatus, these elements form a diffuse chemosensory system. SCCs do not aggregate into groups and in SCCs, as in taste bud cells, immunoreactivity forthe G-protein subunit alpha-gustducin and for other molecules of the chemoreceptive cascade was found. Questions remain about the role of the diffuse chemosensory system in control of complex functions (e.g. airway surface liquid secretion) and about the involvement of chemoreceptors in respiratory diseases. Therapeutic actions targeting chemoreceptors could be tested in the treatment of respiratory diseases.

Yield of Image-Guided Needle Biopsy for Infectious Discitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Image-guided biopsy is routinely conducted in patients with suspected discitis, though the sensitivity reported in the literature ranges widely. PURPOSE: We applied a systematic review and meta-analysis to estimate the yield of image-guided biopsy for infectious discitis. DATA SOURCES: We performed a literature search of 4 data bases: PubMed, Cochrane CENTRAL Register of Controlled Trials, Embase.com, and Scopus from data base inception to March 2016. STUDY SELECTION: A screen of 1814 articles identified 88 potentially relevant articles. Data were extracted for 33 articles, which were eligible if they were peer-reviewed publications of patients with clinical suspicion of discitis who underwent image-guided biopsy. DATA ANALYSIS: Patients with positive cultures out of total image-guided biopsy procedures were pooled to estimate yield with 95% confidence intervals. Hypothesis testing was performed with an inverse variance method after logit transformation. DATA SYNTHESIS: Image-guided biopsy has a yield of approximately 48% (793/1763), which is significantly lower than the open surgical biopsy yield of 76% (152/201; P < .01). Biopsy in patients with prior antibiotic exposure had a yield of 32% (106/346), which was not significantly different from the yield of 43% (336/813; P = .08) in patients without prior antibiotic exposure. LIMITATIONS: The conclusions of this meta-analysis are primarily limited by the heterogeneity of the included studies. CONCLUSIONS: Image-guided biopsy has a moderate yield for the diagnosis of infectious discitis, which is significantly lower than the yield of open surgical biopsy. This yield is not significantly affected by prior antibiotic use.

The adipose organ.

In mammals, the adipose tissues are contained in a multi-depot organ: the adipose organ. It consists of several subcutaneous and visceral depots. Some areas of these depots are brown and correspond to brown adipose tissue, while many are white and correspond to white adipose tissue. The organ is rich of vessels and parenchymal nerve fibers, but their density is higher in the brown areas. White areas contain a variable amount of brown adipocytes and their number varies with age, strain and environmental conditions. All adipocytes of the adipose organ express a specific adrenoceptor: ss3AR. Recent data have stressed the plasticity of the adipose organ in adult animals, and in parallel with the cytological variations there are also vascular as well as neural variations. Of note, treatment of genetically and diet induced obese rats with ss3 adrenoceptor agonists ameliorate their pathological condition and this is accompanied by the appearance of brown adipocytes in white areas of the adipose organ. This drug-induced modification of the anatomy of the organ is also obtained by the treatment with PPARgamma agonists in rats and dogs. We have previously shown that the transformation of white adipose tissue into brown adipose tissue in rats treated with ss3 adrenoceptor agonists is due to a direct transformation of differentiated unilocular adipocytes (transdifferentiation). We recently also showed that the absence of ss3 adrenoceptors strongly depress this type of plasticity in the adipose organ. All together these experiments strongly suggest the possibility to modulate the plasticity of the adipose organ with therapeutic implications for obesity and related disorders.

Omental adipose tissue fibrosis and insulin resistance in severe obesity.

BACKGROUND/OBJECTIVES: The unresolved chronic inflammation of white adipose tissue (WAT) in obesity leads to interstitial deposition of fibrogenic proteins as reparative process. The contribution of omental adipose tissue (oWAT) fibrosis to obesity-related complications remains controversial. The aim of our study was to investigate whether oWAT fibrosis may be related to insulin resistance in severely obese population. SUBJECTS/METHODS: Forty obese subjects were studied by glucose clamp before undergoing bariatric surgery and thus stratified according to insulin resistance severity (M-value). From the first (Group B: n=13; M=1.9±0.7 mg kg(-1) min(-1)) and the highest (Group A: n=14; M=4.5±1.4 mg kg(-1) min(-1)) M-value tertiles, which were age-, waist- and body mass index-matched, oWAT samples were then obtained.Gene expression of collagen type I, III and VI, interleukin-6, profibrotic mediators (transforming growth factor (TGF)-ß1, activin A, connective tissue growth factor), hypoxia inducible factor-1α (HIF-1α) and macrophage (CD68, monocyte chemotactic protein (MCP)-1, CD86, CD206, CD150) markers were analyzed by quantitative reverse transcription PCR. Adipocyte size and total fibrosis were assessed by histomorphometry techniques. RESULTS: Fibrosis at morphological level resulted significantly greater in Group B compared with Group A, although collagens gene expression did not differ. Notably, collagen VI messenger RNA significantly correlated with collagen I, collagen III, HIF-1α, TGF-ß1, CD68, MCP-1 and CD86 transcription levels, supporting their relation with fibrosis development. CONCLUSIONS: In conclusion, we show for the first time that human oWAT fibrosis in severe obesity is consistent with a higher degree of insulin resistance measured by glucose clamp. Therefore, collagen deposition could represent a maladaptive mechanism contributing to obesity-related metabolic complications.

Leptin and UCP1 genes are reciprocally regulated in brown adipose tissue.

In a previous work we showed that only unilocular brown adipocytes express leptin. In order to investigate the relationship between leptin gene expression, brown adipocyte activity (UCP1) and morphology, we studied brown adipose tissues of mice (C57BL, female, 7 weeks old) acclimated at different temperatures (19 degrees C and 28 degrees C). Northern blot analysis revealed higher leptin and lower UCP1 mRNA levels in mice exposed to 28 degrees C than in the group acclimated at 19 degrees C. Also protein expression (immunohistochemistry) differed in the two groups: at 28 degrees C brown adipocytes were positive for leptin and only weakly positive for UCP1, while at 19 degrees C they were leptin-negative and UCP1-positive. In the former group the morphology was mainly unilocular. Our data suggest that in brown adipocytes of warm-acclimated mice leptin expression is closely related to their hypoactive functional stage, as evidenced by their low level of UCP1 synthesis and the morphological rearrangement of the lipid content (unilocularity).