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PubMed2006

Visceral and truncal subcutaneous adipose tissue are associated with impaired capillary recruitment in healthy individuals.

CONTEXT: Central adiposity is associated with cardiovascular risk independently of total adiposity. Microvascular dysfunction is thought to contribute to obesity-associated insulin resistance and hypertension and may thus link central adiposity with cardiovascular risk. OBJECTIVE: Our objective was to investigate how body fat distribution relates to microvascular function and the role of adipocytokines in these relationships. DESIGN, SETTING, AND PARTICIPANTS: We cross-sectionally studied 51 healthy adults and 29 of their prepubertal children born at the VU University Medical Center in Amsterdam. MAIN OUTCOME MEASURES: We measured visceral and abdominal sc adiposity with magnetic resonance imaging and truncal and peripheral sc adiposity with skinfold thickness. Postocclusive skin capillary recruitment was assessed with videomicroscopy. Concentrations of C-reactive protein, IL-6, and TNF-alpha were combined in an inflammation score. RESULTS: In adults, visceral adipose tissue and trunk/extremity skinfold ratio were inversely associated with capillary recruitment (partial correlation coefficients, -0.32, P = 0.03, and -0.37, P < 0.01, respectively). The inflammation score was inversely associated with capillary recruitment (r = -0.50; P < 0.01) and statistically explained 41% of the association between visceral adipose tissue and capillary recruitment. In children, trunk/extremity skinfold ratio was inversely associated with capillary recruitment (r = -0.49; P = 0.01), but other measures of adiposity were not. CONCLUSION: Our data in adults suggest a role for visceral adiposity and its associated proinflammatory state in capillary dysfunction and its possible sequelae such as hypertension and insulin resistance. Also, our findings in children and adults suggest that truncal sc adiposity is detrimental for capillary perfusion and that this process may start before puberty.

Abdominal Fat↗
PubMed1983

In vivo hepatic and peripheral insulin resistance in genetically obese (fa/fa) rats.

The techniques of hyperglycemic and euglycemic clamps previously used in human investigation have been adapted to small rodents to measure in vivo peripheral (muscle, adipose tissues) glucose metabolism and in vivo hepatic glucose production, in lean and genetically obese (fa/fa) rats. The aim of the study was 1) to assess the in vivo relevance of previously described in vitro abnormalities of muscle and adipose tissues producing insulin resistance in genetically obese (fa/fa) rats; 2) to decide whether livers of obese rats were insulin resistant. It was observed that during either hyperglycemic or euglycemic clamps, peripheral glucose metabolism by muscle and adipose tissue of obese rats was similar to that of lean controls but at the cost, for the obese rats, of plasma insulin levels that were 3.5 times higher than control. This indicated that peripheral tissues of obese rats were indeed insulin resistant when tested in vivo. It was also observed that raising plasma insulin levels in lean rats inhibited the in vivo hepatic glucose production. In contrast, in obese rats, hepatic glucose production was high in spite of a marked increase in basal insulinemia. Furthermore, hepatic glucose production of obese rats failed to be inhibited by further increasing their hyperinsulinemia. This is the first demonstration of a hepatic insulin resistance in genetically obese fa/fa rats.

Animals↗
PubMed2003

Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver.

Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. (1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.

Adipocytes↗
PubMed2004

Transgenic mice overexpressing SREBP-1a under the control of the PEPCK promoter exhibit insulin resistance, but not diabetes.

Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor which regulates genes involved in the synthesis of fatty acids and triglycerides. The overexpression of nuclear SREBP-1a in transgenic mice under the control of the PEPCK promoter (TgSREBP-1a) caused a massively enlarged fatty liver and disappearance of peripheral white adipose tissue. In the current study, we estimated the impact of this lipid transcription factor on plasma glucose/insulin metabolism in vivo. TgSREBP-1a exhibited mild peripheral insulin resistance as evidenced by hyperinsulinemia both at fasting and after intravenous glucose loading, and retarded glucose reduction after insulin injection due to decreased plasma leptin levels. Intriguingly, hyperinsulinemia in TgSREBP-1a mice was markedly exacerbated in a fed state and sustained after intravenous glucose loading, and paradoxically decreased after the portal injection of glucose. TgSREBP-1a mice consistently showed very small plasma glucose increases after portal glucose loading because of a large capacity for hepatic glucose uptake. These data suggested that hepatic insulin resistance emerges postprandially. In addition, pancreatic islets from TgSREBP-1a were enlarged. These data demonstrate that SREBP-1a activation in the liver has a strong impact on plasma insulin levels, implicating the potential role of SREBPs in hepatic insulin metabolism relating to insulin resistance.

Animals↗
PubMed1988

Adipose tissue distribution and female carcinomas. A 12-year follow-up of participants in the population study of women in Gothenburg, Sweden.

A longitudinal population study of 1462 women, aged 38-60 years, was carried out in Gothenburg, Sweden, in 1968-69. In univariate analysis anthropometric variables indicating centrally localized adipose tissue (waist circumference, the ratio of waist to hip circumference and the subscapular skinfold) showed significant age-standardized positive associations with the occurrence (prevalence + incidence data) of endometrial carcinoma. Incidence data suggested that measurements of centrally localized adipose tissue might be of predictive value for this malignancy as well as for ovarian carcinoma. In contrast, measurements of generalized obesity (body weight or body mass index) or peripherally localized adipose tissue (triceps skinfold) showed no associations to these malignancies. No relationship was observed between the anthropometric variables studied and breast carcinoma. The association observed between endometrial and ovarian carcinomas with central adipose tissue did, however, not remain in multivariate analysis when generalized obesity was taken into account. Centrally localized adipose tissue is known to be associated with endocrine abberations including irregular ovulation and menstruation, re-emphasizing the importance of endocrine factors for the pathogenesis of endometrial and ovarian carcinomas. No positive association was found between development of the carcinomas and initial measurements of blood glucose, serum lipids or blood pressure, found to be elevated in cross-sectional studies. An increase in these variables therefore probably are parallel phenomena rather than predictors. The women with endometrial or breast carcinomas smoked more than the remaining women. Although the number of end-points observed was limited these results suggest that measurements of adipose tissue distribution might be a valuable addition to the predictors of endometrial and ovarian carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed2003

The influence of obesity and gestational diabetes mellitus on accretion and the distribution of adipose tissue in pregnancy.

OBJECTIVE: The purpose of this study was to evaluate the effect of pregravid obesity and gestational diabetes mellitus (GDM) on the longitudinal accretion and distribution of adipose tissue in pregnancy. STUDY DESIGN: Women with normal glucose tolerance and GDM were evaluated before conception, early (12-14 weeks) and late (33-36 weeks) in gestation. Fat mass, lean body mass, and percent body fat were assessed longitudinally with hydrodensitometry. Serial biceps, triceps, subscapular, iliac, costal, mid thigh, and lower thigh skinfold measurements quantified the changes in fat mass distribution. Pregravid obesity was defined as >25% body fat. RESULTS: Subjects included 19 patients with GDM (5 lean women, 14 obese women), and 33 patients with normal glucose tolerance (controls; 12 lean women, 21 obese women). GDM and control subjects were similar in pregravid percent body fat (29.6% vs 27.9%, P=.47) and fat mass (20.8 kg vs 18.2 kg, P=.37). Values for subjects with GDM and controls were also similar in terms of percent body fat, fat mass, and weight gained (change in percent body fat, -0.7% vs 1.9% [P=.07]; change in fat mass, 3.8 kg vs 5.0 kg [P=.08]; change in weight, 12.0 kg vs 13.2 kg [P=.35]). Lean subjects gained more percent body fat compared with obese subjects (change in percent body fat, 3.3% vs 0.1% [P=.004]) but gained similar amounts of fat mass (change in fat mass, 4.7 kg vs 4.2 kg [P=.58]), lean body mass (7.6 kg vs 8.8 kg [P=.18]), and weight (change in weight, 12.3kg vs 13.0 kg [P=.61]) The distribution of adipose tissue that was accumulated as estimated with skinfold measurements was similar between patients with GDM and glucose tolerance (P>.05 for all changes in skinfolds), but significantly different between lean and obese patients (P<.05 for all changes in skinfolds). Lean women gained a predominance of adipose tissue peripherally over that in obese women. CONCLUSION: Lean women accrue significantly more fat mass than obese women, regardless of glucose tolerance. Pregestational obesity rather than GDM influences the distribution of adipose accretion.

Adipose Tissue↗
PubMed2003

Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation.

Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma stimulation on the development of diabetes in obese diabetes-prone OLETF rats. Chronic administration of a PPAR-alpha agonist (0.5% [wt/wt] fenofibrate) or a PPAR-gamma agonist (3 mg x kg(-1) x day(-1) rosiglitazone) completely prevented the development of glycosuria. Pancreatic islets from untreated OLETF rats underwent sequential hypertrophy and atrophy, which was completely prevented by chronic fenofibrate treatment. In contrast, rosiglitazone treatment did not affect islet hypertrophy at earlier stages but prevented beta-cell atrophy at later stages. Fenofibrate treatment decreased body weight and visceral fat, whereas rosiglitazone treatment increased body weight. Despite the opposite effects on adiposity, both drugs were equally effective in improving insulin actions in skeletal muscle. Furthermore, both drugs significantly decreased the triglyceride content in the soleus muscle and pancreatic islets. The present study demonstrates that the PPAR-alpha agonist fenofibrate prevents the development of diabetes in OLETF rats by reducing adiposity, improving peripheral insulin action, and exerting beneficial effects on pancreatic beta-cells.

Adipose Tissue↗
PubMed2006

A type IV P-type ATPase affects insulin-mediated glucose uptake in adipose tissue and skeletal muscle in mice.

Mice carrying two pink-eyed dilution (p) locus heterozygous deletions represent a novel polygenic mouse model of type 2 diabetes associated with obesity. Atp10c, a putative aminophospholipid transporter on mouse chromosome 7, is a candidate for the phenotype. The phenotype is diet-induced. As a next logical step in the validation and characterization of the model, experiments to analyze metabolic abnormalities associated with these mice were carried out. Results demonstrate that mutants (inheriting the p deletion maternally) heterozygous for Atp10c are hyperinsulinemic, insulin-resistant and have an altered insulin-stimulated response in peripheral tissues. Adipose tissue and the skeletal muscle are the targets, and GLUT4-mediated glucose uptake is the specific metabolic pathway associated with Atp10c deletion. Insulin resistance primarily affects the adipose tissue and the skeletal muscle, and the effect in the liver is secondary. Gene expression profiling using microarray and real-time PCR show significant changes in the expression of four genes--Vamp2, Dok1, Glut4 and Mapk14--involved in insulin signaling. The expression of Atp10c is also significantly altered in the adipose tissue and the soleus muscle. The most striking observation is the loss of Atp10c expression in the mutants, specifically in the soleus muscle, after eating the high-fat diet for 12 weeks. In conclusion, experiments suggest that the target genes and/or their cognate factors in conjunction with Atp10c presumably affect the normal translocation and sequestration of GLUT4 in both the target tissues.

Adenosine Triphosphatases↗
PubMed2005

Neuro-hormonal control of food intake: basic mechanisms and clinical implications.

Obesity is one of the most common metabolic diseases and the greatest threats of the health because of possibility of numerous complications. In order to design effective drugs or apply the helpful surgical procedure it is essential to understand physiology of appetite control and pathophysiology of obesity. According to the first law of thermodynamics, the energy input in the form of food, equals energy expenditure through exercise, basal metabolism, thermogenesis and fat biosynthesis. The control of body weight actually concerns the control of adipose tissue with the key role of hypothalamus, possessing several neuronal centers such as that in lateral hypothalamic nuclei considered to be "hunger" center and in ventromedial nuclei serving as the "satiety" center. In addition, paraventricular and arcuate hypothalamic nuclei (ARC) are the sites where multiple hormones, released from the gut and adipose tissue, converge to regulate food intake and energy expenditure. There are two distinct types of neurons in ARC that are important in control of food intake; (1) preopiomelanocortin (POMC) neurons activated by an orexigenic hormones and releasing alpha-melanocyte-stimulating hormone (alpha-MSH) in satiety center and (2) neurons activated by orexigenic peptides such as ghrelin that release the substances including neuropeptide Y (NPY) and Agouti-Related Peptide (AgRP) in hunger center. ARC integrates neural (mostly vagal) and humoral inputs such as enteropeptides including orexigenic (ghrelin and orexins) and an orexigenic peptides (cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin and others) that exert a physiological role in regulating appetite and satiety. The peripherally (gut, adipose tissue) and centrally expressed modulators of appetitive behavior act through specific receptors in the afferent (mostly vagal) nerves and hypothalamic neurons implicated in adiposity signaling and regulation of food intake.

Adiposity↗
PubMed1998

Phenotypic consequences of a nonsense mutation in the leptin receptor gene (fak) in obese spontaneously hypertensive Koletsky rats (SHROB).

The genetically obese Koletsky rat (SHROB, fak) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentration was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.

Animals↗
PubMed2004

In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes.

A serious metabolic syndrome combining insulin-resistance, dyslipidemia, central adiposity, and peripheral lipoatrophy has arisen in HIV-infected patients receiving highly active antiretroviral therapy. The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism. When induced to differentiate in the presence of efavirenz (5-50 microm), 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol droplets. This phenomenon was rapidly reversible and was also readily detectable in the 3T3-L1 preadipose cell line and in primary cultures of human preadipocytes. When applied to mature 3T3-F442A adipocytes, efavirenz induced a delayed and moderate reduction in cell triglyceride content. Measurement of [(3)H]deoxyglucose uptake, basal and agonist-stimulated lipolysis, and cell viability indicated that these pathways are not involved in efavirenz effects on triacylglycerol accumulation. By contrast, we found that the NNRTI induced a dramatic dose- and time-dependent decrease in gene and protein expression of the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c). Adipose conversion was only altered at the highest efavirenz concentrations, as suggested by the mild reduction in peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein-alpha. CCAAT/enhancer-binding protein-beta remained unchanged. The inhibition of SREBP-1c expression was accompanied by a sharp reduction in the expression of SREBP-1c target genes and in the adipocyte lipogenic activity in efavirenz-treated cells. Finally, the inhibitory effect of efavirenz on cell triglyceride accumulation was prevented by directly providing free fatty acids to the cells and was reversed by overexpression of a dominant positive form of SREBP-1c, reinforcing the implication of this transcription factor in the antilipogenic effect of the drug. When considered together, these results demonstrate for the first time that the NNRTI efavirenz induces a strong inhibition of the SREBP-1c-dependent lipogenic pathway that might contribute to adipose tissue atrophy.

3T3 Cells↗
PubMed2003

Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution.

BACKGROUND: Fatty acid concentrations are increased in patients with HIV and fat redistribution and may contribute to insulin resistance in this population. OBJECTIVE: We determined the effects of acute inhibition of lipolysis on insulin sensitivity in HIV-infected patients with fat redistribution who were receiving a protease inhibitor. DESIGN: Seven HIV-infected men [age: 45 +/- 2 y; body mass index (in kg/m(2)): 28.8 +/- 1.9] with a fasting insulin concentration > or= 104 pmol/L (15 micro IU/mL), combined visceral adiposity and peripheral lipoatrophy, and receiving a protease inhibitor were studied. Tolbutamide-modified frequently sampled intravenous-glucose-tolerance tests (FSIGTTs) were performed after randomized double-blind administration of acipimox (500 mg at -90 and 0 min), a potent inhibitor of lipolysis, and placebo. The subjects completed 2 FSIGTTs separated by 3-7 d. RESULTS: At baseline, fasting insulin and fatty acid concentrations were 27.6 +/- 5.0 micro IU/mL and 0.83 +/- 0.08 mmol/L (normal range: 0.1-0.6 mmol/L), respectively. Fatty acid concentrations were significantly reduced after acipimox compared with placebo (fatty acid area under the curve: acipimox = 73 +/- 8 compared with placebo = 122 +/- 12 mmol x 270 min/L, P = 0.002). Acipimox treatment resulted in a significant increase in the insulin sensitivity index (acipimox = 1.63 +/- 0.5 compared with placebo = 0.88 +/- 0.3 x 10(-4) x min(-1) x micro IU/mL, P = 0.015). CONCLUSIONS: Acute inhibition of lipolysis and reduction in fatty acid concentrations are associated with improved insulin sensitivity in patients with HIV lipodystrophy and hyperinsulinemia. Further studies are needed to determine whether long-term antilipolytic strategies to reduce fatty acid concentrations may be useful in treating the metabolic disturbances associated with HIV lipodystrophy.

Adipose Tissue↗
PubMed2004

Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations.

Mutations in LMNA, the gene that encodes nuclear lamins A and C, cause up to eight different diseases collectively referred to as "laminopathies." These diseases affect striated muscle, adipose tissue, peripheral nerve, and bone, or cause features of premature aging. We investigated the consequences of LMNA mutations on nuclear architecture in skin fibroblasts from 13 patients with different laminopathies. Western-blotting showed that none of the mutations examined led to a decrease in cellular levels of lamin A or C. Regardless of the disease, we observed honeycomb nuclear structures and nuclear envelope blebs in cells examined by immunofluorescence microscopy. Concentrated foci of lamin A/C in the nucleoplasm were also observed. Only mutations in the head and tail domains of lamins A and C significantly altered the nuclear architecture of patient fibroblasts. These results confirm that mutations in lamins A and C may lead to a weakening of a structural support network in the nuclear envelope in fibroblasts and that nuclear architecture changes depend upon the location of the mutation in different domains of lamin A/C.

Adolescent↗
PubMed1993

Striatal implants of fetal striatum or gelfoam protect against quinolinic acid lesions of the striatum.

Previous studies in our laboratory have shown that intrastriatal implants of fetal striatum significantly attenuate excitotoxic damage resulting from a 240 nmol quinolinic acid (QA) challenge delivered 7 days later. In contrast, animals with intrastriatal implants of other tissue types (adipose tissue, peripheral nerve or adrenal medulla) demonstrate a more limited, but consistent trend in protection from QA excitotoxicity. The present study was designed to test the hypothesis that partial striatal protection found in animals receiving peripheral tissue grafts is due to the transplantation procedure eliciting a host response which attenuates excitotoxicity. Adult female Long-Evans rats received either cellular (fetal striatum) or acellular (gelfoam) implants followed 1 week later by a unilateral injection of 240 nmol QA into the grafted striatum. Animals were tested for rotational asymmetries before grafting, post-implantation, and after lesioning. Compared to baseline rotational behavior, rats which received implants did not show changes in ipsilateral turning after QA lesions. This protective effect was not limited to rotational behavior since improvements in spontaneous locomotor activity were evident. In addition, the adipsia and aphagia often associated with striatal lesions were ameliorated in both groups of grafted animals. Morphometric analysis demonstrated that endogenous dopaminergic, cholinergic and enkephalinergic systems in the two transplanted groups sustained less excitotoxic damage than in the QA lesioned, non-grafted animals. These results are consistent with the hypothesis that a host generated response activated by the implantation procedure provides a protective effect against QA excitotoxicity.

Animals↗
PubMed1998

Suprasellar osteolipoma: case report.

BACKGROUND: Osteolipomas are distinguished from other intracranial lipomas by their arrangement of central adipose and peripheral osseous tissues and by characteristically arising in the suprasellar/interpeduncular region. METHODS: We report computed tomography (CT), magnetic resonance imaging (MRI), and pathology findings from this 34-year-old man who underwent surgical removal of this benign lesion. RESULTS: This case displays the distinctive histopathology that has been reported in 13 of 31 (42%) lipomas in this region. In contrast, ossification of lipomas at other intracranial sites is relatively rare. CONCLUSIONS: Ossification should be expected in many suprasellar/interpeduncular lipomas, and osteolipoma should be included in the radiologic differential diagnosis of fat-intensity masses with calcification in this region.

Adult↗
PubMed2003

Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer.

The natural history of breast cancer is closely linked with estrogens. These hormones influence both risk to the disease and growth of many established tumors. Consequently, measures that either inhibit the synthesis or block the mechanism of action of estrogens are attractive strategies for therapeutic intervention. This is particularly true in postmenopausal women in whom hormone responsiveness is common and estrogen synthesis is primarily sited peripherally in adipose tissue, muscle and breast tissue, rather than in the ovaries as in premenopausal women. In terms of inhibiting production, the most specific effects are best achieved by blocking the last step in biosynthesis, the conversion of androgens to estrogens by the heme-containing enzyme, aromatase. Two major classes of aromatase inhibitors have been developed and are currently in clinical use. Type I steroidal drugs include formestane and exemestane; they are androgen substrate analogues that bind competitively but irreversibly to the enzyme and have been marketed as "inactivators." Type II nonsteroidal inhibitors such as anastrozole and letrozole are triazoles; they bind reversibly to the enzyme and fit into the substrate binding site, such that azole nitrogens interact with the heme prosthetic group. This type of association provides exquisite potency for and specificity against the aromatase enzyme. These agents represent several generations of development, with each step in the evolution producing an increase in both potency and specificity. The latest aromatase inhibitors are drugs of immense potential that will undoubtedly play a major role in the management of postmenopausal women with hormone-dependent breast cancer. They also represent tools by which to elucidate the roles of both aromatase and estrogen in the development and growth of breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed1991

Benign mesenchymoma of the tongue. Report of a case, with review of the literature.

A benign mesenchymoma of the dorsal midtongue in an 88-year-old woman is presented. The tumour was excised under local anaesthesia, and microscopic examination revealed cartilage, bone, striated muscle, peripheral nerve, adipose and myxoid tissue, and blood vessels in addition to fibrous tissue. Eight cases including ours were found in the literature.

Aged↗
PubMed2005

The endocannabinoid system: a new approach to control cardiovascular disease.

The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors--cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)--and their natural ligands. The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism. When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance. Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome. Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease. Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.

Appetite Regulation↗