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PubMed2003

Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in agouti yellow (Ay/a) obese mice.

To examine the peripheral and central roles of adiponectin in energy intake and expenditure, we investigated the effects of adiponectin on food intake, adiposity, sympathetic nerve activity (SNA), and mRNA expressions of uncoupling protein (UCP) in the brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in agouti yellow (A(y)/a) obese mice. Intraperitoneal administration of adiponectin (1.5 mg/kg for 7 days) attenuated body weight gain and reduced visceral adiposity in A(y)/a obese mice compared with PBS-treated controls. In addition, adiponectin treatment increased the expression of UCP1 mRNA in BAT, UCP2 mRNA in WAT, and UCP3 mRNA in skeletal muscle compared with PBS-treated A(y)/a controls. Acute peripheral administration of adiponectin (1.5 mg/kg, one injection) also increased SNA in the BAT accompanied by an increase in rectal temperature. Finally, these above responses as well as expression of c-Fos-like immunohistochemistry in the hypothalamus were not induced by central application of adiponectin (0-15 micro g/kg). Taken together, adiponectin effectively regulated visceral adiposity, SNA, and UCP mRNA expression peripherally, suggesting that this substance can be used as a therapeutic tool, administered peripherally, in the treatment of visceral obesity and related metabolic disorders.

Adiponectin↗
PubMed2005

Functional studies of mesenchymal stem cells derived from adult human adipose tissue.

Recent evidence suggests that cells with the properties of human mesenchymal stem cells (hMSCs) can be derived from adult peripheral tissues, including adipose tissue, muscle and dermis. We isolated hMSCs from the stromal-vascular portion of subcutaneous adipose tissue from seven adult subjects. These cells could be readily differentiated into cells of the chondrocyte, osteocyte and adipocyte lineage demonstrating their multipotency. We studied the functional properties of hMSCs-derived adipocytes and compared them with adipocytes differentiated from hMSCs obtained from bone marrow (BM-hMSC). The two cell types displayed similar lipolytic capacity upon stimulation with catecholamines, including a pronounced antilipolytic effect mediated through alpha2A-adrenoceptors, a typical trait in human but not rodent fat cells. Furthermore, both cell types secreted the fat cell-specific factors leptin and adiponectin in comparable amounts per time unit. The fat tissue-derived hMSCs retained their differentiation capacity up to at least fifteen passages. We conclude that hMSCs derived from adult human adipose tissue can be differentiated into fully functional adipocytes with a similar, if not identical, phenotype as that observed in cells derived from BM-hMSCs. Human adipose-tissue-derived MSCs could therefore constitute an efficient and easily obtainable renewable cellular source for studies of adipocyte biology.

Adipocytes↗
PubMed2006

Peripheral metabolic responses to prolonged weight reduction that promote rapid, efficient regain in obesity-prone rats.

Weight regain after weight loss is the most significant impediment to long-term weight reduction. We have developed a rodent paradigm that models the process of regain after weight loss, and we have employed both prospective and cross-sectional analyses to characterize the compensatory adaptations to weight reduction that may contribute to the propensity to regain lost weight. Obese rats were fed an energy-restricted (50-60% kcal) low-fat diet that reduced body weight by 14%. This reduced weight was maintained for up to 16 wk with limited provisions of the low-fat diet. Intake restriction was then removed, and the rats were followed for 56 days as they relapsed to the obese state. Prolonged weight reduction was accompanied by 1) a persistent energy gap resulting from an increased drive to eat and a reduced expenditure of energy, 2) a higher caloric efficiency of regain that may be linked with suppressed lipid utilization early in the relapse process, 3) preferential lipid accumulation in adipose tissue accompanied by adipocyte hyperplasia, and 4) humoral adiposity signals that underestimate the level of peripheral adiposity and likely influence the neural pathways controlling energy balance. Taken together, long-term weight reduction in this rodent paradigm is accompanied by a number of interrelated compensatory adjustments in the periphery that work together to promote rapid and efficient weight regain. These metabolic adjustments to weight reduction are discussed in the context of a homeostatic feedback system that controls body weight.

Adipose Tissue↗
PubMed1997

Direct effects of leptin on brown and white adipose tissue.

Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue.

Adipocytes↗
PubMedDate not supplied

Complete protein sequence and identification of structural domains of human apolipoprotein B.

Epidemiological, pathological and genetic studies show a strong positive correlation between elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol and the risk of premature coronary heart disease. Apolipoprotein (apo) B-100 is the sole protein component of LDL and is the ligand responsible for the receptor-mediated uptake and clearance of LDL from the circulation. Apo B-100 is made by the liver and is essential for the assembly of triglyceride-rich very low-density lipoproteins (VLDL) in the cisternae of the endoplasmic reticulum and for their secretion into the plasma. VLDL transports triglyceride to peripheral muscle and adipose tissue, where the triglyceride is hydrolysed by lipoprotein lipase. The resultant particle, relatively enriched in cholesteryl ester, constitutes LDL. LDL delivers cholesterol to peripheral tissues where it is used for membrane and steroid hormone biosynthesis and to the liver, the only organ which can catabolize and excrete cholesterol. Plasma LDL levels are therefore determined by the balance between their rate of production from VLDL and clearance by the hepatic LDL (apo B/E) receptor pathway. Here we report the complete 4,563-amino-acid sequence of apo B-100 precursor (relative molecular mass (Mr) 514,000 (514K] determined from complementary DNA clones. Numerous lipid-binding structures are distributed throughout the extraordinary length of apo B-100 and must underlie its special functions as a nucleus for lipoprotein assembly and maintenance of plasma lipoprotein integrity. A domain enriched in basic amino-acid residues has been identified as important for the cellular uptake of cholesterol by the LDL receptor pathway.

Amino Acid Sequence↗
PubMed2000

Insulin attenuates the stimulatory effects of tumor necrosis factor alpha on 11beta-hydroxysteroid dehydrogenase 1 in human adipose stromal cells.

Obesity is frequently associated with insulin-resistance and abnormal glucose homeostasis. Recent evidence indicates that TNFalpha may play a role in mediating the insulin-resistance of obesity through its overexpression in adipose tissue. Previously, we have shown that human adipose stromal cells contain 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity. The present study was designed to examine the effects of insulin on 11beta-HSD1 expression in human adipose stromal cells under basal and TNFalpha-stimulated conditions. The cells were obtained from breast adipose tissue by collagenase digestion, and grown to confluence under replicating conditions in 10% fetal bovine serum. The cells were transferred to serum-free medium for 24 h prior to treatment with either TNFalpha, insulin or both for a further 24 h. The level of 11beta-HSD1 reductase activity was determined by measuring the conversion of [(3)H]-cortisone to [(3)H]-cortisol at a substrate concentration of 10 nM. Treatment with TNFalpha at concentrations of 0.1-10 ng/ml resulted in a dose dependent increase in 11beta-HSD1 reductase activity from 1.5 to 10-fold. Insulin (0.1-100 nM) had no effect under basal conditions, but inhibited the stimulatory effects of TNFalpha (5 ng/ml) on 11beta-HSD1 reductase activity in a dose dependent fashion (8-66%) inhibition). Northern blot analysis revealed corresponding changes in the level of 11beta-HSD1 mRNA, suggesting that the effects of TNFalpha and insulin on 11beta-HSD1 activity are mediated at the level of gene transcription. The interaction between insulin and TNFalpha suggests that local and systemic factors may act in a concerted fashion to modulate glucocorticoid activity in adipose and other peripheral tissues.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Leptin concentrations in maternal serum and amniotic fluid during the second trimenon: differential relation to fetal gender and maternal morphometry.

Leptin, a hormone produced by adipocytes, provides information on the availability of fat stores to the hypothalamus and acts as an afferent satiety signal regulating appetite and energy expenditure in both rodents and humans [Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425-432; Sinha MK. Human leptin: the hormone of adipose tissue. Eur J Endocrinol 1997;136:461-4; Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse ob protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-9; Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-6; Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwern J. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995;377:527-9; Campfield LA, Smith FJ, Burn P. The OB protein (leptin) pathway - a link between adipose tissue mass and central neural networks. Horm Metab Res 1996;28:619-632; Blum WF, Kiess W, Rascher W, editors. Leptin - the voice of the adipose tissue. J&J Edition, JA Barth Verlag, Heidelberg, 1997]. In addition, leptin is thought to play an important role for reproduction and during gestation [Kiess W, Blum WF, Aubert ML. Leptin, puberty and reproductive function: lessons from animal studies and observations in humans. Eur J Endocrinol 1997;138:1-4; Barash IA, Cheung CC, Wigle DS, Ren H, Kabitting EB, Kuijer JL, Clifton DK, Steiner RA. Leptin is a metabolic signal to the reproductive system. Endocrinology 1996;133:3144-47; Chehab F, Lim M, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genetics 1996;12:318-20; Kiess W, Schubring C, Prohaska F, Englaro P, Rascher W, Attanasio A, Blum WF. Leptin in amniotic fluid at term and at midgestation. In: Blum WF, Kiess W, Rascher W, editors. Leptin - the voice of the adipose tissue. J&J Edition, JA Barth Verlag, Heidelberg, 1997]. The purpose of this study was to gain more insight into a putative role of leptin during midgestation. Therefore we have measured leptin concentrations in maternal serum and amniotic fluid using a specific radioimmunoassay (RIA) employing human recombinant leptin for tracer and standard preparation [Blum WF, Kiess W, Rascher W, editors, Leptin - The voice of the adipose tissue. J&J Edition, JA Barth Verlag, Heidelberg, 1997; Blum WF, Englaro P, Heiman M, Attanasio Am, Kiess W, Rascher W. Clinical studies of serum leptin. In: Blum WF, Kiess W, Rascher W. Leptin - The voice of the adipose tissue. J&J Edition, JA Barth Verlag, Heidelberg, 1997; Blum WF, Englaro P, Heiman M, Attanasio AM, Kiess W, Rascher W. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage and testosterone. J Clin Endocrinol Metab 1997;82:2904-2910]. In addition, estriol, hCG and alphafetoprotein were measured in maternal serum. (ABSTRACT TRUNCATED)

Adult↗
PubMed2001

Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide.

Gram-negative bacteria-derived lipopolysaccharide (LPS or endotoxin) is known to play an important role in immune and neurological manifestations during bacterial infections. LPS exerts its effects through cytokines, and peripheral or brain administration of LPS activates cytokine production in the brain. In this study, we investigated cytokine and neuropeptide mRNA profiles in specific brain regions and peripheral organs, as well as serum tumor necrosis factor (TNF)-alpha protein levels, in response to the intraperitoneal administration of LPS. For the first time, the simultaneous analysis of interleukin (IL)-1beta system components (ligand, signaling receptor, receptor accessory proteins, receptor antagonist), TNF-alpha, transforming growth factor (TGF)-beta1, glycoprotein 130 (IL-6 receptor signal transducer), OB protein (leptin) receptor, neuropeptide Y, and pro-opiomelanocortin (opioid peptide precursor) mRNAs was done in samples from specific brain regions in response to peripherally administered LPS. The same brain region/organ sample was assayed for all cytokine mRNA components. Peripherally administered LPS up-regulated pro-inflammatory cytokine (IL-1beta and/or TNF-alpha) mRNAs within the cerebral cortex, cerebellum, hippocampus, spleen, liver, and adipose tissue. LPS also increased plasma levels of TNF-alpha protein. LPS did not up-regulate inhibitory (anti-inflammatory) cytokine (IL-1 receptor antagonist and TGF-beta1) mRNAs in most brain regions (except for IL-1 receptor antagonist in the cerebral cortex and for TGF-beta1 in the hippocampus), while they were increased in the liver, and IL-1 receptor antagonist was up-regulated in the spleen and adipose tissue. Overall, peripherally administered LPS modulated the levels of IL-1beta system components within the brain and periphery, but did not affect the neuropeptide-related components studied. The data suggest specificity of transcriptional changes induced by LPS and that cytokine component up-regulation in specific brain regions is relevant to the neurological and neuropsychiatric manifestations associated with peripheral LPS challenge.

Activin Receptors, Type I↗
PubMed2001

Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy.

OBJECTIVE: To determine whether the peripheral fat wasting (lipodystrophy), which is seen in association with highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI), is associated with a decrease in subcutaneous adipose tissue mitochondrial DNA (mtDNA) content or with large mtDNA deletions or insertions. DESIGN: A four cohort cross-sectional study. METHODS: The mtDNA content of subcutaneous fat tissue from the neck, abdomen and thigh was determined by polymerase chain reaction utilizing the amplification of three different mtDNA fragments. The results from HIV-infected patients with peripheral fat wasting following more than 6 months of NRTI-containing HAART were compared with the results from three different control cohorts: HIV-infected patients with a similar treatment history without lipodystrophy; HIV-infected patients naive to antiretroviral therapy and HIV sero-negative participants. RESULTS: A decrease in mtDNA content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts. No large mitochondrial deletions or insertions were found. CONCLUSIONS: Lipodystrophy with peripheral fat wasting following treatment with NRTI-containing HAART is associated with a decrease in subcutaneous adipose tissue mtDNA content.

Adipose Tissue↗
PubMed2005

Possible role of triacylglycerol-rich lipoproteins in the down-regulation of adipose obese mRNA expression in rats re-fed a high-fat diet.

The large amount of absorbed dietary lipid after feeding a high-fat diet is mainly transported as triacylglycerol (TG)-rich lipoproteins (TRL) in the post-prandial blood and is subsequently distributed to peripheral tissues including adipose and muscle tissues. An in vivo and an in vitro study were conducted to investigate the possible role of post-prandial TRL after high fat feeding in the regulation of obese (ob) gene expression. Adult male Wistar rats were fasted for 48 h and re-fed either a fat-free/high-carbohydrate diet or a high-fat diet for 2, 4, or 8 h and plasma glucose, insulin, TG, and leptin as well as ob mRNA expression in epididymal fat pads were examined. Rats re-fed the high-fat diet had significantly higher plasma TG (p < 0.05) and lower plasma leptin and adipose ob mRNA (p < 0.05) than those fed the fat-free/high-carbohydrate diet; however, plasma glucose and insulin concentrations were not significantly different between the two groups. Plasma lipid analysis found large amount of TRL in rats fed with high-fat diet; however, only very small amount of the TRL was found in rats fed with fat-free/high-carbohydrate diet. We speculated that TRL might involve in regulation of ob gene expression. To further examine the regulation of TRL on ob mRNA expression, differentiated 3T3-L1 adipocytes were treated with TRL collected from rats fed 5 ml soybean oil by gastric intubations. TRL down-regulated ob mRNA not only in a dose and time dependent manner but also in the presence of insulin in 3T3-L1 adipocytes. These results suggest a possible role of TRL in the down-regulation of adipose ob mRNA expression and may account, at least in part, for the previous observations that short-term high fat feeding resulted in lower plasma leptin.

3T3-L1 Cells↗
PubMed1997

Comparison of the direct and indirect effects of epinephrine on hepatic glucose production.

To determine the extent to which the effect of a physiologic increment in epinephrine (EPI) on glucose production (GP) arises indirectly from its action on peripheral tissues (muscle and adipose tissue), epinephrine was infused intraportally (EPI po) or peripherally (EPI pe) into 18-h-fasted conscious dogs maintained on a pancreatic clamp. Arterial EPI levels in EPI po and EPI pe groups rose from 97 +/- 29 to 107 +/- 37 and 42 +/- 12 to 1,064 +/- 144 pg/ml, respectively. Hepatic sinusoidal EPI levels in EPI po and EPI pe were indistinguishable (561 +/- 84 and 568 +/- 75 pg/ml, respectively). During peripheral epinephrine infusion, GP increased from 2.2 +/- 0.1 to 5.1 +/- 0.2 mg/kg x min (10 min). In the presence of the same rise in sinusoidal EPI, but with no rise in arterial EPI (during portal EPI infusion), GP increased from 2.1 +/- 0.1 to 3.8 +/- 0.6 mg/kg x min. Peripheral EPI infusion increased the maximal gluconeogenic rate from 0.7 +/- 0.4 to 1.8 +/- 0.5 mg/ kg x min. Portal EPI infusion did not change the maximal gluconeogenic rate. The estimated initial increase in glycogenolysis was approximately 1.7 and 2.3 mg/kg x min in the EPI pe and EPI po groups, respectively. Gluconeogenesis was responsible for 60% of the overall increase in glucose production stimulated by the increase in plasma epinephrine (EPI pe). Elevation of sinusoidal EPI per se had no direct gluconeogenic effect on the liver, thus its effect on glucose production was solely attributable to an increase in glycogenolysis. Lastly, the gluconeogenic effects of EPI markedly decreased (60-80%) its overall glycogenolytic action on the liver.

3-Hydroxybutyric Acid↗
PubMed1983

Hypolipidemia and peroxisome proliferation induced by phenoxyacetic acid herbicides in rats.

Male Wistar rats were treated daily by gavage with two phenoxy herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D)(100-200 mg/kg body wt) and 4-chloro-2-methylphenoxyacetic acid (MCPA) (100-200 mg/kg body wt), and with the chemically different glyphosate N-phosphonomethyl glycine (300 mg/kg body wt) 5 days per week for 2 weeks. A hypolipidemic drug, clofibrate [ethyl-2-(4-chlorophenoxy)-2-methylpropionate], which is structurally related to phenoxy acids, was used as a positive control (200 mg/kg body wt). 2,4-D and MCPA had several effects similar to those of clofibrate: all three compounds induced proliferation of hepatic peroxisomes, decreased serum lipid levels, and increased hepatic carnitine acetyltransferase and catalase activities. 2,4-D and MCPA, but not clofibrate, decreased lipoprotein lipase activity in the adipose tissue to about a third of the control value but did not change the lipoprotein lipase activity in the heart muscle. The data suggest that these compounds cause hypolipidemia not by enhancing the storage of peripheral lipids in adipose tissue but by preferentially increasing lipid utilization in the liver. Glyphosate caused no peroxisome proliferation or hypolipidemia, suggesting that these effects are associated with the structural similarity between phenoxy acid herbicides and clofibrate.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1977

[Endometrial cancer and extraglandular oestrogen biosynthesis (author's transl)].

An increasing incidence of endometrial cancer caused by a higher life expectancy and a number of other facters (i.e. obesity, diabetes, hypertension, lower pregnancy rate) as well as the unfavorable location for early detection when compared with cervical cancer has initiated this review in order to single out women with increased risk. Clinical characteristics of patients with endometrial cancer represented by age, menstrual disorders, reduced fertility, obesity, diabetes, hypertension, hirsutism, hyperplasia of the ovarian stroma or hilus cells in connection with an increased oestrogen effect in the vaginal smear and proliferative changes of the endometrium can be explained by extraglandular respectively peripheral aromatization of androgens to oestrogens, particular by the conversion of androstenedione to oestrone. This is supported by an increased plasma oestrone/oestradiol-ratio and increased conversion rate with age and overweight. In vivo- and in vitro-investigations have demonstrated the participation of adipose tissue in peripheral oestrogene production. The compiled data point towards the importance of the extraglandular oestrone production for the etiology of endometrial cancer by effecting the endometrium over a long period of time. The counter action of the normally cyclic changes of oestradiol and progesterone is lacking. Therefore, a dysoestrogenic effect of oestrone upon the endometrium can be fully effective, depending on the hormone receptor content of the respective endometrium. Based upon these data including recent publications, pre- and postmenopausal oestrogen therapy has to be critically reevaluated.

Adipose Tissue↗
PubMed1986

The role of behavioral variables and fat patterning in explaining ethnic differences in serum lipids and lipoproteins.

Mexican Americans have been previously reported to have greater adiposity, higher triglyceride levels, and lower high density lipoprotein (HDL) cholesterol levels than Anglos. This study investigated the relationship between behavioral variables (caloric balance, cigarette and alcohol consumption, exercise, postmenopausal estrogen or oral contraceptive use) and fat patterning (central vs. peripheral distribution of adiposity) in the San Antonio Heart Study (1979-1982) (n = 2,102) to explain the ethnic difference in lipids and lipoproteins. Adjustment for caloric balance (as reflected by body mass index) narrowed the ethnic difference in triglyceride and HDL levels for both sexes, while adjustment for smoking widened the ethnic difference. For females, the ethnic difference was also decreased by adjustment for alcohol and estrogen use. However, adjustment for these behavioral variables did not completely eliminate the ethnic difference in lipids and lipoproteins in either sex. Increased central adiposity, more characteristic of Mexican Americans than Anglos, was positively associated with triglycerides and negatively associated with HDL levels, especially in females. Fat patterning made a more important contribution to the prediction of triglyceride and HDL levels than did the other behavioral variables (except for caloric balance) and, in general, eliminated ethnic differences in lipids and lipoproteins. Epidemiologists should consider the use of a centrality index to distinguish different types of adiposity since it is easy and inexpensive to measure.

Adipose Tissue↗
PubMed2005

Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy.

BACKGROUND: NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion. Determinants of cellular mtDNA copy number from HIV-infected patients receiving HAART and HIV-seronegative controls were investigated from subcutaneous fat samples, and relation with antiretroviral regimen was studied. STUDY DESIGN: HIV-infected patients receiving HAART (n = 50), HIV-infected patients not currently under HAART regimen (n = 2) and HIV-seronegative controls (n = 9) of similar age and BMI were enrolled prospectively when undergoing Coleman's lipostructure for correction of facial lipoatrophy or plastic surgery, respectively. After centrifugation, abdominal fat tissue was collected and stored at -80 degrees C. MtDNA analysis was blindly performed after a total DNA extraction from adipose tissue, followed by a real-time PCR quantification. The log of mtDNA copies/cell in adipose tissue [log(DNA)] was compared between groups by means of analysis of variance. RESULTS: The log(DNA) in adipose tissue of HIV-infected patients was significantly lower than in the HIV-seronegative control group (P < 0.0001). In HIV-infected patients, log(DNA) was significantly reduced in the 50 NRTI-treated patients (P < 0.01), but not when considering mtDNA level according to the use of PI or NNRTI in current HAART regimen. In NRTI-treated patients, only stavudine (n = 20) and didanosine (n=14) were significantly and independently associated with reduced mtDNA level (P < 0.0001 and <0.05, respectively). Currently stavudine or didanosine-treated patients had a significant reduced mtDNA level compared to past users (P < 0.0001 and <0.05, respectively). Other clinical, biological, and immuno-virological variables than NRTI did not correlate significantly to adipocyte mtDNA level. CONCLUSION: This study supports that current treatment by NRTI is a main determinant of mtDNA depletion in adipose tissue of HIV-seropositive patients with peripheral fat wasting. Stavudine or didanosine current intake is significantly associated with mtDNA depletion in vivo, that could be reversible after the discontinuation of these molecules, when considering mtDNA level according to current use versus past use of these molecules.

Adipose Tissue↗
PubMed2002

Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity.

Cushing's syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11beta-HSD1 activity in women with moderate obesity and insulin resistance. Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11beta-HSD type 1 activity in vitro. Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5alpha- and, to a lesser extent, 5beta-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11beta-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 +/- 28,528, 115,903 +/- 26,032, and 90,460 +/- 18,590 nmol/liter.min; P < 0.001). However, 11beta-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05). In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2002

The effects of peroxisome proliferators on global lipid homeostasis and the possible significance of these effects to other responses to these xenobiotics: an hypothesis.

Peroxisome proliferators (PPs) have been shown to regulate hepatic lipid metabolism via activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). Recent studies have revealed that PPs also exert considerable influence on certain extrahepatic tissues, including adipose tissue and lymphoid organs, in an indirect fashion. Inhibition of the proliferation of thymocytes and splenocytes and alteration of fatty acid uptake into and release from adipose tissue might be consequences of the hypolipidemic effect of PPs involving both PPARalpha-dependent and -independent pathways. Exposure to PPs reduces the cholesterol content of circulating low-density lipoprotein (LDL), which is the major supply of this steroid to most peripheral tissues. In addition, PPs increase serum levels of high-density lipoprotein (HDL), which extracts cholesterol from peripheral tissues and returns it to the liver, thereby further decreasing the cholesterol content of peripheral tissues. This net flux of cholesterol from extrahepatic tissues to the liver represents a change in global lipid homeostasis. In normal healthy young mice, this hypolipidemic effect could result in loss of cholesterol and other lipids from peripheral tissues (e.g., adipose tissue, thymus, and spleen), especially from plasma membrane caveolae, which might perturb normal cellular signaling and result in tissue atrophy. On the other hand, the increased hepatic cholesterol content in the hepatocyte plasma membrane might actually enhance signaling, playing a role in the liver hypertrophy and hepatocarcinogenecally associated with long-term PP treatment. In conclusion, it is important to consider the systemic effects of PPs, rather than to focus on the liver alone.

Adipose Tissue↗
PubMed2005

Hormonal regulation of food intake.

Our knowledge of the physiological systems controlling energy homeostasis has increased dramatically over the last decade. The roles of peripheral signals from adipose tissue, pancreas, and the gastrointestinal tract reflecting short- and long-term nutritional status are now being described. Such signals influence central circuits in the hypothalamus, brain stem, and limbic system to modulate neuropeptide release and hence food intake and energy expenditure. This review discusses the peripheral hormones and central neuronal pathways that contribute to control of appetite.

Animals↗