Gene Expression In Subcutaneous Fat Research Articles

Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice.

Irisin is an exercise-induced myokine, suggested to exert beneficial effects on metabolism. However, the studies on the regulation of irisin secretion and the expression of its precursor FNDC5 have shown conflicting data. The discrepancies among previous correlation studies in humans are related to the heterogeneity of the study population. The fact that irisin is not only a myokine but also an adipokine leads to the further complexity of the role of irisin in metabolic regulation. In this study, we examined the regulation of FNDC5 expression and irisin in circulation in both type 1 and type 2 diabetic mice, and their potential relationships with metabolic parameters. In streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet (HFD)-induced obese mice and db/db mice, the circulating irisin as well as FNDC5 gene expression in subcutaneous fat was downregulated. Muscle FNDC5 expression was only significantly lower in STZ mice, and epididymal fat FNDC5 expression was unaltered. It is interesting to note that plasma irisin levels correlated positively with subcutaneous fat FNDC5 expression, but not epididymal fat or muscle. Moreover, both irisin levels and subcutaneous fat FNDC5 correlated negatively with markers of insulin resistance. These results suggest a regulatory role for subcutaneous fat-derived FNDC5/irisin in metabolic disease.

Determinants of vitamin D receptor gene expression in visceral and subcutaneous adipose tissue in non-obese, obese, and morbidly obese subjects

We aimed to illustrate determinants of VDR gene expression in visceral and subcutaneous adipose tissue among individuals without diabetes. We gathered visceral and subcutaneous adipose tissues during an elective abdominal surgery form 33 morbidly obese (BMI > 40 kg/m2), 23 obese (BMI = 30–40 kg/m2), and 35 non-obese (BMI<30 kg/m2) participants who were free of diabetes. Participants were classified according to their degree of obesity. Before the surgery, habitual dietary intake, physical activity, 25(OH)D, body mass index (BMI), waist circumference (WC), and HOMA-IR was gathered. Non-obese participants had significantly lower mean VDR gene expression in visceral adipose tissues than both the obese and morbidly obese ones and had also lower expression in subcutaneous adipose tissues than the morbidly obese participants. In multiple linear regression models, BMI and HOMA-IR were the independent positive predictors of VDR gene expression in subcutaneous fat. Among non-obese subjects, WC and 25(OH)D were the positive and negative independent predictors of visceral adipose tissue VDR gene expression, respectively. Among obese participants, 25(OH)D was negatively, and BMI and HOMA-IR were positively associated with VDR mRNA levels in visceral adipose tissue. In morbidly obese participants, the independent positive predictors of VDR gene expression in visceral fat were BMI and HOMA-IR, and negative predictors were 25(OH)D and calcium intake. Our findings suggested that 25(OH)D concentrations are the fundamental elements to determine VDR gene expression in visceral fat which by increasing fat depots, the subsequent insulin resistance became another predictor of VDR gene expression.

Genome-wide expression profiling in muscle and subcutaneous fat of lambs in response to the intake of concentrate supplemented with vitamin E

BackgroundThe objective of this study was to acquire a broader, more comprehensive picture of the transcriptional changes in the L. Thoracis muscle (LT) and subcutaneous fat (SF) of lambs supplemented with vitamin E. Furthermore, we aimed to identify novel genes involved in the metabolism of vitamin E that might also be involved in meat quality. In the first treatment, seven lambs were fed a basal concentrate from weaning to slaughter (CON). In the second treatment, seven lambs received basal concentrate from weaning to 4.71 ± 2.62 days and thereafter concentrate supplemented with 500 mg dl-α-tocopheryl acetate/kg (VE) during the last 33.28 ± 1.07 days before slaughter.ResultsThe addition of vitamin E to the diet increased the α-tocopherol muscle content and drastically diminished the lipid oxidation of meat. Gene expression profiles for treatments VE and CON were clearly separated from each other in the LT and SF. Vitamin E supplementation had a dramatic effect on subcutaneous fat gene expression, showing general up-regulation of significant genes, compared to CON treatment. In LT, vitamin E supplementation caused down-regulation of genes related to intracellular signaling cascade. Functional analysis of SF showed that vitamin E supplementation caused up-regulation of the lipid biosynthesis process, cholesterol, and sterol and steroid biosynthesis, and it down-regulated genes related to the stress response.ConclusionsDifferent gene expression patterns were found between the SF and LT, suggesting tissue specific responses to vitamin E supplementation. Our study enabled us to identify novel genes and metabolic pathways related to vitamin E metabolism that might be implicated in meat quality. Further exploration of these genes and vitamin E could lead to a better understanding of how vitamin E affects the oxidative process that occurs in manufactured meat products.

Circulating cortisol‐associated signature of glucocorticoid‐related gene expression in subcutaneous fat of obese subjects

Serum cortisol concentrations fluctuate in a circadian fashion, and glucocorticoids exert strong effects on adipose tissue and induce obesity through the glucocorticoid receptor. To examine the impact of physiologic levels of circulating cortisol on subcutaneous adipose tissue, 25 overweight and obese subjects were employed, and their serum levels of morning (AM) and evening (PM) cortisol, AM/PM cortisol ratios, and 24-h urinary-free cortisol (UFC) were compared with their clinical parameters, serum cytokine levels, and mRNA expression of 93 receptor action-regulating and 93 glucocorticoid-responsive genes in abdominal subcutaneous fat. AM cortisol levels did not correlate with mRNA expression of the all genes examined, whereas PM cortisol levels, AM/PM cortisol ratios, and 24-h UFC were associated with distinct sets of these genes. Body mass index did not significantly correlate with the four cortisol parameters employed. These results suggest that physiologic levels of AM serum cortisol do not solely represent biological effects of circulating cortisol on the expression of glucocorticoid-related genes in subcutaneous adipose tissue, whereas PM levels, amplitude, and net amounts of the diurnally fluctuating serum cortisol have distinct effects. Through the genes identified in this study, glucocorticoids appear to influence intermediary metabolism, energy balance, inflammation, and local circadian rythmicity in subcutaneous fat. Our results may also explain in part the development of metabolic abnormality and obesity in subjects under stress or patients with melancholic/atypical depression who demonstrate elevated levels of PM serum cortisol.

Increased levels and adipose tissue expression of visfatin in morbidly obese women: the relationship with pro‐inflammatory cytokines

The controversial results on the physiopathological role of visfatin led us to examine both circulating visfatin levels and gene expression in visceral (VAT) and subcutaneous fat (SAT) in a homogeneous group of morbidly obese women. We analysed circulating levels of several adipo/cytokines in 133 Spanish women: 40 lean (C) [body mass index (BMI) < 25 kg/m(2) ] and 93 morbidly obese (MO) (BMI > 40 kg/m(2) ). In the MO group, we found 31 diabetic and 62 nondiabetic subjects. We obtained follow-up blood samples at 6 and 12 months after bariatric surgery from 30 MO patients. We determined the circulating levels of visfatin, adiponectin, interleukin-6 (IL6), C-reactive protein (CRP), resistin and tumour necrosis factor-α (TNFα) by ELISA, and visfatin, adiponectin, IL6, resistin and TNFα gene expression in SAT and VAT by real-time RT-PCR. Circulating visfatin levels were higher in MO women compared with lean controls (C = 1·43 ± 0·14 μg/l, MO = 3·60 ± 0·29 μg/l, P < 0·001). After bariatric surgery-induced weight loss, visfatin levels were reduced significantly over 12 months. Visfatin expression in SAT and VAT was similar, but significantly higher in MO compared to C and independent of the presence of diabetes mellitus. Circulating visfatin levels were positively related to IL6 and CRP levels. Visfatin gene expression in VAT and SAT was strongly related to IL6 and TNFα expression. In a homogeneous cohort of morbidly obese women, our findings show that visfatin has a strong relationship with pro-inflammatory factors in severe obesity.

CYP19 gene expression in subcutaneous adipose tissue is associated with blood pressure in women with polycystic ovary syndrome

In polycystic ovary syndrome (PCOS), hypertension has been linked to androgen excess and insulin resistance. Aromatase, an enzyme encoded by the CYP19 gene, affects androgen metabolism and estrogen synthesis, influencing the androgen to estrogen balance. We characterized CYP19 gene expression in subcutaneous adipose tissue of women with PCOS and normal controls and evaluated the association between subcutaneous fat CYP19 mRNA, circulating hormone levels, and blood pressure. This case–control study was carried out with 31 PCOS patients and 27 BMI-matched normotensive non-hirsute women with regular cycles. Participants underwent anthropometric measurements, collection of blood samples, and adipose tissue biopsy (28 PCOS and 19 controls). Hypertension was defined as systolic blood pressure⩾130mmHg and/or diastolic blood pressure⩾85mmHg. PCOS patients were divided into normotensive and hypertensive. Main outcome measures were serum estrogen and androgen levels, estrogen-to-androgen ratio, and CYP19 gene expression in subcutaneous fat. Subcutaneous CYP19 mRNA was higher in hypertensive PCOS than in control and normotensive PCOS women (p=0.014). Estrogen-to-androgen ratio was lower in hypertensive PCOS than controls (p<0.003). Estrogen-to-androgen ratio⩽0.06 (median for the three groups) was observed in 91% of hypertensive PCOS women, vs. 37% and 61% in the control and normotensive PCOS groups (p=0.011). CYP19 gene expression in subcutaneous fat of PCOS patient correlated positively with systolic (p=0.006) and diastolic blood pressure (p=0.009). Androgen excess and hyperinsulinemia may play a role in the molecular mechanisms that activate aromatase mRNA transcription in abdominal fat tissue.

Abdominal subcutaneous fat gene expression and circulating levels of leptin and adiponectin in polycystic ovary syndrome

To determine leptin and adiponectin serum levels and gene expression in subcutaneous adipose tissue from women with polycystic ovary syndrome (PCOS) and nonhirsute, ovulatory women; and leptin/adiponectin (L/A) ratio. Case-control study. University hospital gynecologic endocrinology unit. Thirty-one women with PCOS and 57 controls. Anthropometric, hormonal, and metabolic assessment; subcutaneous adipose tissue biopsy. Leptin and adiponectin serum levels, L/A ratio, controlled by age, and gene expression in women with PCOS and controls, stratified by body mass index and variables associated with androgen excess and insulin resistance. Serum leptin was higher in overweight/obese patients with PCOS than in all normal-weight control women. Adiponectin levels were similar in all subgroups. The L/A ratio was lower in normal-weight controls (1.80; range 0.94-3.72) than in overweight/obese controls (5.27; range 2.66-13.58) and patients with PCOS (7.73; range 3.81-15.04). Subcutaneous leptin messenger RNA was higher in overweight/obese women with PCOS than in normal-weight controls (2.316 [range 1.987-2.580] vs. 1.687 [range 1.518-2.212]). Adiponectin gene expression was similar in all groups. Positive correlations were found between serum and messenger RNA levels for both leptin and adiponectin. On multiple regression analysis, percentage of body fat contributed significantly to L/A ratio in PCOS, independently of body mass index and free androgen index. In PCOS, altered adipocyte secretion seems to relate to adiposity rather than to androgen excess.

Tissue-Specific Increases in 11β-Hydroxysteroid Dehydrogenase Type 1 in Normal Weight Postmenopausal Women

With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11βHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11βHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11βHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5α-tetrahydrocortisol+5β-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11βHSD1 activity. Postmenopausal women had higher 11βHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11βHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11βHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.

6653 Exploratory study of the subcutaneous fat gene expression profile in patients with metastatic pancreatic carcinoma treated with standard gemcitabine chemotherapy regimen

6653 Exploratory study of the subcutaneous fat gene expression profile in patients with metastatic pancreatic carcinoma treated with standard gemcitabine chemotherapy regimen

Effects of exercise training on subcutaneous and visceral adipose tissue in normal- and high-fat diet-fed rats

Regular physical activity improves glucose tolerance and decreases adiposity. Our aim was to investigate the effects of exercise training on subcutaneous (inguinal) and visceral (parametrial) adipose tissue in rats that were fed a chow diet (13% fat) or made insulin resistant by a high-fat diet (60% fat). Sprague-Dawley rats performed 4 wk of voluntary wheel running or were kept as sedentary controls. The training groups fed chow and the high-fat diet achieved similar running distances (8.8 +/- 1.8 and 9.3 +/- 1.9 km/day, respectively). Training improved oral glucose tolerance in chow-fed rats and prevented the glucose intolerance that occurred in sedentary rats fed the high-fat diet. In both subcutaneous and visceral adipose tissue, the high-fat diet-induced increases in fat pad weight (67% and 133%, respectively), adipocyte size (20% and 43%), and cell number (36% and 65%) were completely prevented by exercise training. Cytokine mRNA expression in visceral fat did not change with exercise training. However, in subcutaneous fat, training actually increased mRNA expression of several cytokines [IL-6: 80% (P < 0.05); TNF-alpha: 100% (P < 0.05); IL-1 receptor antagonist (IL-1Ra): 57% (P = 0.08)] with no detectable increases in serum cytokine concentrations. In summary, exercise training can overcome high-fat diet-induced impairments in glucose tolerance and increases in adipocyte size, cell number, and fat pad mass. Improved glucose tolerance was accompanied by an increase in cytokine gene expression in subcutaneous fat. This finding raises the possibility of a specific role of subcutaneous adipose tissue in adaptive responses to exercise training.

Exploratory study of the subcutaneous fat gene expression profile in patients with metastatic pancreatic carcinoma treated with standard gemcitabine chemotherapy regimen

e22220 Background: Most clinical trials are designed to assess the antitumor effect of the chemoterapeutic intervention. There are few examples where the endpoint is to assess the biology of the host response to the treatment of the tumor. A large number of patients with pancreatic cancer present features of the cachexia syndrome and specially a marked weight loss. It has been postulated that a “cytokine storm” is the cause of the profound effect that this cancer has on distant tissues. This trial analyzed changes in the subcutaneous fat gene expression profile in relation with the clinical benefit variable with standard gemcitabine (G) treatment. Methods: Patients with histology confirmed advanced pancreatic cancer, adequate organ function and written informed consent. Eligible pts were intended for a subcutaneous fat biopsy pretreatment and after 7 weeks of gemcitabine 1000 mg/m2 together with response assessment. Clinical benefit (CB) (pain, analgesic consumption, Karnofsky and weight), QLQ-C30, serum cytokines and tumor markers were evaluated pretreatment, at 4 and 8 weeks. Fat gene expression profile was analyzed using Affimetrix U133Plus2.0 with the corresponding bioinformatic software. Serum cytokines where analyzed with xMAP technology with the Luminex 200 platform. Results: 16 pts [8 m, 8 f, median age 62 yrs (range 47–72)]. Median weight change -0.75 kg (range -4.5 to 2). Nine pts had pre and post treatment biopsies and 7 only pretreatment. Three pts achieved CB at 8 weeks. Objective responses: 0 CR, 0 PR, 31% SD and 68%PD. Toxicity was similar to the one reported in gemcitabine's label. It was possible to extract quality RNA for microarray from subcutaneous fat use from all samples but 1. The limited number of samples precluded to obtain genes clearly involved in cachexia, however the IL-8 expression (p0.03) was significantly correlated with CB response either to gene and serum profile. Conclusions: It is feasible to study prospectively the impact of cancer treatment on different tissue biomarkers and correlated with standard antitumor evaluation system. The reduced number of samples in this exploratory trial precludes producing significant biological conclusions. No significant financial relationships to disclose.

Putting your genes on a diet: the molecular effects of carbohydrate

Traditionally, food is thought to influence human health through its nutrient content, whereas drugs are recognized to act through molecular pathways. However, consumption of a meal stimulates the release of numerous hormones that can powerfully affect signal transduction and gene function. The article by Kallio et al (1) in this issue of the Journal highlights this possibility by demonstrating changes in gene expression in individuals consuming diets with different effects on postprandial insulin concentrations. The authors randomly assigned adults with features of the metabolic syndrome to a rye-pasta (low insulin response) or an oat-wheat-potato (high insulin response) diet for 12 wk. The diets were designed to be similar in energy, fiber, and macronutrient contents, although modest differences in fiber, carbohydrate, and protein contents were documented by food records. Gene expression in subcutaneous fat was evaluated at baseline and at 12 wk with microarrays and quantitative polymerase chain reaction. In individuals in the low-insulin-response group, 71 genes showed decreased expression and none showed increased expression. Of particular interest, several down-regulated genes have links to insulin-signaling pathways and apoptosis. In contrast, in individuals in the high-insulin-response group, 62 genes showed increased expression and none showed decreased expression. Prior microarray studies found differences in gene expression between overweight and lean individuals (2) and after energy restriction (3); however, changes in the ratio of fat to carbohydrate did not alter gene expression (3). The study by Kallio et al makes a significant contribution to the literature by demonstrating the potentially major effects of dietary composition on gene regulation, independent of energy intake and body weight. Two specific findings concerning the low-insulin-response diet merit particular attention: the down-regulation of both hormonesensitive lipase (HSL) and TCF7L2. HSL, a key enzyme in the release of fatty acids from adipose tissue, has been proposed to affect body weight and metabolic variables. Mice made deficient in HSL by genetic manipulation are resistant to geneticor diet-induced obesity (4, 5). Women carrying an allele associated with decreased HSL activity have lower fasting and simulated insulin concentrations, and men with this allele have lower nonesterified fatty acid concentrations (6). In light of these data, proteins involved in lipolysis have become targets of drug development for the treatment of obesity and the metabolic syndrome. Thus, decreased HSL activity might mediate some of the purported benefits of diets designed to lower insulin secretion. The transcription factor TCF7L2 is the strongest known genetic predictor of type 2 diabetes. A microsatellite within intron 3 of this transcription factor occurs with increased frequency in individuals with type 2 diabetes, which corresponds to an estimated population attributable risk of 21% (7). Although the mechanisms involved in disease risk have not been fully elucidated, TCF7L2 affects the Wnt signaling pathway and may be critical for glucagon-like peptide 1 (GLP-1) secretion by intestinal endocrine L cells. Decreased secretion of GLP-1 appears to play a role in the development of type 2 diabetes, and GLP-1 agonists have recently been developed for the treatment of diabetes. The present study has direct implications concerning our understanding of the dietary glycemic index (GI). The GI is a system for classifying carbohydrate-containing foods according to how blood glucose concentrations change in the postprandial period (reviewed in reference 8). High-GI meals produce greater postprandial insulin concentrations and C-peptide excretion than do nutrient-controlled low-GI meals. Observational and interventional studies have linked GI to the risk of obesity, diabetes, heart disease, and cancer, although the topic remains much debated. One factor contributing to this ongoing controversy is the relative paucity of data regarding the relevant molecular mechanisms. If differences in insulin secretion mediate the genetic effects observed by Kallio et al, similar effects would be expected to occur with both low-GI and high-GI diets. This possibility is supported by a human study and several rodent studies, which showed potentially beneficial changes in the expression of HSL and other relevant genes with a low-GI diet (8, 9). Several methodologic issues should be considered in the interpretation of this study. Microarray analyses have well-known technical limitations and statistical problems, especially when involving small sample sizes (10). The unidirectional change in gene expression within each diet group provides some grounds

GIP receptor mRNA expression in different fat tissue depots in postmenopausal non-diabetic women

Aims Gastric inhibitory polypeptide (GIP) is an insulinotropic duodenal hormone released in response to meals. Recent studies in rodents suggested that GIP directly links overnutrition to obesity. Despite evidence for GIP effects on fat metabolism in humans, the GIP receptor (GIPR) has not been identified in fat tissues. We identified the GIPR gene in human subcutaneous and visceral fat tissues and tested the hypothesis that that the expression of this gene is influenced by central obesity and weight loss. Methods GIPR gene mRNA expression in subcutaneous fat tissue biopsies ( n = 70) and in paired subcutaneous and visceral fat tissue samples ( n = 25) of non-diabetic postmenopausal women was studied by real-time reverse transcription polymerase chain reaction. The effect of weight reduction on GIPR gene expression in subcutaneous fat tissue was studied in a subset of 14 women. Results GIPR adipose tissue gene expression was significantly lower in insulin resistant obese non-diabetic women ( p = 0.004). The GIPR mRNA expression was higher in the visceral fat tissue compared with subcutaneous fat ( p < 0.001). Despite adjustment for obesity-associated variables, waist circumference was the most significant predictor of GIPR gene expression in subcutaneous fat depot ( F = 4.066; β = − 0.997; p = 0.0001) and, together with fasting insulin levels, in visceral fat ( F = 3.553; β = − 0.507 and β = 0.495; p = 0.0001). Moderate weight reduction did not change gene expression levels of the GIPR gene ( p = 0.085). Conclusions Decreased expression of the GIPR gene in subcutaneous fat tissue is associated with signs of insulin resistance in non-diabetic women with central obesity and demonstrates that fasting hyperinsulinemia is a possible negative regulator of GIPR gene expression in subcutaneous fat. Higher GIPR gene expression levels in visceral fat vs. subcutaneous fat reflect regional differences in adipose tissue biology. Moderate weight reduction did not change gene expression levels of GIPR in subcutaneous fat.

Abdominal adipose tissue cytokine gene expression: relationship to obesity and metabolic risk factors

Adipose tissue is a major source of inflammatory and thrombotic cytokines. This study investigated the relationship of abdominal subcutaneous adipose tissue cytokine gene expression to body composition, fat distribution, and metabolic risk during obesity. We determined body composition, abdominal fat distribution, plasma lipids, and abdominal subcutaneous fat gene expression of leptin, TNF-alpha, IL-6, PAI-1, and adiponectin in 20 obese, middle-aged women (BMI, 32.7 +/- 0.8 kg/m2; age, 57 +/- 1 yr). A subset of these women without diabetes (n = 15) also underwent an OGTT. In all women, visceral fat volume was negatively related to leptin (r = -0.46, P < 0.05) and tended to be negatively related to adiponectin (r = -0.38, P = 0.09) gene expression. Among the nondiabetic women, fasting insulin (r = 0.69, P < 0.01), 2-h insulin (r = 0.56, P < 0.05), and HOMA index (r = 0.59, P < 0.05) correlated positively with TNF-alpha gene expression; fasting insulin (r = 0.54, P < 0.05) was positively related to, and 2-h insulin (r = 0.49, P = 0.06) tended to be positively related to, IL-6 gene expression; and glucose area (r = -0.56, P < 0.05) was negatively related to, and insulin area (r = -0.49, P = 0.06) tended to be negatively related to, adiponectin gene expression. Also, adiponectin gene expression was significantly lower in women with vs. without the metabolic syndrome (adiponectin-beta-actin ratio, 2.26 +/- 0.46 vs. 3.31 +/- 0.33, P < 0.05). We conclude that abdominal subcutaneous adipose tissue expression of inflammatory cytokines is a potential mechanism linking obesity with its metabolic comorbidities.

In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue.

Highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing's syndrome, but in which plasma cortisol is not elevated. We tested the hypothesis that this HAART-associated lipodystrophy is explained by increased local regeneration of cortisol from inactive cortisone within adipose tissue, catalysed by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In this cross-sectional study, a previously described cohort of 30 HIV-infected patients with lipodystrophy were compared with 13 HIV-infected patients without lipodystrophy. Intra-abdominal and subcutaneous adipose tissue were quantified using magnetic resonance imaging. Gene expression in subcutaneous fat was measured using real-time PCR. Urine cortisol and its metabolites were analysed by gas chromatography/mass spectrometry. Patients with lipodystrophy had significantly higher 11beta-HSD1 mRNA concentrations (relative to beta2-microglobulin mRNA) in subcutaneous adipose tissue than non-lipodystrophic patients (0.29+/-0.20 vs 0.09+/-0.07, p=0.0004) and higher ratios of urinary cortisol : cortisone metabolites. Adipose tissue 11beta-HSD1 mRNA correlated with multiple features of insulin resistance and with mRNA concentrations for glucocorticoid receptor and angiotensinogen. In adipose tissue of patients with HAART-associated lipodystrophy, 11beta-HSD1 mRNA is increased and its concentration is correlated with features of insulin resistance. We suggest that increased adipose tissue 11beta-HSD1 may explain the pseudo-Cushing's features in patients with HAART-associated lipodystrophy, and is a potential therapeutic target.

The regulation of body fat distribution and the modulation of insulin action.

Body fat distribution may determine insulin resistance and its metabolic syndrome in humans, independent of obesity. Surgical removal of visceral fat (VF) in obese rats was associated with decreased leptin plasma levels and its gene expression in subcutaneous fat (SC). Chronic leptin treatment to rats decreased VF specifically supporting the role of leptin in determining fat distribution. Surgical removal of selected VF provided direct evidence of improved in vivo insulin action on hepatic glucose production (HGP) by over 2-fold vs sham-operated control. The impact of decreased VF on improved in vivo insulin action was further supported by obtaining similar decreases in VF by treating rats with leptin (Lep), beta3-aderenoreceptor agonist, or by severe caloric restriction (CR). All these three interventions improved insulin action on the modulation of HGP and were mostly attributed to preservation of hepatic glycogen stores. Because free fatty acids (FFA) plasma levels were unchanged, this effect may not be mediated portally by substrates. Improved peripheral insulin sensitivity and glycogen synthesis was demonstrated only in Lep. These data suggest that VF is a major determinant of hepatic insulin action. In obese rats, the ability of leptin to prevent visceral adiposity and its own expression is attenuated. Thus, the failure of leptin to regulate fat distribution and its own secretion suggest that 'leptin resistance' may be a pathologic feature in obesity.