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Adipose tissue macrophages are associated with insulin resistance and are linked to changes in the extracellular matrix. To better characterize adipose macrophages, the extracellular matrix, and adipocyte-macrophage interactions, gene expression from adipose tissue and the stromal vascular fraction was assessed for markers of inflammation and fibrosis, and macrophages from obese and lean subjects were counted and characterized immunohistochemically. Coculture experiments examined the effects of adipocyte-macrophage interaction. Collagen VI gene expression was associated with insulin sensitivity and CD68 (r = -0.56 and 0.60, P < 0.0001) and with other markers of inflammation and fibrosis. Compared with adipose tissue from lean subjects, adipose tissue from obese subjects contained increased areas of fibrosis, which correlated inversely with insulin sensitivity (r = -0.58, P < 0.02) and positively with macrophage number (r = 0.70, P < 0.01). Although macrophages in crownlike structures (CLS) were more abundant in obese adipose tissue, the majority of macrophages were associated with fibrosis and were not organized in CLS. Macrophages in CLS were predominantly M1, but most other macrophages, particularly those in fibrotic areas, were M2 and also expressed CD150, a marker of M2c macrophages. Coculture of THP-1 macrophages with adipocytes promoted the M2 phenotype, with a lower level of IL-1 expression and a higher ratio of IL-10 to IL-12. Transforming growth factor-[beta] (TGF-[beta]) was more abundant in M2 macrophages and was further increased by coculture with adipocytes. Downstream effectors of TGF-[beta], such as plasminogen activator inhibitor-l, collagen VI, and phosphorylated Smad, were increased in macrophages and adipocytes. Thus adipose tissue of insulin-resistant humans demonstrated increased fibrosis, M2 macrophage abundance, and TGF-[beta] activity. alternatively activated macrophages; inflammation; crownlike structures doi: 10.1152/ajpendo.00329.2010.

We compared the effects of high and low oral and intravenous (iv) fat load on blood pressure (BP), endothelial function, autonomic nervous system, and oxidative stress in obese healthy subjects. Thirteen obese subjects randomly received five 8-h infusions of iv saline, 20 (32 g, low iv fat) or 40 ml/h intralipid (64 g, high iv fat), and oral fat load at 32 (low oral) or 64 g (high oral). Systolic BP increased by 14 [+ or -] 10 (P = 0.007) and 12 [+ or -] 9 mmHg (P = 0.007) after low and high iv lipid infusions and by 13 [+ or -] 17 (P = 0.045) and 11 [+ or -] 11 mmHg (P = 0.040) after low and high oral fat loads, respectively. The baseline flow-mediated dilation was 9.4%, and it decreased by 3.8 [+ or -] 2.1 (P = 0.002) and 4.1 [+ or -] 3.1% (P < 0.001) after low and high iv lipid infusion and by 3.8 [+ or -] 1.8 (P = 0.002) and 5.0 [+ or -] 2.5% (P < 0.001) after low and high oral fat load, respectively. Oral and iv fat load stimulated oxidative stress, increased heart rate, and decreased R-R interval variability. Acute iv fat load decreased blood glucose by 6-10 mg/dl (P < 0.05) without changes in insulin concentration, whereas oral fat increased plasma insulin by 3.7-4.0 [micro]U/ml (P < 0.01) without glycemic variations. Intravenous saline and both oral and iv fat load reduced leptin concentration from baseline (P < 0.01). In conclusion, acute fat load administered orally or intravenously significantly increased blood pressure, altered endothelial function, and activated sympathetic nervous system by mechanisms not likely depending on changes in leptin, glucose, and insulin levels in obese healthy subjects. Thus, fat load, independent of its source, has deleterious hemodynamic effects in obese subjects. obesity; endothelial dysfunction; hypertension; autonomic nervous system doi: 10.1152/ajpendo.00469.2010.

Body fat distribution is an important predictor of the metabolic consequences of obesity, but the cellular mechanisms regulating regional fat accumulation are unknown. We assessed the changes in adipocyte size (photomicrographs) and number in response to overfeeding in upper- and lower-body s.c. fat depots of 28 healthy, normal weight adults (15 men) age 29 [+ or -] 2 y. We analyzed how these changes relate to regional fat gain (dual energy X-ray absorptiometry and computed tomography) and baseline preadipocyte proliferation, differentiation [peroxisome proliferator-activated receptor-[gamma]2 (PPAR[gamma]2) and CCAAT/enhancer binding protein-[alpha] (C/EBP[alpha]) mRNA]), and apoptotic response to TNF-[alpha]. Fat mass increased by 1.9 [+ or -] 0.2 kg in the upper body and 1.6 [+ or -] 0.1 kg in the lower body. Average abdominal s.c. adipocyte size increased by 0.16 [+ or -] 0.06 [micro]g lipid per cell and correlated with relative upper-body fat gain (r = 0.74, P < 0.0001). However, lower-body fat responded to overfeeding by fat-cell hyperplasia, with adipocyte number increasing by 2.6 [+ or -] 0.9 x [10.sup.9] cells (P < 0.01). We found no depot-differences in preadipocyte replication or apoptosis that would explain lower-body adipocyte hyperplasia and abdominal s.c. adipocyte hypertrophy. However, baseline PPAR[gamma]2 and C/EBP[alpha] mRNA were higher in abdominal than femoral s.c. preadipocytes (P < 0.005 and P < 0.03, respectively), consistent with the ability of abdominal s.c. adipocytes to achieve a larger size. Inherent differences in preadipocyte cell dynamics may contribute to the distinct responses of different fat depots to overfeeding, and fat-cell number increases in certain depots in adults after only 8 wk of increased food intake. adipocyte | bodycomposition | bodyfatgain | fatdistribution | preadipocyte doi/ 10.1073/pnas.1005259107

The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulin-resistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 [+ or -] 1.3 kg/[m.sup.2] were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 [+ or -] 27 vs. 316 [+ or -] 91 [cm.sup.2]), number of macrophages in omental adipose tissue (4.9 [+ or -] 0.8 vs. 13.2 [+ or -] 1.4%), mean omental adipocyte size (528 [+ or -] 76 vs. 715 [+ or -] 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values visceral adipose tissue; insulin resistance; inflammation; adipokines; macrophages doi: 10.1152/ajpendo.00586.2009.

R1PI40 is a transcriptional coregulator highly expressed in metabolic tissues where it has important and diverse actions. RIP140-null mice show that it plays a crucial role in the control of lipid metabolism in adipose tissue, skeletal muscle, and the liver and is essential for female fertility. RIP140 has been shown to act as a ligand-dependent transcriptional corepressor for metabolic nuclear receptors such as estrogen-related receptors and peroxisome proliferator-activated receptors. The role of RIP140 as a corepressor has been strengthened by the characterization of RIP140-overexpressing mice, although it emerges through several studies that RIP140 can also behave as a coactivator. Nuclear localization of RIP140 is important for controlling transcription of target genes and is subject to regulation by posttranslational modifications. However, cytoplasmic RIP140 has been shown to play a role in the control of metabolism through direct regulation of glucose transport in adipocytes. In this review, we focus on recent advances highlighting the growing importance of RIP140 as a regulator of energy homeostasis. receptor-interacting protein-140; corepressor coactivator; transcription; cytoplasm; nuclear receptors; metabolism; adipose tissue; skeletal muscle; mitochondria doi: 10.1152/ajpendo.00243.2010.

We investigated the involvement of basal sympathetic tone in brown adipose tissue (BAT) recruitment and gene expression profile induced by peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) activation. Innervated and surgically denervated BAT pads of rats treated or not with rosiglitazone (15 mg x [kg.sup.-1] x [day.sup.-1], 7 days) were evaluated for weight, triacylglycerol (TAG) and DNA content, mitochondrial mass, and gene expression. Rosiglitazone induced BAT recruitment (increased mass, TAG and DNA content) and mRNA levels of lipolytic (adipose tissue triglyceride lipase and CGI58) and lipogenic (lipoprotein lipase, phosphoenolpyruvate carboxykinase, fatty acid binding protein 4, and diacylglycerol acyltransferase 1) proteins independently of tissue innervation status. Mitochondrial mass and mRNA levels of its regulators peroxisome proliferator-activated receptor coactivator-[alpha] and CCAAT/enhancer binding protein-[beta] were not affected by rosiglitazone, while being significantly reduced by denervation. By contrast, maximal stimulation of uncoupling protein 1 (UCP1) (thermogenesis), cell death-inducing DNA fragmentation factor-45-1ike effector A (inhibitor of UCP1 activity), monoacylglycerol lipase (lipolysis), small heterodimer partner (transcription), and glycerokinase (TAG synthesis) by rosiglitazone depended on the presence of intact BAT innervation. Cold exposure (5 [degrees]C, 24 h) significantly increased UCPI mRNA levels in innervated BAT pads of untreated rats, without affecting the already high BAT UCPI levels of rosiglitazone-treated animals. A similar pattern of response was found in denervated pads, but with markedly lower UCP1 expression than that in innervated BAT. In conclusion, whereas the mass (hyperplasia and hypertrophy), lipogenic, and lipolytic components of BAT recruitment induced by rosiglitazone occur independently of tissue sympathetic innervation, maximal UCP1 expression induced by PPAR-[gamma] in vivo depends on the presence of basal BAT adrenergic tone. The residual sympathetic tone found under rosiglitazone treatment is, therefore, involved in the modulation of a subset of major components of PPAR-[gamma]-mediated BAT recruitment. thermogenesis; sympathetic innervation; mitochondria; peroxisome proliferator-activated receptor coactivator-[alpha]; rosiglitazone doi: 10.1152/ajpregu.00821.2009.

Norepinephrine (NE) released from the sympathetic nerves innervating white adipose tissue (WAT) is the principal initiator of lipolysis in mammals. Central WAT sympathetic outflow neurons express melanocortin 4-receptor (MC4-R) mRNA. Single central injection of melanotan II (MTII; MC3/4-R agonist) nonuniformly increases WAT NE turnover (NETO), increases interscapular brown adipose tissue (IBAT) NETO, and increases the circulating lipolytic products glycerol and free fatty acid. The WAT pads that contributed to this lipolysis were inferred from the increases in NETO. Because phosphorylation of perilipin A (p-perilipin A) and hormone-sensitive lipase are necessary for NE-triggered lipolysis, we tested whether MTII would increase these intracellular markers of lipolysis. Male Siberian hamsters received a single 3rd ventricular injection of MTII or saline. Trunk blood was collected at 0.5, 1.0, and 2.0 h postinjection from excised inguinal, retroperitoneal, and epididymal WAT (IWAT, RWAT, and EWAT, respectively) and IBAT pads. MTII increased circulating glycerol concentrations at 0.5 and 1.0 h, whereas free fatty acid concentrations were increased at 1.0 and 2.0 h. Western blot analysis showed that MTII specifically increased p-perilipin A and hormone-sensitive lipase only in fat pads that previously had MTII-induced increases in NETO. Phosphorylation increased in IWAT at all time points and IBAT at 0.5 h, but not RWAT or EWAT at any time point. These results show for the first time in rodents that p-perilipin A can serve as an in vivo, fat pad-specific indictor of lipolysis and extend our previous findings showing that central melanocortin stimulation increases WAT lipolysis. sympathetic nervous system; method; Western blot analysis doi: 10.1152/ajpregu.00535.2009.

Adipose tissue is a primary site for lipid storage containing trace amounts of glycogen. However, refeeding after a prolonged partial fast produces a marked transient spike in adipose glycogen, which dissipates in coordination with the initiation of lipid resynthesis. To further study the potential interplay between glycogen and lipid metabolism in adipose tissue, the aP2-PTG transgenic mouse line was utilized since it contains a 100- to 400-fold elevation of adipocyte glycogen levels that are mobilized upon fasting. To determine the fate of the released glucose 1-phosphate, a series of metabolic measurements were made. Basal and isoproterenol-stimulated lactate production in vitro was significantly increased in adipose tissue from transgenic animals. In parallel, basal and isoproterenol-induced release of nonesterified fatty acids (NEFAs) was significantly reduced in transgenic adipose tissue vs. control. Interestingly, glycerol release was unchanged between the genotypes, suggesting that enhanced triglyceride resynthesis was occurring in the transgenic tissue. Qualitatively similar results for NEFA and glycerol levels between wild-type and transgenic animals were obtained in vivo during fasting. Additionally, the physiological upregulation of the phosphoenolpyruvate carboxykinase cytosolic isoform (PEPCK-C) expression in adipose upon fasting was significantly blunted in transgenic mice. No changes in whole body metabolism were detected through indirect calorimetry. Yet weight loss following a weight gain/loss protocol was significantly impeded in the transgenic animals, indicating a further impairment in triglyceride mobilization. Cumulatively, these results support the notion that the adipocyte possesses a set point for glycogen, which is altered in response to nutritional cues, enabling the coordination of adipose glycogen turnover with lipid metabolism. glycogenolysis; fasting; lipolysis; protein phosphatase-1 doi: 10.1152/ajpendo.00741.2009.

Physical training affects insulin secretion and action, but there is a paucity of data on the direct effects in skeletal muscle and adipose tissue and on the effect of training in first-degree relatives (FDR) of patients with type 2 diabetes. We studied insulin action at the whole body level and peripherally in skeletal muscle and adipose tissue as well as insulin-secretory capacity in seven FDR and eight control (CON) subjects before and after 12 wk of endurance training. Training improved physical fitness. Insulin- mediated glucose uptake (GU) increased (whole body and leg; P < 0.05) after training in CON but not in FDR, whereas glucose-mediated GU increased (P < 0.05) in both groups. Adipose tissue GU was not affected by training, but it was higher (abdominal, P < 0.05; femoral, P = 0.09) in FDR compared with CON. Training increased skeletal muscle lipolysis (P < 0.05), and it was markedly higher (P < 0.05) in subcutaneous abdominal than in femoral adipose tissue and quadriceps muscle with no difference between FDR and CON. Glucosestimulated insulin secretion was lower in FDR compared with CON, but no effect of training was seen. Glucagon-like peptide-1 stimulated insulin secretion five- to sevenfold. We conclude that insulin-secretory capacity is lower in FDR than in CON and that there is dissociation between training-induced changes in insulin secretion and insulin-mediated GU. Maximal GU rates are similar between groups and increases with physical training. glucagon-like peptide-1; hyperglycemic clamp; blood flow; intravenous glucose tolerance test; hyperinsulinemic euglycemic clamp; microdialysis; arteriovenous balance doi: 10.1152/ajpendo.00765.2009.

The importance of dietary fat components, such as fatty acids, in the expression of multiple genes is clear. In the case of beef cattle, fat in the form of fatty acids (saturated or unsaturated), vitamin A (mainly retinoic acid), or carotenoids ([beta]-carotene and lutein) is obtained from dietary feed or pasture. The aim of this work was to study the effect of fatty acids (phytanic and pristanic acids), vitamin A (all-trans and 9-cis retinoic acid), and carotenoids ([beta]-carotene and lutein) on the expression of PPAR[gamma] and its coactivator PGC-l[alpha] during differentiation of bovine white adipose tissue. Samples were collected at slaughter from subcutaneous adipose tissue and processed in a solution containing type II collagenase for 2 h at 37[degrees]C. Cells were resuspended in basal medium, Dulbecco's modified Eagle's medium containing 5% fetal bovine serum, plated on 24-well culture plates at a density of 1 x [10.sup.4] cells/ [cm.sup.2], and incubated at 37[degrees]C in a 5% C[O.sub.2] atmosphere. Preadipocyte differentiation after reaching confluence was induced by various treatments: rosiglitazone (20 [micro]M); unsaturated fatty acids: phytanic acid (25, 50, 100 [micro]M) and pristanic acid (25, 50, 100 [micro]M); retinoids: 9-cis retinoic acid (0.5, 0.75, 1 [micro]M) and all-trans retinoic acid (0.5, 0.75, 1 [micro]M); and carotenoids: [beta]-carotene (10, 20, 30 [micro]M) and lutein (10, 20, 30 [micro]M). Expression of PPAR[gamma] and PGC-1[alpha] was measured in differentiated cells. Phytanic acid, all-trans retinoic acid, and 9-cis retinoic acid were the best activators of PPAR[gamma] expression, and the combination of 9-cis and all-trans retinoic acid was the best activator of PGC-l[alpha] expression (P < 0.05). Therefore, these are powerful agents for the promotion of bovine adipogenesis and constitute promising compounds to be used in bovine fattening. Key words: beef cattle, dietary fat, peroxisomal proliferator-activated receptor [gamma], peroxisomal proliferatoractivated receptor [gamma] coactivator 1 doi: 10.2527/jas.2009-2579

The possibility that maternal diets during gestation could affect growth and tissue development of offspring and program their later phenotype is an emerging challenge in pig production. The objective of the current study was to investigate the effects of contrasted protein levels in diets of pregnant sows on the proteomic features of subcutaneous adipose tissue (SCAT) of the offspring at birth and its possible persistence later in age. Sows were fed control (Con), low (LP), or high protein (HP) diets throughout gestation. A subset of piglets was killed at 1 d of age for SCAT sampling. The remaining piglets were cross-fostered to nonexperimental sows during lactation. They were fed standard diets during postweaning and fattening periods until 186 d of age. Modifications in SCAT protein abundance shortly after birth were investigated by 2-dimensional gel electrophoresis followed by mass spectrometry. A total of 65 spots were found differentially expressed (P [less than or equal to] 0.10) in SCAT of l-d-old experimental piglets vs. Con piglets. Proteins with a greater abundance in LP piglets compared with Con piglets were involved in pathways related to glucose and fatty acid metabolisms, lipid transport, and regulation of apoptosis. Upregulation of 5 proteins representative of these biological pathways in LP group vs. Con group were further validated (P < 0.05) by Western blot analyses. Furthermore, the specific activity of the key lipogenic enzyme fatty acid synthase was found greater (P = 0.06) in SCAT of 1-d-old LP piglets than in Con piglets. The main changes evidenced in SCAT of HP piglets compared with Con animals at 1 d of age rather concerned proteins putatively involved in AA metabolism or in protein turnover. Adipose tissue contents in some proteins that had displayed a greater (P [less than or equal to] 0.10) abundance in experimental pigs compared with Con at d 1 (e.g., transaldolase, annexin II, and apolipoprotein A4) were, however, similar (P > 0.10) in the 3 groups at d 186 of age. Enolase 1 has less abundance (P < 0.05) in LP pigs compared with Con pigs at this stage. In conclusion, the proteomics tool has allowed the identification of early changes in various molecular pathways of SCAT in response to the levels of maternal protein supply during gestation. Key words: adipose tissue, annexin, glycolytic pathway, pig, prenatal diet, proteome doi: 10.2527/jas.2009-2542

We used quantitative magnetic resonance body composition analysis and radiotelemetry to examine whether fat and lean body mass affected stopover durations of 11 birds captured during autunm migration in New York City, USA. Two Swainson's Thrushes (Catharus ustulatus), two Hermit Thrushes (C. guttatus), and seven Ovenbirds (Seiurus aurocapilla) were used in the study. Ovenbird stopover duration was significantly and negatively related to fat mass but unrelated to lean body mass. The same relationships were found when data from all three species were combined to increase sample sizes. Birds that departed within 1 day had fat stores upon capture that represented at least 11% of their total body mass whereas those with fat content, Migrating landbirds require several stopovers for rest and refueling, as most are incapable of completing their migration in a single flight. Time and energy spent during stopover periods greatly exceeds [...]

Angiopoietin-like protein 4 (ANGPTL4; also known as fasting-induced adipose factor) is a plasma protein that stimulates oxidation of fatty acids and inhibits fat accumulation. The gastrointestinal tract appears to play an important role in regulating plasma ANGPTL4 concentration in some situations and may be influenced by microbes within the gastrointestinal tract. Our aim was to determine which tissues express ANGPTL4 in the bovine. Rumen, omasum, abomasum, duodenum, jejunum, ileum, colon, pancreas, liver, and subcutaneous adipose tissue samples were collected postmortem from 2 steers. Abundance of ANGPTL4 messenger RNA was quantified by quantitative real-time PCR, and was most abundant in liver and adipose tissue (P < 0.05). We also detected ANGPTL4 messenger RNA throughout the gastrointestinal tract, although its abundance was approximately 10% of that found in liver and adipose tissue. Western blot analysis revealed that ANGPTL4 protein was most abundant in liver and adipose tissue (P < 0.05), but omasal, abomasal, and ileal samples contained at least 60% as much ANGPTL4 protein as the liver and adipose tissue samples, and the protein was detected in all tissues. Finally, cross-sections of the liver, pancreas, and rumen wall were used for indirect immunofluorescent detection of ANGPTL4. Despite the low abundance of ANGPTL4 measured by quantitative real-time PCR and Western blot in ruminal tissue, immunofluorescence demonstrated that expression of ANGPTL4 in ruminal epithelial cells was equivalent to or greater than that in liver hepatocytes. These findings indicate that, as in other species studied, liver and adipose tissue are key sources of ANGPTL4 in cattle. However, the protein was also highly abundant in ruminal epithelium, making it possible that commensal microbes may influence ANGPTL4 synthesis and secretion in the ruminant gastrointestinal tract. Key words: angiopoietin-like protein, bovine, fasting-induced adipose factor, steer doi: 10.2527/jas.2009-2258

Reduced testosterone as a result of catabolic illness or aging is associated with loss of muscle and increased adiposity. We hypothesized that these changes in body composition occur because of altered rates of protein synthesis under basal and nutrient-stimulated conditions that are tissue specific. The present study investigated such mechanisms in castrated male rats (75% reduction in testosterone) with demonstrated glucose intolerance. Over 9 wk, castration impaired body weight gain, which resulted from a reduced lean body mass and preferential sparing of adipose tissue. Castration decreased gastrocnemius weight, but this atrophy was not associated with reduced basal muscle protein synthesis or differences in plasma IGF-I, insulin, or individual amino acids. However, oral leucine failed to normally stimulate muscle protein synthesis in castrated rats. In addition, castration-induced atrophy was associated with increased 3-methylhistidine excretion and in vitrodetermined ubiquitin proteasome activity in skeletal muscle, changes that were associated with decreased atrogin-1 or MuRF1 mRNA expression. Castration decreased heart and kidney weight without reducing protein synthesis and did not alter either cardiac output or glomerular filtration. In contradistinction, the weight of the retroperitoneal fat depot was increased in castrated rats. This increase was associated with an elevated rate of basal protein synthesis, which was unresponsive to leucine stimulation. Castration also decreased whole body fat oxidation. Castration increased TNF[alpha], IL-l[alpha], IL-6, and NOS2 InRNA in fat but not muscle. In summary, the castrationinduced muscle wasting results from an increased muscle protein breakdown and the inability of leucine to stimulate protein synthesis, whereas the expansion of the retroperitoneal fat depot appears mediated in part by an increased basal rate of protein synthesis-associated increased inflammatory cytokine expression. hypogonadal; testosterone; atrophy; adiposity; inflammation doi: 10.1152/ajpendo.00473.2009.

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40-60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues. fibroblast growth factor 21; blood glucose; insulin; signal transduction; hepatic glucose production doi: 10.1152/ajpendo.00348.2009.

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice (n = 10-12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (~70%) and end-systolic and end-diastolic areas (~100% and ~45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium. fatty acids; mitochondria; obesity doi: 10.1152/ajpheart.00599.2009.

Adipose tissue is one of the major sites for fatty acid synthesis and lipid storage. We generated adipose (fat)-specific ACC1 knockout (FACC1KO) mice using the aP2-Cre/IoxP system. FACC1KO mice showed prenatal growth retardation; after weaning, however, their weight gain was comparable to that of wild-type (WT) mice on a normal diet. Under lipogenic conditions of fasting/re-feeding a fat-free diet, lipid accumulation in adipose tissues of FACC1KO mice was significantly decreased; this is consistent with a 50-66% reduction in the ACC activity in these tissues compared with that of WT mice. Surprisingly, FACC1KO mice manifested skeletal growth retardation phenotype accompanied by decreased chondrocyte proliferation in the growth plate and lower trabecular bone density. In addition, there was about a 30% decrease in serum insulin-like growth factor I (IGF1), and while the serum leptin level was decreased by about 50%, it did not counteract the osteopenic effects of IGF1 on the bone. Fatty acid analyses of mutant bone lipids revealed relatively higher levels of C18:2n-6 and C18:3n-3 and lower levels of their elongation C20 homologs than that of WT cohorts, leading to lower levels of C20 homologs and bone development. Moreover, aP2-Cre-mediated ACC1 inactivation in bone tissue led to a decreased number of osteoblasts but not of osteoclasts. The downregulation of ACC1 on osteoblastogenesis may be the cause for the osteopenia phenotype of FACC1KO bone homeostasis. Fat-specific ACC1 knockout | osteoblastogenesis doi/ 10.1073/pnas.0909055106

A white adipose-tissue-specific intracellular phospholipase, which releases arachidonic acid from position sn-2 of phospholipids, was recently discovered and named AdPLA. When AdPLA was induced by feeding or by insulin treatment, the arachidonic acid released from phospholipids acted as a precursor for the formation of prostaglandin [E.sub.2] ([PGE.sub.2]). Subsequent activation of the prostaglandin receptor EP3 caused decreased levels of cAMP that led to decreased lipolysis and increased adiposity. Ablation of AdPLA in knockout mice resulted in the reverse sequence of events, with a decline in arachidonic acid release and prostaglandin synthesis and an increase in levels of cAMP, leading to increased lipolysis and a decline in adiposity, even though food intake was not affected. The newly discovered AdPLA enzyme in white adipose tissue functions as a regulator of lipolysis by acting as an antilipolytic agent mediated by increased [PGE.sub.2] formation and decreased intracellular cAMP.

Endogenous periadventitial adipose-derived factors have been shown to contribute to coronary vascular regulation by impairing endothelial function through a direct inhibition of endothelial nitric oxide synthase (eNOS). However, our understanding of the underlying mechanisms remains uncertain. Accordingly, this study was designed to test the hypothesis that periadventitial adipose tissue releases agents that attenuate coronary endothelial nitric oxide production via a protein kinase C (PKC)-[beta]dependent mechanism. Isometric tension studies were conducted on isolated canine circumflex coronary arteries with and without natural amounts of periadventitial adipose tissue. Adipose tissue significantly diminished coronary endothelial-dependent vasodilation and nitric oxide production in response to bradykinin and acetylcholine. The selective inhibition of endothelial PKC-[beta] with ruboxistaurin (1 [micro]M) abolished the adipose-induced impairment of hradykinin-mediated coronary vasodilation and the endothelial production of nitric oxide. Western blot analysis revealed a significant increase in eNOS phosphorylation at the inhibitory residue [Thr.sup.495] in arteries exposed to periadventitial adipose tissue. This site-specific phosphorylation of eNOS was prevented by the inhibition of PKC-[beta]. These data demonstrate that periadventitial adipose-derived factors impair coronary endothelial nitric oxide production via a PKC-[beta]-dependent, site-specific phosphorylation of eNOS at [Thr.sup.495]. coronary circulation; adipokine; endothelial nitric oxide synthase; protein kinase C-[beta]

Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. [Rb.sup.+/-] mice had body weight and adiposity indistinguishable from that of wild-type ([Rb.sup.+/+]) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, [Rb.sup.+/-] mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)[gamma] as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, [Rb.sup.+/-] mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPAR[alpha] in liver and of PPAR[delta] in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances. brown adipose tissue; white adipose tissue; energy metabolism; genetic animal model

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)[beta] agonists. In the present study, to investigate the relative contributions of ER[alpha] and ER[beta] in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER-/- mice. ER[beta]-/- mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ER[alpha]-/- mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ER[alpha]-/- mice, Tam increased GLUT4 and improved insulin sensitivity, i.e., it behaved as an ER[beta] antagonist in SM but had no effect on WAT. In ER[beta]-/- mice, Tam did not affect GLUT4 in SM but acted as an ER[alpha] antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ER[alpha] and ER[beta], ER[beta]-mediated repression of GLUT4 predominates in SM but ER[alpha]-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ER[alpha] predominates in WAT and ER[beta] in SM. estrogen receptor-[alpha]; estrogen receptor-[beta]; glucose transporter 4; tamoxifen

Increased mortality and overexpression of interleukin-6 (IL-6) during inflammatory stress are well-documented age- associated phenomena: however, the site of IL-6 overexpression is not entirely known. Here, we report that white adipose tissue is a major source of IL-6 in aged animals during lipopolysaccharide (LPS)-induced systemic inflammation. Among the various tissues examined, white adipose tissue from the epididymal fat pad (located in the abdominal cavity) expressed the highest level of IL-6 messenger RNA in both young and aged mice with a 5.5-fold higher level in the aged. Immunohistochemistry revealed that, within the adipose tissue, LPS-induced IL-6 expression is localized to both the adipocytes and stromal cells. Compared with age-matched wild-type mice, aged IL-[6.sup.(-/-)] mice exhibited reduced mortality to LPS suggesting a deleterious effect of IL-6 overexpression in the aged. These results demonstrate that increased vulnerability to systemic inflammation with age is due in part, to augmented IL-6 production by the adipose tissue. Key Words: Aging--IL-6--Adipose tissue--Sepsis--Endotoxemia.

Isomers of conjugated linoleic acids (CLA) reduce fat mass (FM) and increase insulin sensitivity in some, but not all, murine studies. In humans, this effect is still debatable. In this study, we compared the effect of 2 CLA supplements on total and regional FM assessed by dual energy X-ray absorptiometry, changes in serum insulin and glucose concentrations, and adipose tissue (AT) gene expression in humans. In a double-blind, parallel, 16-wk intervention, we randomized 81 healthy postmenopausal women to I) 5.5 g/d of 40/40% of cis9, trans11-CLA (c9,t11-CLA) and trans10, cis12-CLA (t10,c12-CLA) (CLA-mix); 2) cis9, trans11-CLA (c9,t11-CLA); or 3) control (olive oil). We assessed all variables before and after the intervention. The CLA-mix group had less total FM (4%) and lower-body FM (7%) than the control (P = 0.02 and < 0.001, respectively). Post hoc analyses showed that serum insulin concentrations were greater in the CLA-mix group (34%) than the control group (P = 0.02) in the highest waist circumference tertile only. AT mRNA expression of glucose transporter 4, leptin, and lipoprotein lipase was lower, whereas expression of tumor necrosis factor-[alpha] was higher in the CLA-mix group than in the control group (P < 0.04). In conclusion, a 50:50 mixture of c9,t11-and t10,c12-CLA isomers resulted in less total and lower-body FM in postmenopausal women and greater serum insulin concentrations in the highest waist circumference tertile. Future research is needed to confirm the insulin desensitizing effect of the CLA mixture and the effect on the mRNA expression of adipocyte-specific genes in humans.

We hypothesized that L-arginine and conjugated linoleic acid (CLA) would have additive effects in decreasing adiposity. Sprague Dawley rats were assigned to the following dietary groups (n = 6/group; 5 wk total): 1) control (2.55% L-alanine plus 1.5% canola oil); 2) arginine (1.25% L-arginine plus 1.5% canola oil); 3) CLA (2.55% L-alanine plus 1.5% CLA); and 4) arginine plus CLA (1.25% L-arginine plus 1.5% CLA). Supplemental amino acids were provided in drinking water and CLA was incorporated into the food pellets. Daily weight gain, food intake, arginine intake, and final body and eviscerated body weights were greater in rats fed supplemental CLA then in rats fed canola oil. The retroperitoneal adipose tissue:body weight ratio was less in rats fed supplemental CLA than in rats fed canola oil, but epididymal adipose tissue, liver, and soleus and extensor digitorum Iongus muscle weights were unaffected by arginine or CLA. CLA decreased epididymal adipose tissue concentrations of palmitoleic, oleic, and cis-vaccenic acid. CLA and arginine increased palmitate oxidation to C[O.sub.2] in epididymal adipose tissue in vitro relative to control rats. Glucose and palmitate incorporation into total lipids in epididymal adipose tissue was lower in rats fed supplemental arginine than in alanine-fed rats. Arginine increased plasma glycerol relative to alanine-fed rats and CLA and arginine independently decreased most serum essential amino acids and alanine, glutamate, glutamine, and ornithine. We conclude that CLA and arginine modulated adipose tissue metabolism by separate, but not additive, effects. Also, CLA and arginine may have depressed muscle protein turnover.

Milk fat depression (MFD) is a naturally occurring condition in dairy cows where milk fat synthesis is inhibited by intermediates of ruminal biohydrogenation. One of these bioactive fatty acids (FA), trans-10, cis-12 conjugated linoleic acid (CLA), decreases milk fat synthesis through transcriptional downregulation of genes involved in mammary lipid synthesis. Energy partitioning during MFD is not well characterized because of the complexity of observing energy metabolism in ruminant animals. To investigate energy partitioning during MFD, adipose tissue biopsies were taken from 4 cows arranged in a switchback design. Treatments were control and 4-d abomasal infusion of trans-10, cis-12 CLA (7.5 g/d). CLA decreased milk fat yield by 38 % and milk fat content by 34%, but yields of milk and other milk components were unchanged. In contrast to reported changes in mammary tissue, adipose tissue expression of lipid synthesis enzymes, including lipoprotein lipase, FA synthase, stearoyl-CoA desaturase, and FA binding protein 4, was increased. Expression of regulators of lipid synthesis, including sterol-response element binding protein 1, thyroid hormone responsive spot 14, and PPAR-[gamma], also increased in adipose tissue. Thus, a CLA dose resulting in near maximal inhibition of mammary lipid synthesis resulted in increased expression of lipid synthesis-related genes in adipose tissue. A meta-analysis of intake response during CLA infusion was conducted to extend the investigation of energy metabolism during MFD. Voluntary intake decreased (P< 0.001) by 1.5 kg/d during CLA-induced MFD in the 14 studies analyzed, but the reduction in intake only partially accounts for the energy spared from reduced milk fat synthesis. Results are consistent with energy spared from the reduction in milk fat synthesis being partitioned toward adipose tissue fat stores during short-term MFD.

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/ T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[[sup.3]H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin [A.sub.1c]. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans. insulin sensitivity; adipokines; pathogenesis; type 2 diabetes mellitus

Fenofibrate is a peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha]) activator that has been clinically used to treat dyslipidemia and insulin resistance. To better understand the molecular mechanisms underlying fenofibrate action, we investigated whether fenofibrate affects serum levels of retinal-binding protein-4 (RBP4), an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly decreased serum RBP4 levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. To elucidate the biochemical mechanisms of fenofibrate action, we investigated the effect of fenofibrate on RBP4 expression in obese rats. Fenofibrate greatly decreased RBP4 mRNA levels in adipose tissue but not in the liver, which correlated with decreased serum RBP4 levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on RBP4 expression, fenofibrate treatment significantly reduced the mRNA expression levels of RPB4 in 3T3-L1 adipocytes. Together, our results demonstrate for the first time that fenofibrate inhibits RPB4 expression in dyslipidemic human subjects and suggest that inhibition of RBP4 expression in adipocytes may provide a mechanism by which fenofibrate improves insulin sensitivity in dyslipidemic patients. insulin resistance; liver

The quality and value of the carcass in domestic meat animals are reflected in its protein and fat content. Preadipocytes and adipocytes are important in establishing the overall fatness of a carcass, as well as being the main contributors to the marbling component needed for consumer preference of meat products. Although some fat accumulation is essential, any excess fat that is deposited into adipose depots other than the marbling fraction is energetically unfavorable and reduces efficiency of production. Hence, this review is focused on current knowledge about the biology and regulation of the important cells of adipose tissue: preadipocytes and adipocytes. Key words: adipocyte, meat animal, preadipocyte, review

The paraventricular nucleus of the hypothalamus (PVH) plays an important role in energy homeostasis, regulating neuroendocrine, behavioral, and autonomic functions. However, the role of the PVH in regulating thermogenesis and energy expenditure in brown adipose tissue (BAT) is unclear. The present study investigated the effect of activating neurons within the PVH on BAT thermogenesis. In urethane- and chloralose-anesthetized, artificially ventilated rats maintained at a core body temperature of 37.0-38.0[degrees]C, microinjection of N-methyl-D-aspartate (NMDA, 12 pmol in 60 nl) in the PVH did not increase BAT sympathetic nerve activity (SNA) or BAT thermogenesis. In contrast, the increase in BAT SNA evoked by body cooling was completely reversed by microinjection of NMDA in the PVH. Additionally, the increases in BAT SNA evoked by body cooling, by microinjection of prostaglandin [E.sub.2] (170 pmol in 60 nl) in the medial preoptic area or by microinjection of bicuculline (30 pmol in 60 nl) in the dorsomedial hypothalamus were completely reversed by microinjection of bicuculline (30 pmol in 60 nl) in the PVH. Although the increases in BAT SNA and thermogenesis evoked by microinjection of NMDA (12 pmol in 60 nl) in the raphe pallidus (RPa) was markedly attenuated following microinjection of bicuculline (30 pmol) in the PVH, the increases in BAT SNA and thermogenesis evoked by microinjection of bicuculline (30 pmol in 60 nl) in the RPa were unaffected by microinjection of bicuculline in the PVH. These results demonstrate that disinhibition of neurons in the PVH inhibits BAT SNA likely via activation of a GABAergic input to BAT sympathetic premotor neurons in the RPa. thermoregulation; sympathetic premotor neurons; raphe; paraventricular nucleus; metabolism

The origins of the sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) have been defined using the transneuronal viral retrograde tract tracer, pseudorabies virus. Activation of this SNS innervation is acknowledged as the principal initiator of WAT lipolysis. The central control of WAT lipolysis may require neural feedback to a brain-SNS-WAT circuit via WAT afferents. Indeed, conventional tract tracing studies have demonstrated that peripheral pseudounipolar dorsal root ganglion (DRG) sensory cells innervate WAT. The central nervous system projections of WAT afferents remain uncharted, however, and form the focus of the present study. We used the H 129 strain of the herpes simplex virus-1 (HSV-1), an anterograde transneuronal viral tract tracer, to define the afferent circuits projecting from WAT to the central nervous system. Siberian hamster inguinal (IWAT) or epididymal WAT was injected with H129 and the neuraxis processed for HSV-1 immunoreactivity. We found substantial overlap in the pattern of WAT sensory afferent projections with multiple SNS outflow sites along the neuraxis, suggesting the possibility of WAT sensory-SNS circuits that could regulate WAT SNS drive and thereby lipolysis. Previously, we demonstrated that systemic 2-deoxy-D-glucose (2DG) elicited increases in the SNS drive to IWAT. Here, we show that systemic 2DG administration also significantly increases multiunit spike activity arising from decentralized IWAT afferents. Collectively, these data provide structural and functional support for the existence of a sensory WAT pathway to the brain, important in the negative feedback control of lipid mobilization. 2-deoxy-D-glucose; lipolysis; sympathetic nervous system; electrophysiology

Mobilization of fatty acids from stored triacylglycerol (TG) in adipose tissue and skeletal muscle [intramyocellular triacylglycerol (IMTG)] requires activity of lipases. Although exercise training increases the lipolytic capacity of skeletal muscle, the expression of hormone-sensitive lipase (HSL) is not changed. Recently, adipose triglyceride lipase (ATGL) was identified as a TG-specific lipase in various rodent tissues. To investigate whether human skeletal muscle ATGL protein is regulated by endurance exercise training, 10 healthy young men completed 8 wk of supervised endurance exercise training. Western blotting analysis on lysates of skeletal muscle biopsy samples revealed that exercise training induced a twofold increase in skeletal muscle ATGL protein content. In contrast to ATGL, expression of comparative gene identification 58 (CGI-58), the activating protein of ATGL, and HSL protein was not significantly changed after the training period. The IMTG concentration was significantly decreased by 28% at termination of the training program compared with before. HSL-phoshorylation at [Ser.sup.660] was increased, HSL-[Ser.sup.659] phosporylation was unchanged, and HSL-phoshorylation at [Ser.sup.565] was decreased altogether, indicating an enhanced basal activity of this lipase. No change was found in the expression of diacylglycerol acyl transferase 1 (DGAT1) after training. Inhibition of HSL with a monospecific, small molecule inhibitor (76-0079) and stimulation of ATGL with CGI-58 revealed that significant ATGL activity is present in human skeletal muscle. These results suggest that ATGL in addition to HSL may be important for human skeletal muscle lipolysis. comparative gene identification 58; hormone sensitive lipase; diacylglycerol acyl transferase 1; intramyocellular triacylglycerol; lipolysis

A total of 600 crossbred pigs, whereof 56 were randomly selected for more in-depth studies of carcass and pork quality, were employed to test different tuna oil feeding regimens. The focus was put on the efficiency to enrich lean and adipose tissue with n-3 fatty acids and the expression of adverse side-effects on performance, carcass, and pork quality. The 4 treatments were 0% tuna oil in diet (T0; control), 1% of unrefined tuna oil in diet fed from 35 to 90 kg of BW (T1), and 3% of unrefined tuna oil in diet offered during the early (35 to 60 kg of BW; T3-E) or late stage of fattening (75 to 90 kg of BW; T3-L). With this arrangement, pigs consumed equal lifetime amounts of tuna oil (approximately 1.6 kg per pig). None of the tuna oil treatments had significant effects on performance. There were no differences in carcass quality among tuna oil groups except for group T3-E where carcasses and loin chops were fatter than those of the other groups. Water-holding capacity and texture of the loin as well as firmness and melting properties of the backfat remained widely unaffected by the treatments. Tuna oil feeding resulted in a lighter, less red and less yellow backfat and was found to increase the proportion of n-3 fatty acids to total fatty acids in all treatments. This especially concerned eicosapentaenoic acid and docosahexaenoic acid, but not [alpha]-linolenic acid. There was also a slight increase in oleic acid, whereas n-6 fatty acids largely decreased. Feeding tuna oil during a short period at the end of fattening (T3-L) or permanently during fattening (T1) proved to be similarly efficient in increasing n-3 fatty acid content of lean and adipose tissue (to about 1.6-fold of T0). By contrast, only two-thirds of this increase was found when the same amount of tuna oil had been fed exclusively during early fattening (T3-E). The decreased efficiency in T3-E was associated with better sensory flavor, overall acceptability grading, and oxidative status. The results show that, particularly under the condition of a continuous supply, much of the n-3 fatty acids ingested in early fattening can be recovered in pork. These findings give farmers flexibility as to when and how pork can be enriched in n-3 fatty acids with fish oil. Key words: fatty acid, fish oil, n-3, pig, pork, tuna oil

The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS. renin-angiotensin system; angiotensinogen; myocardium; rat; plasma

The objective was to examine pathways of androgen metabolism in abdominal adipose tissue in women. Abdominal subcutaneous (SC) and omental (OM) adipose tissue samples were surgically obtained in women. Total RNA was isolated from whole adipose tissue samples and from primary preadipocyte cultures before and after induction of differentiation. Expression levels of several steroid-converting enzyme transcripts were examined by real-time RT-PCR. Androgen conversion rates were also measured. We found higher expression levels in SC compared with OM adipose tissue for type 1 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD-1; P < 0.05), for aldo-keto reductase 1C3 (AKR1C3; P < 0.0001), for AKR1C2 (P < 0.0001), and for the androgen receptor (P < 0.0001). 17[beta]-HSD-2 mRNA levels were lower in SC adipose tissue (P < 0.05). Induction of adipocyte differentiation led to significantly increased expression levels in SC cultures for AKR1C3 (4.7-fold, P < 0.01), 11-cis-retinol dehydrogenase (6.9-fold, P < 0.02), AKR1C2 (5.6-fold, P < 0.004), P-450 aromatase (5.7-fold, P < 0.02), steroid sulfatase (3.1-fold, P < 0.02), estrogen receptor-[beta] (11.8-fold, P < 0.01), and the androgen receptor (4.0-fold, P < 0.0005). Generally similar but nonsignificant trends were obtained in OM cultures. DHT inactivation rates increased with differentiation, this effect being mediated by dexamethasone alone, through a glucocorticoid receptor-dependent mechanism. In conclusion, higher mRNA levels of enzymes synthesizing and inactivating androgens are found in differentiated adipocytes, consistent with higher androgen-processing rates in these cells. Glucocorticoidinduced androgen inactivation may locally modulate the exposure of adipose cells to active androgens. aldo-keto reductases; short-chain dehydrogenases; adipocyte differentiation; omental visceral fat; estrogen

Circulating adiponectin is emerging as an important link between obesity, type 2 diabetes, and cardiovascular disease (CVD). However, the spectrum of lifestyle factors that modulate the adiponectin concentration remains to be elucidated, particularly among women. We conducted a cross-sectional study of 877 female twin pairs from the TwinsUK adult twin registry. Using a co-twin design, we examined dietary and body composition influences on adiponectin by conducting matched, within-pair analyses to eliminate confounding. Following multivariable adjustment within-twin pairs, significant influences on adiponectin (log-transformed, percent change per SD of the dietary/body composition variable) were observed for nonstarch polysaccharides (3.25%; 95% CI: 0.06, 6.54; P < 0.05) and magnesium intake (3.80%; 95%C1: 0.17, 7.57; P < 0.05), with a trend toward an association for fruit and vegetable (F&V) intakes (2.55%; 95% CI: -0.26, 5.45; P = 0.08). These modest positive associations cannot be explained by confounding through other lifestyle factors shared by the twins. A significant relationship between adiponectin and 3 derived dietary patterns (F&V, dieting, traditional English), carbohydrate, protein, trans fat, and alcohol intake was also observed. Strong inverse associations with adiponectin were observed for BMI (-10.72 %; 95% CI: -13.78, -7.55), total (-6.89%: 95% CI: -10.34, -3.30; P < 0.05), and central fat mass (-12.50%; 95% CI: -15.82, -9.05; P < 0.05); these relationships were significant both when twins were analyzed as individuals and when characteristics were contrasted within-twin pairs, suggesting a direct effect. We observed modest associations between dietary factors and adiponectin in female twins, independent of adiposity, and report strong inverse associations with body composition. These data reinforce the importance of weight maintenance and increasing consumption of diets rich in plant-based foods to prevent CVD and type 2 diabetes. J. Nutr. 139: 353-358, 2009.

In vivo studies show that [alpha]-tocotrienol and [gamma]-tocotrienol accumulate in adipose tissue. Furthermore, a recent study reports that the oral administration of [gamma]-tocotrienol from a tocotrienol-rich fraction from palm oil (TRF) decreases body fat levels in rats. The objective of this study was to evaluate the effect of TRF and its components on adipocyte differentiation in 3T3-L1 preadipocytes, which differentiated into adipocytes in the presence of 1.8 [micro]mol/L insulin. TRF suppressed the insulin-induced mRNA expression of adipocyte-specific genes such as PPAR[gamma], adipocyte fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein-[alpha] (C/EBP[alpha]) compared with the differentiation of 3T3-L1 preadipocytes into adipocytes only in the presence of insulin. To confirm the suppressive effect of TRF, the major components of TRF, such as [alpha]-tocotrienol, [gamma]-tocotrienol, and [alpha]-tocopherol, were investigated. [alpha]-Tocotrienol and [gamma]-tocotrienol decreased the insulin-induced PPAR[gamma] mRNA expression by 55 and 90%, respectively, compared with insulin, whereas [alpha]-tocopherol increased the mRNA expression. In addition, [gamma]-tocotrienol suppressed the insulin-induced aP2 and C/EBP[alpha] mRNA expression, triglyceride accumulation, and PPART protein levels compared with insulin. The current results also revealed that [gamma]-tocotrienol inhibited the insulin-stimulated phosphorylation of Akt but not extracellular signal-regulated kinase (ERK)1/2 in the insulin signaling pathway of 3T3-L1 preadipocytes. Thus, the antiadipogenic effect of TRF depends on [alpha]-tocotrienol and [gamma]-tocotrienol, and [gamma]-tocotrienol may be a more potent inhibitor of adipogenesis than [alpha]-tocotrienol. Therefore, the results of this study suggest that tocotrienol suppresses insulin-induced differentiation and Akt phosphorylation in 3T3-L1 preadipocytes. Furthermore, tocotrienol could act as an antiadipogenic vitamin in the nutrient-mediated regulation of body fat through its effects on differentiation.

This review highlights the inflammatory and insulin-antagonizing effects of saturated fatty acids (SFA), which contribute to the development of metabolic syndrome. Mechanisms responsible for these unhealthy effects of SFA include: 1) accumulation of diacylglycerol and ceramide; 2) activation of nuclear factor-[kappa]B, protein kinase C-[theta], and mitogen-activated protein kinases, and subsequent induction of inflammatory genes in white adipose tissue, immune cells, and myotubes; 3) decreased PPAR[gamma], coactivator-1 [alpha]/[beta] activation and adiponectin production, which decreases the oxidation of glucose and fatty acids (FA); and 4) recruitment of immune cells like macrophages, neutrophils, and bone marrow-derived dendritic cells to WAT and muscle. Several studies have demonstrated potential health benefits of substituting SFA with unsaturated FA, particularly oleic acid and (n-3) FA. Thus, reducing consumption of foods rich in SFA and increasing consumption of whole grains, fruits, vegetables, lean meats and poultry, fish, low-fat dairy products, and oils containing oleic acid or (n-3) FA is likely to reduce the incidence of metabolic disease.

The common practice in North American feedlot industries is to add antibiotics to the diet to prevent disease and improve both BW gain and feed efficiency. In this study, 240 crossbred steer calves were backgrounded on a 54% silage diet for 80 d and fed a finishing diet consisting of 81% barley grain, 10% barley silage, and 7.5% supplement (DM basis) with and without in-feed antibiotics for approximately 120 d. Calves were assigned to 1 of 5 treatments: a control with no antibiotics, 11 mg/kg of chlortetracycline, 44 mg/kg of chlortetracycline, 44 mg/kg of chlortetracycline plus 44 mg/kg of sulfamethazine, and 11 mg/ kg of tylosin phosphate. A combination of GLC and silver-ion HPLC methods was used to analyze the fatty acid composition of brisket adipose tissue, with emphasis on trans-18:1 and CLA isomers. The inclusion of nonionophore antibiotics in the diet had little effect on the fatty acid composition, except that feeding either 44 mg/kg of chlortetracycline or 11 mg/kg of tylosin caused small increases in 9c-14:1 and 16:0 relative to the control (0.26 and 0.9 g/100 g of total fatty acids, respectively). Likewise, profiles of trans-18:1 and CLA isomers were unchanged by antibiotics, but across treatments the predominant trans-18:1 isomer was 10t-18:1 (where t = trans; 3.22%) at 3 times the concentration of the second most abundant isomer (11t-118:l; vaccenic acid, 1.05%). Rumenic acid (9c,11t-18:2, where c = cis) was the major CLA isomer at 61% of total CLA, followed by 7t,9c-18:2 at 9%. Because no other effects on fatty acid composition were evident, data for trans-18:1 and CLA were pooled across treatments to investigate possible relationships among rumen PUFA metabolites. The total trans-18:1 content in brisket adipose tissue was positively correlated with 10t-18:l, but not with 11t-18:l, whereas the total CLA was positively correlated with 9c,11t-18:2, but not with 7t,9c-18:2. The 7t,9c-18:2 was, however, positively correlated with 10t-18:l and 6t/7t/8t-18:1 but was negatively correlated with rumenic acid. These metabolic interrelationships suggest the presence of bacterial populations with distinct pathways for PUFA biohydrogenation in which either 10t-18:l or 11t-18:1 predominate. Overall, the nonionophore antibiotics tested did not appreciably change adipose tissue composition and consequently could not be used to improve the trans-18:1 or CLA profile (i.e., increase vaccenic and rumenic acids at the expense of 10t-18:l). Key words: adipose tissue, antibiotic, beef, conjugated linoleic acid, trans-18:1

Vitamin A (retinoic acid) is known to be an adipogenic factor influencing both in vitro and in vivo cell development. This study aimed to determine its effect on lamb adipose tissue development during the early phase of postnatal development until 100 d of age. Male lambs (n = 24) of the Rasa Aragonesa breed were used. At birth, lambs were assigned to 1 of 2 experimental groups: 1) the control (C) group, which received feed without vitamin A supplementation, and 2) the vitamin A (V) group, which received a supplement of 500,000 IU/animal twice per week from birth to slaughter. The effect of vitamin A supplementation was studied at 16.8 [+ or -] 0.35 kg of BW (58 [+ or -] 0.7 d of age) and at 27.8 [+ or -] 0.78 kg of BW (101 [+ or -] 6.5 d of age). The variables of lamb growth, carcass, LM area, and lipid content were analyzed. To study adipose tissue development, the amount of adipose tissue accumulated, the size and number of adipocytes, and lipogenic enzyme activities (glycerol 3-phosphate dehydrogenase, fatty acid synthase, and glucose 6-phosphate dehydrogenase) of the omental, perirenal, and s.c. depots were quantified. Results showed that vitamin A supplementation had no influence on growth, carcass variables, LM area, and lipid content during lamb growth but that the number of adipocytes in the perirenal depot was 30% greater in lambs of the V group (P < 0.05) and that these lambs had smaller adipocytes in the omental and perirenal depots (P = 0.06) at 28 kg of BW (101 d of age). These results suggest that the intake of this level of vitamin A during the whole period of growth of the lambs influenced the processes of hyperplasia and hypertrophy in the different adipose depots, depending on their degree of maturity. Key words: adipose tissue, growth, lamb, vitamin A

Impairments in adiponectin multimerization lead to defects in adiponectin secretion and function and are associated with diabetes, yet the underlying mechanisms remain largely unknown. We have identified an adiponectin-interacting protein, previously named GST-kappa, by yeast 2-hybrid screening. The adiponectin-interacting protein contains 2 thioredoxin domains and has very little sequence similarity to other GST isoforms. However, this protein shares high sequence and secondary structure homology to bacterial disulfide-bond A oxidoreductase (DsbA) and is thus renamed DsbA-like protein (DsbA-L). DsbA-L is highly expressed in adipose tissue, and its expression level is negatively correlated with obesity in mice and humans. DsbA-L expression in 3T3-L1 adipocytes is stimulated by the insulin sensitizer rosiglitazone and inhibited by the inflammatory cytokine TNF[alpha]. Overexpression of DsbA-L promoted adiponectin multimerization while suppressing DsbA-L expression by RNAi markedly and selectively reduced adiponectin levels and secretion in 3T3-L1 adipocytes. Our results identify DsbA-L as a key regulator for adiponectin biosynthesis and uncover a potential new target for developing therapeutic drugs for the treatment of insulin resistance and its associated metabolic disorders. obesity | yeast 2-hybrid system | adipose tissue | insulin resistance

Background. Observational studies have demonstrated similarities between the underpinning of frailty and biological features of centenarians, suggesting that adaptability to age-related multiple physiological decline may be a core component of successful aging. The aim of this study is to determine whether hormonal pathways potentially involved in energy homeostasis contribute to survival beyond 100 years of age. Methods. We assessed a total of 252 centenarians (mean [standard deviation (SD)] age, 101.5 (1.8) years, range 100-108 years) using a complete set of biomarkers of adipose endocrine function and the insulin-like growth factor-1 (IGF-1) axis. Conventional risk factors at baseline were also assessed. The participants were followed up for all-cause mortality every 12 months by telephone contact. Results. During 2253 days of follow-up, 208 centenarians (82.5%) died. The lowest tertile of leptin and the highest tertile of tumor necrosis factor-[alpha] were associated with higher mortality risk among centenarians after adjusting for age (per 6-month increase), sex, education, smoking, activities of daily living (ADL), cognitive function, and comorbidities (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.14-2.35; and HR 1.45; 95% CI, 1.00-2.08, respectively). The lowest tertiles of both IGF-1 and IGF binding protein 3 (IGFBP3) were also associated with increased mortality. The adipose risk score, indicating cumulative effects of adipokine dysregulation, was strongly associated with increased mortality risk; ADL; cognitive function; and levels of albumin, cholinesterase, high-density lipoprotein-cholesterol, C-reactive protein, inteleukin 6, and IGF-1 at baseline. Conclusions. The results suggested that preservation of adipose endocrine function and the IGF-1 axis may be potentially important for maintaining health and function and promoting survival at an extremely old age. Key Words: Centenarians--Leptin--Adiponectin--Tumor necrosis factor-alpha--Insulin-like growth factor 1--Mortality-- Frailty--Metabolic network.

Energy balance controls the expression of the leptin receptor (Lepr) in the ruminant hypothalamus but whether similar regulation occurs in peripheral tissues is unknown. To address this issue, we measured Lepr expression in the liver and adipose tissue of dairy cows during the transition from late pregnancy (LP) to early lactation (EL). This period is characterized by the development of a profound state of energy insufficiency and is associated with reduced plasma insulin and leptin and with increased plasma growth hormone. Hepatic expression of the short (Lepr-a) and long (Lepr-b) isoforms was 40% higher during EL (8 days postpartum) than LP (30 days prepartum). A similar effect was observed when negative energy balance was induced in nonpregnant, late-lactation dairy cows by food restriction, implicating energy insufficiency as a specific cause in EL. The stimulation of hepatic Lepr expression was reversed after a 48-h period of hyperinsulinemic euglycemia in EL. Changes in hepatic Lepr expression during chronic elevation of plasma leptin in EL or plasma growth hormone in nonpregnant, late-lactation cows did not support a role for these hormones in mediating the effects of energy insufficiency on hepatic Lepr expression. In adipose tissue, Lepr expression was increased 10-fold during the transition from LP to EL. Overall, these data indicate that hypoinsulinemia is partly responsible for the induction of Lepr expression in the liver, and perhaps adipose tissue, of energy-deficient dairy cows. bovine; energy balance; liver; adipose

Adipose tissue development is associated with neovascularization, which might be exploited therapeutically. We investigated the neovasculogenesis antigenic profile and kinetics in adipose tissue-derived stromal cells (ADSCs) to understand the potential of ADSCs to generate new vessels. Murine and human visceral adipose tissues were processed with collagenase to obtain ADSCs from the stromal vascular fraction. Freshly isolated murine and human ADSCs featured the expression of early markers of endothelial differentiation [uptake of DiI-labeled acetylated LDL, CD133, CD34, kinase insert domain receptor (KDR)], but not markers for more mature endothelial cells (CD31 and von Willebrand factor). In methylcellulose medium, multilocular cells positive for Oil Red O staining appeared after 6 days. After 10 days, clusters of ADSCs spontaneously formed branched tubelike structures, which were strongly positive for CD34 and CD31, while losing their ability to undergo adipocyte differentiation. In Matrigel, in the presence of endothelial growth factors ADSCs formed branched tubelike structures. By clonal assays in methylcellulose we also determined the frequency of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming units from ADSCs, compared with bone marrow-derived stromal cells (BMSCs) used as a positive control. After 4-14 days, BMSCs formed 8 [+ or -] 3 BFU-E and 40 [+ or -] 10 CFU-GM, while ADSCs never produced colonies of myeloid progenitors. The developing adipose tissue has neovasculogenic potential, based on the recruitment of local rather than circulating progenitors. Adipose tissue might therefore be a viable autonomous source of cells for postnatal neovascularization. adipogenesis; neovasculogenesis; progenitor cells; stromal cells; biopolymers

Green tea (GT) and its components have been shown to possess antiobesity properties and the corresponding mechanisms of action are being investigated, given the epidemic proportions of obesity incidence. In the current work, we used 12-mo-old male Wistar rats to test the effect of 6 mo of treatment with GT as the sole drinking beverage (52.8 [+ or -] 6.4 mL/d) on adipose tissue (AT). AT aromatase expression was determined by Western blotting, plasma concentrations of 17 [beta]-estradiol and testosterone were determined by RIA, and adipocyte size determined by measuring diameter in tissue sections. Proliferation and apoptosis were also assessed by Ki67 immunostaining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, respectively. Evaluations were made in subcutaneous (sc) AT and visceral (v) AT. Body weight increased over time in both groups (P < 0.001), but the increase was more pronounced in controls (P < 0.001) and food and fluid intake did not influence that effect. At the end of the experiment, aromatase expression increased in the AT (318.5 [+ or -] 60.6% of control in scAT, P< 0.05, and 285.5 [+ or -] 82.9% of control in vAT, P < 0.01). AT of GT-treated rats had a higher percentage of proliferating cells (204.1 [+ or -] 19.5% of control in scAT, P < 0.01, and 246.6 [+ or -] 50.2% of control in vAT, P< 0.01) and smaller adipocytes (78.3 [+ or -] 1.7% of control in scAT, P< 0.001, and 87.9 [+ or -] 3.2% of control in vAT, P < 0.05). GT also increased the number of apoptotic cells in vAT (320.4 [+ or -] 21.9% of control; P < 0.001). These results suggest new mechanisms for GT on body weight and highlight its potential benefit to prevent or treat obesity and the metabolic syndrome.

Biliary tree structures are embedded in adipose tissue and, therefore, cannot be visualized directly by the surgeon during cholecystectomy operations. This can lead to inadvertent injuries with serious complications for the patient. Computational studies were performed to assess the feasibility of noninvasively localizing these structures from spectrally resolved near-infrared reflectance measurements. Methodologies were developed for vessel localization, both on the adipose tissue surface and depthwise, by use of semi-infinite and two-layer models of diffuse photon propagation in tissues, respectively. The simulation results, along with some preliminary experimental measurements on tissue-simulating phantoms, prove the feasibility of these methods and show promise for their future clinical application. OCIS codes: 170.3660, 170.1610, 290.1990, 290.7050.

Many bird species migrate long distances without any food intake and must optimize storage of energy with respect to minimization of aerodynamic drag. To contribute to the understanding of this issue, we investigated, by magnetic resonance imaging (MRI), spatial distributions of body fat during the accumulation process before migration. We collected data from 12 Lesser Whitethroats (Sylvia curruca), 9 European Robins (Erithacus rubecula), 8 Blackcaps (Sylvia atricapilla), and 5 Willow Warblers (Phylloscopus trochilus). On average, each bird was examined 3.2 times. Adipose tissue was visualized using T1-weighted spin-echo MRI at 1.5 T. Fat-containing pixels were identified by an image-segmentation procedure. Data were analyzed with respect to (1) fat distribution within the body, (2) relationship between frontal surface area and fat mass increase, (3) fat mass increase in comparison with increase in total body mass, and (4) fat mass in relation to standardized visual classification of fat deposits. Fat increase was reflected by a larger frontal area, though adipose tissue was not deposited equally along the length of the bird. Slices with largest frontal area showed relatively low fractions of fat. Frontal area increased less than expected from conventional geometrical models, which indicates that the body shape is altered. The increase in total body mass was generally higher than the total fat mass increase, which indicates that other tissue, most likely flight muscle, can metabolize rapidly in correlation with fat accumulation. In Blackcap, total fat mass was not linearly related to standardized fat-deposit classes. Key words: adipose tissue, fat storage, fuel load, magnetic resonance imaging, migration, migratory birds. Plusieurs especes d'oiseaux migrent sur de longues distances sans s'alimenter et doivent optimiser l'accumulation d'energie tout en minimisant la trainee aerodynamique. Afin d'ameliorer notre comprehension sur cette question, nous avons etudie, a l'aide de l'imagerie par resonance magnetique (IRM), la repartition spatiale des graisses corporelles au cours du processus d'accumulation precedant la migration. Nous avons recolte des donnees de 12 Sylvia curruca, 9 Erithacus rubecula, 8 Sylvia atricapilla et 5 Phylloscopus trochilus. En moyenne, chaque oiseau etait examine 3,2 fois. Le tissu adipeux etait observe de l'aide d'IRM en sequence spin echo ponderee en T1 a 1,5 T. Les pixels correspondant aux graisses etaient identifies par une procedure de segmentation des images. Les donnees etaient analysees relativement h (1) la distribution des graisses dans le corps, (2) la relation entre la superficie frontale et l'augmentation de la masse adipeuse, (3) l'augmentation de la masse adipeuse comparativement a l'augmentation de la masse corporelle totale et (4) la masse adipeuse en fonction de la classification visuelle standardisee des depots adipeux. L'augmentation des graisses se refletait par une plus grosse superficie frontale, bien que le tissu adipeux ne se soit pas depose egalement tout le long de l'oiseau. Les tranches avec de plus grosses superficies frontales presentaient des proportions de graisses relativement faibles. La superficie frontale a moins augmente que prevu selon les modales geometriques conventionnels, lesquels indiquent que la forme du corps est alteree. L'augmentation de la masse corporelle totale etait generalement plus importante que l'augmentation de la masse adipeuse totale, ce qui indique que d'autres tissus, probablement des muscles de vol, peuvent metaboliser rapidement en correlation avec l'accumulation de graisses. Chez S. atricapilla, la masse adipeuse totale n'etait pas reliee lineairement aux classes standardisees de depot adipeux.

The subcutaneous (S) and visceral (V) adipose tissue (AT) depots are increasingly recognized as distinct. To test the hypothesis that depot differences exist for adiponectin, fresh and cultured human VAT and SAT from obese type 2 diabetic (T2D) and obese nondiabetic (ND) subjects was examined to determine whether differences in adiponectin content and secretion occurred as a function of depot studied, diabetic status, and response to thiazolidinedione treatment. VAT and SAT were obtained by biopsy and AT explants cultured in defined media for 7 days. Protein expression was assessed by Western blot. Adiponectin content of conditioned medium was determined by radioimmunoassay. Diabetic status had no effect on adiponectin secretion over days 0-2 of culture. In ND SAT, secretion fell over days 2-4 but was sustained at greater levels vs. T2D SAT. In both ND and T2D VAT, adiponectin secretion was low, similar to T2D SAT. Over the 7-day culture period, cellular adiponectin increased in ND SAT and VAT; it remained unchanged in T2D SAT and VAT. Pioglitazone increased adiponectin secretion and content in all SAT. Pioglitazone failed to increase adiponectin secretion from either ND or T2D VAT and increased cellular content only in ND VAT. AT depot differences exist in the secretion of adiponectin and responsiveness to thiazolidinedione treatment. These data suggest that SAT, not VAT, appears to be the major contributor to increased circulating adipopnectin levels in response to pioglitazone treatment. adipose tissue physiology; type 2 diabetes mellitus; body tat distribution; thiazolidinediones; leptin

Hypothalamic neurons are regarded as essential for integrating thermal afferent information from skin and core and issuing commands to autonomic and behavioral effectors that maintain core temperature ([T.sub.c]) during cold exposure and for the control of energy expenditure more generally. Caudal brain stem neurons are necessary elements of the hypothalamic effector pathway and also are directly driven by skin and brain cooling. To assess whether caudal brain stem processing of thermal afferent signals is sufficient to drive endemic effectors for thermogenesis, heart rate (HR), [T.sub.c], and activity responses of chronic decerebrate (CD) and control rats adapted to 23[degrees]C were compared during cold exposure (4, 8, or 12[degrees]C) for 6 h. Other CDs and controls were exposed to 4 or 23[degrees]C for 2 h, and tissues were processed for norepinephrine turnover (NETO), a neurochemical measure of sympathetic drive. Controls maintained [T.sub.c] for all temperatures. CDs maintained [T.sub.c] for the 8 and 12[degrees]C exposures, but [T.sub.c] declined 2[degrees]C during the 4[degrees]C exposure. Cold exposure elevated HR in CDs and controls alike. Tachycardia magnitude correlated with decreases in environmental temperature for controls, but not CDs. Cold increased NETO in brown adipose tissue, heart, and some white adipose tissue pads in CDs and controls compared with their respective room temperature controls. These data demonstrate that, in neural isolation from the hypothalamus, cold exposure drives caudal brain stem neuronal activity and engages local effectors that trigger sympathetic energetic and cardiac responses that are comparable in many, but not in all, respects to those seen in neurologically intact rats. energy balance; thermoregulation; anterior hypothalamus; heart rate; body temperature; sympathetic drive; norepinephrine turnover; white adipose tissue; brown adipose tissue

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient ([Lep.sup.Ob]), and obese hyperleptinemic ([Lep.sup.Db]) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 [micro]g/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1[beta] and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: [Lep.sup.Ob] mice were heaviest; however, [Lep.sup.Db] mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity. adiponectin; leptin

Exercise promotes weight loss and improves insulin sensitivity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Obesity correlates with increased production of inflammatory cytokines, which in turn, contributes to systemic insulin resistance. To test the hypothesis that exercise mitigates this inflammatory response, thereby improving insulin sensitivity, we developed a model of voluntary exercise in mice made obese by feeding of a high fat/high sucrose diet (HFD). Over four wk, mice fed chow gained 2.3 [+ or -] 0.3 g, while HFD mice gained 6.8 [+ or -] 0.5 g. After 4 wk, mice were subdivided into four groups: chow-no exercise, chow-exercise, HFD-no exercise, HFD-exercise and monitored for an additional 6 wk. Chow-no exercise and HFD-no exercise mice gained an additional 1.2 [+ or -] 0.3 g and 3.3 [+ or -] 0.5 g respectively. Exercising mice had higher food consumption, but did not gain additional weight. As expected, GTT and ITT showed impaired glucose tolerance and insulin resistance in HFD-no exercise mice. However, glucose tolerance improved significantly and insulin sensitivity was completely normalized in HFD-exercise animals. Furthermore, expression of TNF-[alpha], MCP-1, PAI-1 and IKK[beta] was increased in adipose tissue from HFD mice compared with chow mice, whereas exercise reversed the increased expression of these inflammatory cytokines. In contrast, expression of these cytokines in liver was unchanged among the four groups. These results suggest that exercise partially reduces adiposity, reverses insulin resistance and decreases adipose tissue inflammation in diet-induced obese mice, despite continued consumption of HFD. insulin resistance; cytokine; adiposity; high-fat diet