Retroperitoneal Adipose Tissue Mass Research Articles

Estrogen deficiency reduces maximal running capacity and affects serotonin levels differently in the hippocampus and nucleus accumbens in response to acute exercise.

Estrogen deficiency is associated with unfavorable changes in body composition and metabolic health. While physical activity ameliorates several of the negative effects, loss of ovarian function is associated with decreased physical activity levels. It has been proposed that the changes in brain neurochemical levels and /or impaired skeletal muscle function may underlie this phenomenon. We studied the effect of estrogen deficiency induced via ovariectomy (OVX) in female Wistar rats (n = 64). Rats underwent either sham or OVX surgery and were allocated thereafter into four groups matched for body mass and maximal running capacity: sham/control, sham/max, OVX/control, and OVX/max, of which the max groups had maximal running test before euthanasia to induce acute response to exercise. Metabolism, spontaneous activity, and maximal running capacity were measured before (PRE) and after (POST) the surgeries. Three months following the surgery, rats were euthanized, and blood and tissue samples harvested. Proteins were analyzed from gastrocnemius muscle and retroperitoneal adipose tissue via Western blot. Brain neurochemical markers were measured from nucleus accumbens (NA) and hippocampus (HC) using ultra-high performance liquid chromatography. OVX had lower basal energy expenditure and higher body mass and retroperitoneal adipose tissue mass compared with sham group (p ≤ 0.005). OVX reduced maximal running capacity by 17% (p = 0.005) with no changes in muscle mass or phosphorylated form of regulatory light chain (pRLC) in gastrocnemius muscle. OVX was associated with lower serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level in the NA compared with sham (p = 0.007). In response to acute exercise, OVX was associated with low serotonin level in the HC and high level in the NA (p ≤ 0.024). Our results highlight that OVX reduces maximal running capacity and affects the response of brain neurochemical levels to acute exercise in a brain region-specific manner. These results may offer mechanistic insight into why OVX reduces willingness to exercise.

Moderate Exercise Training Combined With a High-Fat and Sucrose Diet Protects Pancreatic Islet Function in Male C57BL/6J Mice.

Obesity is mainly caused by excess energy intake and physical inactivity, and the number of overweight/obese individuals has been steadily increasing for decades. Previous studies showed that rodents fed westernized diets exhibit endocrine pancreas deterioration and a range of metabolic disorders. This study evaluated the effects of moderated aerobic treadmill exercise training on pancreatic islet cell viability and function in mice consuming a high-fat and sucrose diet. In the present study, 60-day-old male C57BL/6J mice were divided into four groups: control (C), fed a standard diet AIN-93M (3.83 kcal/g; 70% carbohydrate (cornstarch and dextrinized starch were chosen as the major source of carbohydrate for the AIN-93 diet. In addition, a small amount of sucrose), 20% protein (casein), and 10% fat (soybean) with no training (i.e., sedentary); C + training (CTR, fed the standard diet with eight weeks of exercise; high-fat diet + sucrose (HFDS), fed a high fat and sucrose diet (5.2 kcal/g; 20% carbohydrate (cornstarch and dextrinized starch were chosen as the major source of carbohydrate), 20% protein (casein), 60% fat (Lard was chosen as the major source of fat and a small amount of soybean) + 20% sucrose diluted in drinking water with no training; and HFDS + training (HFDSTR). After eight weeks, the HFDS mice displayed increased body weight (P<0.001) and epididymal, inguinal and retroperitoneal adipose tissue mass (P<0.01). These mice also presented insulin resistance (P<0.01), glucose intolerance (P<0.001), impaired glucose-stimulated insulin secretion (GSIS) and were less responsive to the physiological net ROS production induced by glucose stimulus. The HFDS group’s pancreatic islet cells were 38% less viable and 59% more apoptotic than those from the C group (P<0.05). The HFDSTR improved glucose tolerance, body mass, insulin sensitivity and GSIS (P<0.05). Furthermore, HFDSTR mice had 53% more viable isolated pancreatic islets cells and 29% fewer apoptotic cells than the HFDS group (P<0.01). Thus, exercise training may slow down and/or prevent adverse metabolic effects associated with consuming a westernized diet.

Restricted feeding for 9 h in the active period partially abrogates the detrimental metabolic effects of a Western diet with liquid sugar consumption in mice

BackgroundObesity is a major public health concern that can result from diets high in fat and sugar, including sugar sweetened beverages. A proposed treatment for dietary-induced obesity is time-restricted feeding (TRF), which restricts consumption of food to specific times of the 24-hour cycle. Although TRF shows great promise to prevent obesity and the development of chronic disease, the effects of TRF to reverse metabolic changes and the development of NAFLD in animal models of a Western diet with sugary water consumption is not known. ObjectiveThe objective of the current study was to evaluate the role of TRF in the treatment of obesity and NAFLD through examination of changes in metabolic and histopathologic parameters. MethodsTo better understand the role of TRF in the treatment of obesity and NAFLD, we investigated the metabolic phenotype and NAFLD parameters in a mouse model of NAFLD in which obesity and liver steatosis are induced by a Western Diet (WD): a high-fat diet of lard, milkfat and Crisco with sugary drinking water. Mice were subjected to a short-term (4-weeks) and long-term (10-weeks) TRF in which food was restricted to 9h at night. ResultsPrior to TRF treatment, the WD mice had increased body mass, and exhibited less activity, and higher average daytime energy expenditure (EE) than chow fed mice. Approximately 4- and 10-weeks following TFR treatment, WD-TRF had moderate but not statistically significant weight loss compared to WD-ad libitum (WD-AL) mice. There was a modest but significant reduction in the inguinal adipose tissue weight in both WD-TRF groups compared to the WD-AL groups; however, there was no difference in epididymal and retroperitoneal adipose tissue mass or adipocyte size distribution. In contrast, the diet-induced increase in normalized liver tissue weight, hepatic triglyceride, and NAFLD score was partially abrogated in the 4-week WD-TRF mice, while systemic insulin resistance was partially abrogated and glucose intolerance was completely abrogated in the 10-week WD-TRF mice. Importantly, WD-induced metabolic dysfunction (substrate utilization, energy expenditure, and activity) was partially abrogated by 4- and 10-week TRF. ConclusionsOur results support the hypothesis that TRF aids in reducing the detrimental metabolic effects of consuming a WD with sugary drinking water but does not ameliorate obesity.

Obese Melanocortin‐4 Receptor (MC4R)‐Deficient Pregnant Rats Have Increased Blood Pressure With Reduced Circulating Placental Growth Factor Levels

Preeclampsia is a pregnancy‐specific disorder of hypertension, which significantly increases the immediate and long‐term morbidity of mother and offspring. Obesity is a major risk factor for preeclampsia, but the mechanisms linking obesity to this maternal disorder are unknown. Studies in humans have suggested that a greater angiogenic imbalance mediates this increased risk. Preeclampsia is thought to result from placental ischemia and release of anti‐angiogenic factors, such as sFlt‐1, into the maternal circulation where it reduces bioavailability of vascular protective and angiogenic factors, like placental growth factor (PlGF). We have shown previously, in two separate studies, the PlGF prevents placental ischemia‐induced hypertension in rats and that obese MC4R‐deficient rats have increased sFlt‐1 levels and blood pressure during pregnancy. Therefore, we tested the hypothesis that MC4R‐deficient pregnant rats have increased blood pressure with reduced circulating levels of PlGF. MC4R+/+ and MC4R+/− rats were maintained on a standard chow diet and timed‐pregnancies generated at 15 weeks of age using genotyped‐matched males. Carotid catheters were implanted on gestational day 18 for conscious mean arterial pressure (MAP) measurements and plasma collection on day 19. At day 19, absolute body weights were greater in MC4R+/− (n=13) over MC4R+/+ (n=10) pregnant rats (371±9 vs. 340±6 g, P&lt;0.05), as was retroperitoneal adipose tissue mass (13±1 vs. 9±1 g, P&lt;0.05). Circulating levels of leptin (6.7±1.0 vs. 3.5±0.4 ng/mL, P&lt;0.05) were also greater in the obese pregnant rats. MAP was greater in the obese pregnant rats (108±2 vs. 101±1, P&lt;0.05). In addition, circulating sFlt‐1 levels were doubled in the obese pregnant rats (440±128 vs. 252±106 ng/mL) but not in placental tissue (136±10 vs. 143±7 ng/mL). In contrast, the obese MC4R+/− pregnant rats had significantly reduced plasma levels of PlGF (45±10 vs. 121±34 pg/mL, P&lt;0.05) but not in the placenta (496±152 vs. 508±183). In conclusion, these data suggest that the increased blood pressure found in obese MC4R‐deficient pregnant rats is associated with reduced circulating PlGF, and that therapeutic strategies to restore PlGF levels may be a way to reduce the increased incidence of preeclampsia in obese pregnancies.Support or Funding InformationK99HL130577, HL51971, P20GM104357

Regulation of Metabolism by Estrogen Receptor Alpha

Postmenopausal estrogen deficiency increases the risk for metabolic syndrome, obesity, and type 2 diabetes. Estrogen treatment improves metabolic function in postmenopausal women, and estrogen receptor α (ERα) is thought to be the primary player in these protective metabolic effects. However, the mechanisms behind ERα regulation of metabolic function have not been elucidated. The purpose of this study was to investigate the impact of ERα loss on whole body and skeletal muscle oxidative capacity in a rat model. 14 wk‐old female Wildtype (WT) and ERα knockout (ERα−/−) rats were exercised to exhaustion and one week later a glucose tolerance test was performed. At sacrifice, body weight and adipose tissue depot weights (subcutaneous, retroperitoneal and periuterine) were measured. Adipocyte cell size and mitochondrial protein content were assessed by immunohistochemistry and western blot, respectively. Intramuscular triglyceride storage was also assessed. ERα deficient rats had increased body weight and subcutaneous adipose tissue mass compared with WT rats. Although there was no increase in retroperitoneal adipose tissue mass, adipocyte size was increased in ERα deficient rats. HOMA‐IR values were also increased in ERα−/− animals indicating increased insulin resistance. ERα deficiency also decreased exercise time to exhaustion when compared with WT rats. Mitochondrial proteins Complex IV and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) were significantly decreased and intramuscular triglyceride storage was increased in skeletal muscles from ERα deficient rats. Our data demonstrate the potential regulatory role of ERα to enhance oxidative capacity and improve energy metabolism both systemically and in skeletal muscle. Pharmacological activation of ERα could be an effective strategy for the prevention and treatment of metabolic dysfunction. Selective estrogen receptor modulators currently used as treatment for various postmenopausal symptoms may have the potential to restore metabolic function in postmenopausal women and improve quality of life.Support or Funding InformationThis research was supported in part by an NIH grant (R01 AG031575) and the IRHRM Pilot grant.

Divergent role of nitric oxide in insulin-stimulated aortic vasorelaxation between low- and high-intrinsic aerobic capacity rats

Low-intrinsic aerobic capacity is associated with increased risk for cardiovascular and metabolic diseases and is a strong predictor of early mortality. The effects of intrinsic aerobic capacity on the vascular response to insulin are largely unknown. We tested the hypothesis that rats selectively bred for a low capacity to run (LCR) exhibit vascular dysfunction and impaired vascular reactivity to insulin compared to high capacity running (HCR) rats. Mature female LCR (n = 21) and HCR (n = 17) rats were maintained under sedentary conditions, and in vitro thoracic aortic vascular function was assessed. LCR exhibited greater body mass (13%), body fat (35%), and subcutaneous, perigonadal, and retroperitoneal adipose tissue mass, than HCR. During an intraperitoneal glucose tolerance test, glucose area under the curve (AUC) was not different but insulin AUC was 2-fold greater in LCR than HCR. Acetylcholine and insulin-stimulated aortic vasorelaxation was significantly greater in LCR (65.2 ± 3.8%, and 32.7 ± 4.1%) than HCR (55.0 ± 3.3%, and 16.7 ± 2.8%). Inhibition of nitric oxide synthase (NOS) with L-NAME entirely abolished insulin-mediated vasorelaxation in the aorta of LCR, with no effect in HCR. LCR rats exhibited greater expression of Insulin Receptor protein, lower Endothelin Receptor-A protein, a down-regulation of transcripts for markers of immune cell infiltration (CD11C, CD4, and F4/80) and up-regulation of pro-atherogenic inflammatory genes (VCAM-1 and MCP-1) in the aorta wall. Contrary to our hypothesis, low-aerobic capacity was associated with enhanced aortic endothelial function and NO-mediated reactivity to insulin, despite increased adiposity and evidence of whole body insulin resistance.

Intermittent Physical Activity Produces a Leaner but “Sedentary Obese” White Adipose Tissue Phenotype

Adipose tissue (AT) dysfunction plays a pivotal role in the development of insulin resistance in obesity. Regular physical activity (PA) is effective in reducing AT mass and inflammation; however, whether intermittent PA affords beneficial effects is unknown. The purpose of this study was to evaluate the influence of intermittent PA on adiposity and retroperitoneal AT expression of genes related to inflammation and oxidative stress. Male C57BL/6 mice (age 5 weeks) were randomly assigned to four groups (n=10/group): low‐fat diet sedentary (LFD‐SED), high‐fat diet sedentary (HFD‐SED), HFD regular PA (HFD‐RPA), and HFD intermittent PA (HFD‐IPA) for 24 weeks. All animals were single‐caged. RPA mice had access to voluntary running wheels throughout the study period, whereas IPA mice had access to running wheels for three‐week intervals (i.e., 3 weeks on/3 weeks off) throughout the study period. Both HFD‐RPA and HFD‐IPA were associated with a similar reduction in retroperitoneal AT mass (~‐24%, p&lt;0.05) relative to HFD‐SED. However, HFD‐RPA, but not HFD‐IPA, exhibited a decrease in retroperitoneal adipose mRNA markers of inflammation (F4/80, CD11c, leptin, VCAM‐1) and oxidative stress (p22phox and p47phox). Collectively, these data suggest that episodic PA over a prolonged period of time leads to a reduction in adiposity albeit with retention of a “sedentary obese” white AT phenotype.

Reduced Food Intake is the Major Contributor to the Protective Effect of Rimonabant on Islet in Established Obesity-Associated Type 2 Diabetes

PurposeAlthough the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake.Materials and MethodsAfter diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group).ResultsCompared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p<0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups.ConclusionRimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.

Direct renin inhibition improved insulin resistance and adipose tissue dysfunction in type 2 diabetic KK-Ay mice

The renin-angiotensin system affects insulin sensitivity mainly through the angiotensin II type 1 receptor. In this study, the effects of renin inhibition on insulin resistance and adipose tissue dysfunction were explored in type 2 diabetic KK-A(y) mice. Male KK-A mice were treated with a direct renin inhibitor, aliskiren, administered subcutaneously at a dose of 50 mg/kg per day for 14 days using an osmotic minipump. This dose of aliskiren strongly inhibited plasma renin activity and lowered blood pressure about 17% in KK-A(y) mice. Aliskiren decreased body weight and plasma glucose level, and increased plasma insulin level in a fed condition. Aliskiren also lowered the plasma levels of cholesterol, fatty acids and triglycerides. In the oral glucose tolerant test, the plasma glucose elevation after glucose load was reduced by aliskiren, without a significant change in insulin level. Insulin tolerance test showed that aliskiren enhanced insulin's effect on plasma glucose. Aliskiren also reduced the epididymal adipose tissue mass by 25% and retroperitoneal adipose tissue mass by 35%. In adipose tissue, expression of the insulin receptor was not changed by aliskiren; however, expression of insulin receptor substrate-1, glucose transporter type 4, adiponectin, peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding proteindelta was increased by aliskiren. Moreover, NADPH oxidase activity and expression of inflammatory factors were reduced in adipose tissue. Aliskiren increased the pancreatic beta-cell area in KK-A(y) mice. These results suggest that renin inhibition by aliskiren improved insulin resistance and adipose tissue dysfunction in type 2 diabetic mice through an increase in insulin sensitivity, insulin secretion and adipocyte differentiation, and a reduction of oxidative stress.

Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity

Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. To explain this, we assessed the roles of metabolic factors in 32 affected family members with apoB-defective FHBL and 33 related and unrelated normolipidemic controls matched for age, sex, and indices of adiposity. Two hour, 75 g oral glucose tests, with measurements of plasma glucose and insulin levels, body mass index, and waist-hip ratios were obtained. Abdominal subcutaneous, intraperitoneal (IPAT), and retroperitoneal adipose tissue masses were quantified by MR imaging, and hepatic fat was quantified by MR spectroscopy. Mean +/- SD liver fat percentage values of FHBL and controls were 14.8 +/- 12.0 and 5.2 +/- 5.9, respectively (P = 0.001). Means for these measures of obesity and insulin action were similar in the two groups. Important determinants of liver fat percentage were FHBL-affected status, IPAT, and area under the curve (AUC) insulin in both groups, but the strongest predictors were IPAT in FHBL (partial R(2) = 0.55, P < 0.0002) and AUC insulin in controls (partial R(2) = 0.59, P = 0.0001). Regression of liver fat percentage on IPAT fat was significantly greater for FHBL than for controls (P < 0.001). In summary, because apoB-defective FHBL imparts heightened susceptibility to liver triglyceride accumulation, increasing IPAT and insulin resistance exert greater liver fat-increasing effects in FHBL.

Chronic effects of dehydroepiandrosterone on rat adipose tissue metabolism

The goal of the present study was to examine cellular mechanisms that regulate adipose cell metabolism in ovariectomized (OVX) and intact rats that were subjected to long-term (27 weeks) treatment with dehydroepiandrosterone (DHEA). Forty-eight 16-month-old female rats were divided into 4 groups of 9 to 11 animals (intact, intact-DHEA, OVX, OVX-DHEA). Adipose tissue lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), and cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (cAMP-PDE) activities were determined, and α2-, β1/β2-, and β3-adrenoceptors (ARs) were quantified. DHEA did not affect body weight, fat, or muscle mass in intact rats. The similar retroperitoneal fat pad weight of intact-DHEA rats compared to intact animals was in agreement with the lack of difference in the enzyme activities and AR densities. The increased body weight of OVX rat was paralleled by a greater retroperitoneal adipose tissue mass (P <.01), which was in turn associated with a marked rise in LPL activity (P <.005) and a slight decrease in HSL activity (P <.05) compared to intact animals. OVX-DHEA rats, compared to untreated OVX animals, had a smaller retroperitoneal fat depot, which correlated with a decrease in LPL activity (P <.005) and moderate increase in both HSL activity and β3-AR density (P <.05). DHEA-treatment lowered fasting insulin and triglyceride levels in both intact and OVX rats (P <.05). Plasma testosterone, androsterone, androstenedione, and androstenediol levels were also significantly increased in both intact-DHEA and OVX-DHEA rats compared to untreated animals (P <.0001). These findings suggest that the antiobesity action of DHEA may be related in part to changes in lipase activities and in β3-AR density, and that it is dependent on the ovarian status of the animal. Copyright 2003, Elsevier Science (USA). All rights reserved.

Prediction of total subcutaneous abdominal, intraperitoneal, and retroperitoneal adipose tissue masses in men by a single axial magnetic resonance imaging slice

To develop a simplified but accurate method for determining the masses of various abdominal adipose tissue compartments, we studied the predictive value of masses of intraperitoneal, retroperitoneal, and subcutaneous abdominal adipose tissue determined on single axial abdominal magnetic resonance imaging (MRI) slices taken at various intervertebral levels from the 12th thoracic to 1st sacral vertebra (identified on a sagittal section) for the respective total masses of each compartment calculated from contiguous 10-mm thick MRI slices covering the entire abdomen in 49 men (26 without diabetes and 23 with non-insulin-dependent diabetes mellitus). The MRI slice at the intervertebral level between the lumbar (L) 2 and 3 vertebrae showed the highest and most consistent predictive value for all three compartments (R2 = 0.85 for all). Furthermore, compared with other intervertebral levels, the L2-L3 level had a higher amount of intraperitoneal and retroperitoneal adipose tissue mass. We conclude that determining the masses of various abdominal adipose tissue compartments at the L2-L3 intervertebral level by MRI is an acceptably reliable and accurate method for studying abdominal adiposity in men.

Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone.

To determine the effects of testosterone (T) on lipid assimilation in different adipose tissue depots, T (250 mg, im) was given to 17 middle-aged men 5 days before abdominal surgery. Twenty-four hours before surgery, 10 microCi labeled oleic acid in 80 g milk fat were administered orally. Lipid radioactivity was measured in adipose tissue biopsies from abdominal ac, omental, and retroperitoneal adipose tissues. Subcutaneous, visceral (omental plus mesenteric), and retroperitoneal adipose tissue masses were determined using computerized tomography scans at 22 levels. Sixteen men who were not treated with T served as controls. T administration was followed by an increase in serum concentrations from 17.7 +/- 1.1 to 32.6 +/- 1.8 nmol/L (P < 0.001) and a marked (> 50%) reduction compared with controls in lipid radioactivity in omental and retroperitoneal adipose tissues, but not in sc adipose tissue. In controls, sc, visceral, and retroperitoneal adipose tissues assimilated 59.2 g (73.4%), 16.9 g (20.9%), and 4.6 g (5.7%), respectively, of the orally administered fat. In the T-treated men, this was changed to 73.5 g (88.8%), 6.4 g (7.7%), and 2.9 g (3.5%), respectively. It was concluded that T inhibits triglyceride assimilation in intra-abdominal depots and apparently directs this lipid to sc fat in men.