Interleukin‐15 Contributes to the Regulation of Murine Adipose Tissue and Human Adipocytes

An alarming global rise in the prevalence of obesity and its contribution to the development of chronic diseases is a serious health concern. Recently, obesity has been described as a chronic low‐grade inflammatory condition, influenced by both adipose tissue and immune cells suggesting proinflammatory cytokines may play a role in its etiology. Here we examined the effects of interleukin‐15 (IL‐15) on adipose tissue and its association with obesity. Over expression of IL‐15 (IL‐15tg) was associated with lean body condition whereas lack of IL‐15 (IL‐15^?/?) results in significant increase in weight gain without altering appetite. Interestingly, there were no differences in proinflammatory cytokines such as IL‐6 and tumor necrosis factor‐α (TNF‐α) in serum between the three strains of mice. In addition, there were significant numbers of natural killer (NK) cells in fat tissues from IL‐15tg and B6 compared to IL‐15^?/? mice. IL‐15 treatment results in significant weight loss in IL‐15^?/? knockout and diet‐induced obese mice independent of food intake. Fat pad cross‐sections show decreased pad size with over expression of IL‐15 is due to adipocyte shrinkage. IL‐15 induces weight loss without altering food consumption by affecting lipid deposition in adipocytes. Treatment of differentiated human adipocytes with recombinant human IL‐15 protein resulted in decreased lipid deposition. In addition, obese patients had significantly lower serum IL‐15 levels when compared to normal weight individuals. These results clearly suggest that IL‐15 may be involved in adipose tissue regulation and linked to obesity.     

S 23521 Decreases Food Intake and Body Weight Gain in Diet‐Induced Obese Rats

Objective: To investigate the effect of S 23521, a new glucagon‐like peptide‐1‐(7‐36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis. Research Methods and Procedures: Lean and diet‐induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 μg/kg) or subcutaneously (100 μg/kg) for 14 and 20 days, respectively. Because the low‐dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end‐points. Results: Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle‐treated counterparts (3401 ± 65 vs. 3898 ± 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein‐1, uncoupling protein‐3, leptin, resistin, and peroxisome proliferator‐activated receptor (PPAR)‐γ were observed. Discussion: S 23521 is an effective glucagon‐like peptide‐1‐(7‐36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet‐induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.     

The Estrogen Antagonist EM‐652 and Dehydroepiandrosterone Prevent Diet‐ and Ovariectomy‐Induced Obesity

Objective: EM‐652 is a pure antiestrogen in human breast and uterine cancer cells that also reduces bone loss and plasma lipid levels in the rat. This study aimed to assess the ability of EM‐652, alone or with dehydroepiandrosterone (DHEA), to prevent obesity and related metabolic abnormalities induced by an obesity‐promoting diet and ovariectomy. Research Methods and Procedures: Female rats were fed a high‐sucrose, high‐fat (HSHF) diet, were left intact or ovariectomized (OVX), and were treated with EM‐652, DHEA, or both for 20 days. Variables of energy balance and determinants of lipid metabolism and insulin sensitivity were assessed. Results: The HSHF diet (vs. chow) and OVX both increased energy intake and gain, as well as energetic efficiency. Both EM‐652 and DHEA prevented diet‐ and OVX‐induced energy gain mainly by decreasing fat deposition, without being additive. The modest EM‐652‐induced increase in liver triglycerides of intact rats was prevented by its combination with DHEA. EM‐652, but not DHEA, decreased cholesterolemia. The HSHF diet and OVX reduced insulin sensitivity, an effect that was attenuated by EM‐652 and abrogated by DHEA and EM‐652+DHEA. Treatment with EM‐652, DHEA, or their combination abolished the diet‐ and OVX‐induced increase in adipose lipoprotein lipase activity that accompanied fat gain. Discussion: EM‐652 is an effective agent to prevent diet‐ and OVX‐induced obesity and its associated cardiovascular risk factors such as insulin resistance. The addition of DHEA prevents hepatic lipid accumulation and further ameliorates insulin sensitivity. The beneficial metabolic effects of such combined steroid therapy may, therefore, eventually prove to be clinically relevant.     

Meal Pattern Analysis of Diet‐Induced Obesity in Susceptible and Resistant Rats

Objective: To characterize the meal patterns of free feeding Sprague‐Dawley rats that become obese or resist obesity when chronically fed a high‐fat diet. Research Methods and Procedures: Male Sprague‐Dawley rats (N = 120) were weaned onto a high‐fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet‐induced obese (DIO)] and lower [diet‐resistant (DR)] deciles for body‐weight gain were selected for study. A cohort of chow‐fed (CF) rats weight‐matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system. Results: DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups. Discussion: The hyperphagia of a Sprague‐Dawley rat model of chronic diet‐induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.     

Fat Intake Affects Adiposity,Comorbidity Factors,and Energy Metabolism of Sprague‐Dawley Rats

Objective: Childhood obesity is an emerging health problem. This study assesses the effects of three levels of dietary fat (10%, 32%, and 45% measured by kilocalories) on weight gain, body composition, energy metabolism, and comorbidity factors in rats from weaning through maturation. Research Methods and Procedures: The role of dietary fat on the susceptibility to obesity was assessed by feeding diets containing three levels of dietary fat to rats from weaning through 7 months of age. Body composition was analyzed by DXA after 6 and 12 weeks of dietary treatment. Energy metabolism was measured by indirect calorimetry. Results: Energy intake, weight gain, fat mass, and plasma glucose, cholesterol, triglyceride, free fatty acid, leptin, and insulin levels increased dose‐dependently with increased dietary fat. No difference in absolute lean mass among the three groups was observed. Therefore, the differences in weight gain are accounted for primarily by increased fat accretion. Compared with rats that were relatively resistant to obesity when on a 45% fat diet, diet‐induced obesity‐prone rats were in positive energy balance and had an elevated respiratory quotient, indicating a switch in energy substrate use from fat to carbohydrate, which promotes body‐fat accretion. Discussion: Our data support the hypothesis that administration of increasing amount of dietary fat to very young rats enhances susceptibility to diet‐induced obesity and its comorbidities.     

Role of food intake in estradiol-induced body weight changes in female rats

In two experiments, we examined the relationship between estradiol-induced undereating and body weight loss in ovariectomized (OVX) rats. In the first experiment, both estradiol benzoate (EB) and the nonsteroidal anti-estrogen, MER-25, produced body weight losses that could not be duplicated simply by pair-feeding. In the second experiment, we compared the effects of EB treatments in obese OVX rats and in OVX rats in which the post-OVX obesity was prevented by food restriction. When fed ad libitum, both groups of oil-treated OVX rats exhibited substantial body weight gains that were not accompanied by overeating. In lean OVX rats, EB treatments caused a transient hypophagia but did not reduce body weight. These results suggest three conclusions. (1) Changes in food intake are neither necessary nor sufficient to cause some of the body weight changes induced by ovarian hormones. (2) Estradiol can depress food intake in female rats without altering the regulated body weight. (3) More attention should be paid to metabolic factors when studying gonadal influences on body weight.     

Influence of metabolic syndrome on biomarkers of oxidative stress and inflammation in obese adults

Objective: Both obesity and the metabolic syndrome (MetS) have been independently linked with increased oxidative and inflammatory stress. This study tested the hypothesis that obesity with MetS is associated with greater oxidative and inflammatory burden compared with obesity alone. Research Methods and Procedures: Forty‐eight normal‐weight and 40 obese (20 without MetS; 20 with MetS) adults were studied. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Plasma concentrations of oxidized low‐density lipoprotein, C‐reactive protein, tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐18 were determined by enzyme immunoassay. Results: Plasma biomarkers of oxidative stress and inflammation were lowest in normal‐weight controls. Of note, obese MetS adults demonstrated significantly higher plasma concentrations of oxidized low‐density lipoprotein (62.3 ± 3.2 vs. 54.0 ± 4.0 U/L; p < 0.05), C‐reactive protein (3.0 ± 0.6 vs. 1.5 ± 0.3 mg/L; p < 0.01), tumor necrosis factor‐α (2.1 ± 0.1 vs. 1.6 ± 0.1 pg/mL; p < 0.05), IL‐6 (2.8 ± 0.4 vs. 1.4 ± 0.2 pg/mL; p < 0.01), and IL‐18 (253 ± 16 vs. 199 ± 16 pg/mL; p < 0.01), compared with obese adults without MetS. Discussion: These results suggest that MetS heightens oxidative stress and inflammatory burden in obese adults. Increased oxidative and inflammatory stress may contribute to the greater risk of coronary heart disease and cerebrovascular disease in obese adults with MetS.     

Metabolic effects of estrogen substitution in combination with targeted exercise training on the therapy of obesity in ovariectomized Wistar rats

Postmenopausal women tend to have a higher risk in developing obesity and thus metabolic syndrome. Recently we could demonstrate that physical activity and estrogen replacement are effective strategies to prevent the development of nutritional induced obesity in an animal model. The aim of this study was to determine the combined effects of estrogen treatment and exercise training on already established obesity. Therefore ovariectomized (OVX) and sham-operated (SHAM) female Wistar rats were exposed to a high fat diet for ten months. After this induction period obese SHAM and OVX rats either remained sedentary or performed treadmill training for six weeks. In addition OVX rats were treated with 17β-Estradiol (E(2)) alone, or in combination with training. Before and after intervention effects on lipid and glucose metabolism were investigated. Training resulted in SHAM and OVX rats in a significant decrease of body weight, subcutaneous and visceral body fat, size of adipocytes and the serum levels of leptin, cholesterol, low-density lipoprotein and triglycerides. In OVX animals E(2) treatment resulted in similar effects. Often the combination of E(2) treatment and training was most effective. Analysis of the respiratory quotient indicates that SHAM animals had a better fat burning capacity than OVX rats. There was a tendency that training in SHAM animals and E(2) treatment in OVX animals could improve this capacity. Analysis of glucose metabolism revealed that obese SHAM animals had higher glucose tolerance than OVX animals. Training improved glucose tolerance in SHAM and OVX rats, E(2) treatment in OVX rats. The combination of both was most effective. Our results indicate that even after a short intervention period of six weeks E(2) treatment and exercise training improve parameters related to lipid as well as glucose metabolism and energy expenditure in a model of already established obesity. In conclusion a combination of hormone replacement therapy and exercise training could be a very effective strategy to encourage the therapy of diet-induced obesity and its metabolic consequences in postmenopausal women.     

Effect of Diet‐induced Obesity on Acute Pancreatitis Induced by Administration of Interleukin‐12 Plus Interleukin‐18 in Mice

Obesity is associated with increased severity of acute pancreatitis (AP). We recently developed a model of AP induced by administration of interleukin (IL)‐12+IL‐18, two cytokines that are elevated in patients with AP. In this model, severe AP develops in obese leptin‐deficient ob/ob mice compared to lean littermates. In the present report, we evaluated the pancreatic response of diet‐induced obesity (DIO) mice to IL‐12+IL‐18. Body weight loss and adipose tissue necrosis were more severe and prolonged in cytokine‐injected DIO compared to lean mice. Edematous AP developed in lean mice, whereas DIO mice developed necrotizing AP. Obese DIO mice developed more severe hypocalcemia, increased liver damage and a heightened acute‐phase response compared to lean mice, although leukopenia and thrombocytopenia were of comparable severity in lean and DIO mice. Serum levels of IL‐6, IL‐10, and IL‐22 were significantly higher in DIO compared to lean mice, whereas interferon‐γ and tumor necrosis factor‐α did not differ between the two groups. In conclusion, obesity induced by high‐fat diet is associated with increased disease severity and duration in the model of AP induced by administration of IL‐12+IL‐18.     

The Macrophage‐Specific Serum Marker,Soluble CD163, Is Increased in Obesity and Reduced After Dietary‐Induced Weight Loss

Objective: Soluble CD163 (sCD163) is a new macrophage‐specific serum marker elevated in inflammatory conditions. sCD163 is elevated in obesity and found to be a strong predictor of the development of type 2 diabetes. We investigated whether dietary intervention and moderate exercise was related to changes in sCD163 and how sCD163 is associated to insulin resistance in obesity. Design and Methods: Ninety‐six obese subjects were enrolled: 62 followed a very low energy diet (VLED) program for 8 weeks followed by 3‐4 weeks of weight stabilization, 20 followed a moderate exercise program for 12 weeks, and 14 were included without any intervention. Fasting blood samples and anthropometric measures were taken at baseline and after intervention. Thirty‐six lean subjects were included in a control group. Results: sCD163 was significantly higher in obese subjects (2.3 ± 1.0 mg/l) compared with lean (1.6 ± 0.4 mg/l, P < 0.001). Weight loss (11%) induced by VLED resulted in a reduction and partial normalization of sCD163 to 2.0 ± 0.9 mg/l (P < 0.001). Exercise for 12 weeks had no effect on sCD163. At baseline, sCD163 was significantly correlated with BMI (r = 0.46), waist circumference (r = 0.40), insulin resistance measured by the homeostasis model assessment (HOMA‐IR; r = 0.41; all P < 0.001), and the leptin‐to‐adiponectin ratio (r = 0.28, P < 0.05). In a multivariate linear regression analysis with various inflammatory markers, sCD163 (β = 0.25), adiponectin (β = ?0.24), and high sensitivity C‐reactive protein (hs‐CRP; β = 0.20) remained independently and significantly associated to HOMA‐IR (all P < 0.05). After further adjustment for waist circumference, only sCD163 was associated with HOMA‐IR (P < 0.05). Conclusion: The macrophage‐specific serum marker sCD163 is increased in obesity and partially normalized by dietary‐induced weight loss but not by moderate exercise. Furthermore, we confirm that sCD163 is a good marker for obesity‐related insulin resistance.     

Differential secretion of satiety hormones with progression of obesity in JCR:LA-corpulent rats

Objective: To characterize the gastrointestinal tract at the onset and in well‐established obesity. Methods and Procedures: Lean (+/?) and obese (cp/cp) male JCR:LA‐cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified. Results: At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well‐established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide‐1 (GLP‐1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats. Discussion: Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.     

Calcium and Magnesium ATPase Activities in Women with Varying BMIs

Objective: Intracellular calcium (Ca) is increased in obese humans, and magnesium (Mg)‐ATPase activity is increased in monosodium glutamate‐induced obese rats. The aims of this study were to test the hypotheses that Ca‐ATPase activity is negatively correlated with BMI, and that Mg‐ATPase activity is positively correlated with BMI and Ca‐ATPase activity in obese women. Research Methods and Procedures: Thirty healthy adult women, with BMIs of 20 to 40, donated a single sample of whole blood and were interviewed as to medical history and family history of obesity. Erythrocyte membranes were isolated and assayed for Ca‐ATPase and Mg‐ATPase. Weight and height were self‐reported. Regression analysis was used to determine relationship between BMI and enzyme activity. Family history of obesity served as a covariant. Results: Ca‐ATPase was negatively correlated with increasing BMI (r = ? 0.38, p = 0.02). The relationship between BMI and Ca‐ATPase remained valid after controlling for family history of obesity (r = ?0.36, p = 0.03). There was a positive correlation between Mg‐ATPase activity and Ca‐ATPase (r = 0.42, p = 0.024), and this relationship remained valid after controlling for BMI and family history of obesity (r = 0.41, p = 0.03). Discussion: Ca‐ATPase activity decreases as BMI increases. Decreased ATPase activity may contribute to increased intracellular calcium, previously reported in obese persons. Further studies are needed to determine whether a drop in Ca‐ATPase activity can serve as a marker for the development of obesity.     

Intentional Weight Loss Reduces Mortality Rate in a Rodent Model of Dietary Obesity

Objective: We used a rodent model of dietary obesity to evaluate effects of caloric restriction‐induced weight loss on mortality rate. Research Measures and Procedures: In a randomized parallel‐groups design, 312 outbred Sprague‐Dawley rats (one‐half males) were assigned at age 10 weeks to one of three diets: low fat (LF; 18.7% calories as fat) with caloric intake adjusted to maintain body weight 10% below that for ad libitum (AL)‐fed rat food, high fat (HF; 45% calories as fat) fed at the same level, or HF fed AL. At age 46 weeks, the lightest one‐third of the AL group was discarded to ensure a more obese group; the remaining animals were randomly assigned to one of three diets: HF‐AL, HF with energy restricted to produce body weights of animals restricted on the HF diet throughout life, or LF with energy restricted to produce the body weights of animals restricted on the LF diet throughout life. Life span, body weight, and leptin levels were measured. Results: Animals restricted throughout life lived the longest (p < 0.001). Life span was not different among animals that had been obese and then lost weight and animals that had been nonobese throughout life (p = 0.18). Animals that were obese and lost weight lived substantially longer than animals that remained obese throughout life (p = 0.002). Diet composition had no effect on life span (p = 0.52). Discussion: Weight loss after the onset of obesity during adulthood leads to a substantial increase in longevity in rats.     

Attenuation of inflammation and cellular stress‐related pathways maintains insulin sensitivity in obese type I interleukin‐1 receptor knockout mice on a high‐fat diet

The development of insulin resistance in the obese is associated with chronic, low‐grade inflammation. We aimed to identify novel links between obesity, insulin resistance and the inflammatory response by comparing C57BL/6 with type I interleukin‐1 receptor knockout (IL‐1RI^?/?) mice, which are protected against diet‐induced insulin resistance. Mice were fed a high‐fat diet for 16 wk. Insulin sensitivity was measured and proteomic analysis was performed on adipose, hepatic and skeletal muscle tissues. Despite an equal weight gain, IL‐1RI^?/? mice had lower plasma glucose, insulin and triacylglycerol concentrations, compared with controls, following dietary treatment. The higher insulin sensitivity in IL‐1RI^?/? mice was associated with down‐regulation of antioxidant proteins and proteasomes in adipose tissue and hepatic soluble epoxide hydrolase, consistent with a compromised inflammatory response as well as increased glycolysis and decreased fatty acid β‐oxidation in their muscle. Their lower hepatic triacylglycerol concentrations may reflect decreased flux of free fatty acids to the liver, decreased hepatic fatty acid‐binding protein expression and decreased lipogenesis. Correlation analysis revealed down‐regulation of classical biomarkers of ER stress in their adipose tissue, suggesting that disruption of the IL‐1RI‐mediated inflammatory response may attenuate cellular stress, which was associated with significant protection from diet‐induced insulin resistance, independent of obesity.     

Dietary supplementation with Agaricus blazei murill extract prevents diet‐induced obesity and insulin resistance in rats

Objective:

Dietary supplement may potentially help to fight obesity and other metabolic disorders such as insulin‐resistance and low‐grade inflammation. The present study aimed to test whether supplementation with Agaricus blazei murill (ABM) extract could have an effect on diet‐induced obesity in rats.

Design and Methods:

Wistar rats were fed with control diet (CD) or high‐fat diet (HF) and either with or without supplemented ABM for 20 weeks.

Results:

HF diet‐induced body weight gain and increased fat mass compared to CD. In addition HF‐fed rats developed hyperleptinemia and insulinemia as well as insulin resistance and glucose intolerance. In HF‐fed rats, visceral adipose tissue also expressed biomarkers of inflammation. ABM supplementation in HF rats had a protective effect against body weight gain and all study related disorders. This was not due to decreased food intake which remained significantly higher in HF rats whether supplemented with ABM or not compared to control. There was also no change in gut microbiota composition in HF supplemented with ABM. Interestingly, ABM supplementation induced an increase in both energy expenditure and locomotor activity which could partially explain its protective effect against diet‐induced obesity. In addition a decrease in pancreatic lipase activity is also observed in jejunum of ABM‐treated rats suggesting a decrease in lipid absorption.

Conclusions:

Taken together these data highlight a role for ABM to prevent body weight gain and related disorders in peripheral targets independently of effect in food intake in central nervous system.     

Chronic dietary vitamin A supplementation regulates obesity in an obese mutant WNIN/Ob rat model

Objective: To understand the possible role of chronic dietary high vitamin A supplementation in body weight regulation and obesity using a novel WNIN/Ob obese rat model developed at the National Centre for Laboratory Animal Sciences of National Institute of Nutrition, India. Research Methods and Procedures: Thirty‐six 7‐month‐old male rats of lean, carrier, and obese phenotypes were broadly divided into two groups; each group was subdivided into three subgroups consisting of six lean, six carrier, and six obese rats and received diets containing either 2.6 or 129 mg vitamin A/kg of diet for 2 months. Body weight gain, food intake, and weights of various organs were recorded. Adiposity index and BMI were calculated. Serum and liver retinol and brown adipose tissue (BAT)‐uncoupling protein1 (UCP1) mRNA expression levels were quantified. Results: Chronic feeding of high but non‐toxic doses of vitamin A through diet significantly reduced (P ≤ 0.05) body weight gain, adiposity index, and retroperitoneal white adipose tissue mass (without affecting food intake) in obese rats compared with their lean and carrier counterparts. In general, vitamin A treatment significantly improved hepatic retinol stores (P ≤ 0.05) in all phenotypes without affecting serum free retinol levels. However, augmented BAT‐UCP1 expression was observed only in carrier and obese rats (whose basal expression was low). Discussion: Our data suggest that chronic dietary vitamin A supplementation at high doses effectively regulates obesity in obese phenotype of the WNIN/Ob strain, possibly through up‐regulation of the BAT‐UCP1 gene and associated adipose tissue loss. However, in vitamin A‐supplemented lean and carrier rats, changes in adiposity could not be related to BAT‐UCP1 expression levels.     

Adipose tissue interleukin-18 mRNA and plasma interleukin-18: effect of obesity and exercise

Objectives: Obesity and a physically inactive lifestyle are associated with increased risk of developing insulin resistance. The hypothesis that obesity is associated with increased adipose tissue (AT) interleukin (IL)‐18 mRNA expression and that AT IL‐18 mRNA expression is related to insulin resistance was tested. Furthermore, we speculated that acute exercise and exercise training would regulate AT IL‐18 mRNA expression. Research Methods and Procedures: Non‐obese subjects with BMI < 30 kg/m² (women: n = 18; men; n = 11) and obese subjects with BMI >30 kg/m² (women: n = 6; men: n = 7) participated in the study. Blood samples and abdominal subcutaneous AT biopsies were obtained at rest, immediately after an acute exercise bout, and at 2 hours or 10 hours of recovery. After 8 weeks of exercise training of the obese group, sampling was repeated 48 hours after the last training session. Results: AT IL‐18 mRNA content and plasma IL‐18 concentration were higher (p < 0.05) in the obese group than in the non‐obese group. AT IL‐18 mRNA content and plasma IL‐18 concentration was positively correlated (p < 0.05) with insulin resistance. While acute exercise did not affect IL‐18 mRNA expression at the studied time‐points, exercise training reduced AT IL‐18 mRNA content by 20% in both sexes. Discussion: Because obesity and insulin resistance were associated with elevated AT IL‐18 mRNA and plasma IL‐18 levels, the training‐induced lowering of AT IL‐18 mRNA content may contribute to the beneficial effects of regular physical activity with improved insulin sensitivity.     

Effects of Weight Cycling Induced by Diet Cycling in Rats Differing in Susceptibility to Dietary Obesity

LAUER, JOAN B., GEORGE W. REED, AND JAMES O. HILL. Effects of weight cycling induced by diet cycling in rats differing in susceptibility to dietary obesity. Obes Res. Objective Although the majority of evidence in rodents does not support the view that weight cycling (consisting of bouts of food restriction and refeeding) promotes obesity, the effects of weight cycling on body weight regulation remain controversial. We have previously demonstrated that some rats within a strain are more susceptible to develop obesity than others when given free access to a high-fat diet. In this study, we tested the hypothesis that rats most susceptible to weight gain on a high-fat diet would also be most susceptible to weight gain as a consequence of weight cycling. Research Methods and Procedures Rats were provided a low-fat diet (12% corn oil) for 2 weeks, then given a high-fat diet (45% corn oil) for 2 weeks to identify those most (obesity prone) and least (obesity resistant) susceptible to weight gain. Half of each group was then subjected to three 30-day cycles of food restriction (10 days) and refeeding (20 days) [weight cycler (WC) rats]. The other half were allowed free access to the high-fat diet [control (CO) rats]. All rats were then followed for an additional 10 weeks, with free access to the high-fat diet. Results When considering the entire 160 days of the study, we found no evidence that WC rats relative to CO rats had increased body weight, increased body fat content, or elevated energy efficiency. We found no evidence that rats most prone to dietary obesity were also prone to weight gain after weight cycling. During the weight cycling phase (days 1 to 90), weight cycled groups consumed less energy and gained less weight than controls. During the follow-up phase, WC and CO rats did not differ significantly in weight gain or energy intake. Discussion In this study, weight cycling did not exacerbate the obesity produced by high-fat diet feeding.     

Severe Obesity Is Associated With Impaired Arterial Smooth Muscle Function in Young Adults

The degree of arterial dilatation induced by exogenous nitrates (nitrate‐mediated dilatation, NMD) has been similar in obese and normal‐weight adults after single high‐dose glyceryl trinitrate (GTN). We examined whether NMD is impaired in obesity by performing a GTN dose‐response study, as this is a potentially more sensitive measure of arterial smooth muscle function. In this cross‐sectional study, subjects were 19 obese (age 31.0 ± 1.2 years, 10 male, BMI 44.1 ± 2.1) and 19 age‐ and sex‐matched normal‐weight (BMI 22.4 ± 0.4) young adults. Blood pressure (BP), triglycerides, high‐density lipoprotein (HDL), and low‐density lipoprotein (LDL)‐cholesterol, glucose, insulin, high‐sensitivity C‐reactive protein (hs‐CRP), carotid intima‐media thickness (CIMT), and flow‐mediated dilatation (FMD) were measured. After incremental doses of GTN, brachial artery maximal percent dilatation (maximal NMD) and the area under the dose‐response curve (NMD AUC) were calculated. Maximal NMD (13.4 ± 0.9% vs. 18.3 ± 1.1%, P = 0.002) and NMD AUC (54,316 ± 362 vs. 55,613 ± 375, P = 0.018) were lower in obese subjects. The obese had significantly higher hs‐CRP, insulin, and CIMT and lower HDL‐cholesterol. Significant bivariate associations existed between maximal NMD or NMD AUC and BMI‐group (r = ?0.492, P = 0.001 or r = ?0.383, P = 0.009), hs‐CRP (r = ?0.419, P = 0.004 or r = ?0.351, P = 0.015), and HDL‐cholesterol (r = 0.374, P = 0.01 or r = 0.270, P = 0.05). On multivariate analysis, higher BMI‐group remained as the only significant determinant of maximal NMD (r² = 0.242, β = ?0.492, P = 0.002) and NMD AUC (r² = 0.147, β = ?0.383, P = 0.023). In conclusion, arterial smooth muscle function is significantly impaired in the obese. This may be important in their increased cardiovascular risk.