Mesenteric Adipocytes Research Articles

Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn's disease

ObjectiveMesenteric fat hyperplasia is a hallmark of Crohn's disease (CD), and C reactive protein (CRP) is correlated with disease activity. The authors investigated whether mesenteric adipocytes may be a source...

Dietary fructo-oligosaccharides improve insulin sensitivity along with the suppression of adipocytokine secretion from mesenteric fat cells in rats

Short-chain fructo-oligosaccharides (FOS) are known to have beneficial effects on health. However, the effects of FOS on insulin resistance have not been fully clarified. We observed the effects of FOS feeding on insulin sensitivity and adipocytokine release from abdominal adipocytes in weaning rats. Male Sprague-Dawley rats, 3 weeks old, were divided into three groups and fed a sucrose-based American Institute of Nutrition (AIN)-93 growth diet (control), the control diet containing 5% FOS for 5 weeks (FOS-5wk) or the control diet for 2 weeks followed by the 5% FOS diet for 3 weeks (FOS-3wk). Tail blood was collected after fasting for 9h on day 33 of feeding, and glucose and insulin levels were measured. On the last day, rats were anaesthetised and killed after the collection of aortic blood. Small- and large-intestinal mesenteric fat tissues were immediately excised, and the release of adiponectin, leptin and TNF-α was evaluated from the subsequently isolated adipocytes. The weight of the large-intestinal mesenteric fat, fasting blood insulin level and homeostatic model assessment for insulin resistance decreased in a time-dependent manner, and were much lower in the FOS-5wk group than in the control group. These values were correlated with aortic blood leptin levels. The secretion rate of leptin from the isolated mesenteric adipocytes in the small intestine, but not in the large intestine, was lower in the FOS-fed groups than in the control group. In conclusion, FOS feeding improved insulin sensitivity accompanied by the reduction in large-intestinal fat mass and leptin secretion from the mesenteric adipocytes of the small intestine.

Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance

Trehalose has been shown to evoke lower insulin secretion than glucose in oral saccharide tolerance tests in humans. Given this hypoinsulinemic effect of trehalose, we hypothesized that trehalose suppresses adipocyte hypertrophy by reducing storage of triglyceride and mitigates insulin resistance in mice fed a high-fat diet (HFD). Mice were fed an HFD and given drinking water containing 2.5% saccharide (glucose [Glc], trehalose [Tre], maltose [Mal], high-fructose corn syrup, or fructose [Fru]) ad libitum. After 7 weeks of HFD and saccharide intake, fasting serum insulin levels in the Tre/HFD group were significantly lower than in the Mal/HFD and Glc/HFD groups (P < .05). Furthermore, the Tre/HFD group showed a significantly suppressed elevation of homeostasis model assessment-insulin resistance compared with the Mal/HFD group (P < .05) and showed a trend toward lower homeostasis model assessment-insulin resistance than the Glc/HFD group. After 8 weeks of feeding, mesenteric adipocyte size in the Tre/HFD group showed significantly less hypertrophy than the Glc/HFD, Mal/HFD, high-fructose corn syrup/HFD, or Fru/HFD group. Analysis of gene expression in mesenteric adipocytes showed that no statistically significant difference in the expression of monocyte chemoattractant protein-1 (MCP-1) messenger RNA (mRNA) was observed between the Tre/HFD group and the distilled water/standard diet group, whereas a significant increase in the MCP-1 mRNA expression was observed in the Glc/HFD, Mal/HFD, Fru/HFD, and distilled water/HFD groups. Thus, our data indicate that trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in HFD-fed mice by reducing insulin secretion and down-regulating mRNA expression of MCP-1. These findings further suggest that trehalose is a functional saccharide that mitigates insulin resistance.

Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids

GPR41 is reportedly expressed in murine adipose tissue and mediates short chain fatty acid (SCFA)-stimulated leptin secretion by activating Gαi. Here, we agree with a contradictory report in finding no expression of GPR41 in murine adipose tissue. Nevertheless, in the presence of adenosine deaminase to minimise Gαi signalling via the adenosine A1 receptor, SCFA stimulated leptin secretion by adipocytes from wild-type but not GPR41 knockout mice. Expression of GPR43 was reduced in GPR41 knockout mice. Acetate but not butyrate stimulated leptin secretion in wild-type mesenteric adipocytes, consistent with mediation of the response by GPR43 rather than GPR41. Pertussis toxin prevented stimulation of leptin secretion by propionate in epididymal adipocytes, implicating Gαi signalling mediated by GPR43 in SCFA-stimulated leptin secretion.

Interferon‐gamma Induced Adipose Inflammation Linked to the Impairment of Vascular Function in Type 2 diabetic mice

We hypothesized that IFNγ induces inflammatory cell infiltration and chemoattractant gene expression in mesenteric adipose tissue (MAT) and impairs vascular function of mesenteric arteries (MA) of type 2 diabetic mice. Acetylcholine (ACh)‐induced vasodilation was impaired in Leprdb vs. m Leprdb, but sodium nitroprusside (SNP)‐induced vasodilation was comparable. Both anti‐IFNγ and anti‐MCP‐1 improved endothelial function in Leprdb, while IFNγ induced impaired vascular function in m Leprdb. Mesenteric bed weight and MAT adipocyte size were greatly elevated (P&lt;0.05) in Leprdb vs. m Leprdb. Immunohistochemical staining results revealed that CD3‐positve T‐lymphocytes, Mac‐3 positive macrophages infiltration into the adventitia of small mesenteric arteries was significantly increased in Leprdb and IFNγ‐treated m Leprdb, suggesting the possible crosstalk between adipose inflammation and vascular dysfunction. Western blotting results showed that anti‐IFNγ decreased MAT IFNγ and MCP‐1 protein expression in Leprdb,while IFNγ and MCP‐1 expression was elevated in IFNγ‐treated m Leprdb. Anti‐MCP‐1 treatment only decreased MCP‐1 expression in Leprdb without affecting IFNγ levels, indicating that IFNγ may act as an initiator of MAT inflammation. These results suggest a role for IFNγ in the regulation of visceral adipose inflammatory response and vascular dysfunction in type 2 diabetes.

Adrenaline-Induced Lipolysis in Isolated Rat Mesenteric Adipocytes Is Higher in the Large Intestine Than in the Small Intestine

We determined adrenaline-induced lipolysis in mesenteric adipocytes separated from the small and large intestinal parts, because there are large differences in absorbed nutrients and substances between these two intestinal segments. The adrenaline sensitivity was much higher in the mesenteric adipocytes associated with the large intestine without any significant difference in lipolytic capacity. Intestinal bacteria or their metabolites possibly contributed to this phenomenon.

Metabolic disease prevention and suppression of fat accumulation by Salacia reticulata

In Ayurvedic medicine, Salacia reticulata is known to be useful against various metabolic diseases, including diabetes and obesity. In this study, we attempted to clarify the antiobesity mechanism and the safety of S. reticulata in vivo and in vitro. We gave ordinary MF feed, alone or mixed with S. reticulata (0.3 or 1.0%), to Tsumura Suzuki obesity diabetes (TSOD) mice (spontaneous obese type II diabetes model mice) and Tsumura Suzuki non-obese (TSNO) mice (the corresponding reference animals), ad libitum for 2 months. As compared with the TSNO control mice, the TSOD control mice became obese due to fat accumulation and developed various signs of metabolic diseases. The TSOD mouse group receiving S. reticulata showed the following effects: suppression of body weight increase and fat accumulation, alleviation of abnormal lipid metabolism and abnormal glucose tolerance, and suppression of intrahepatic fat accumulation. Also, S. reticulata prevented the mesenteric adipocyte hypertrophy recognized in TSOD mice. In the TSNO controls, the feed containing 1.0% S. reticulata exerted a suppressing effect on body weight increase and fat accumulation, but the feed containing 0.3% S. reticulata did not show any effect at all. In an in vitro experiment using mouse-derived adipocyte precursor 3T3-L1 cells, S. reticulata significantly suppressed fat accumulation in the differentiation induction phase and maturation phase. This suggested that the metabolic disease-preventing effects of S. reticulata, including the antiobesity effect, may involve suppression of differentiation and accumulation in the adipocytes.

Effect of Honeycomb-Patterned Surface Topography on the Function of Mesenteric Adipocytes

Excessive accumulation of visceral adipose tissue, particularly mesenteric adipose tissue, is one of the most important factors in the pathogenesis of the metabolic syndrome. We previously developed a system for physiologically differentiating rat mesenteric-stromal vascular cells (mSVCs) to mesenteric-visceral adipocytes (mVACs) and are currently implementing various approaches to elucidate the details of the pathophysiology of mVACs. However, there is a critical problem to overcome, namely, that mature mVACs detach from the culture dishes and lose their function after approx. 10 days in culture. Therefore, we examined a culture of mSVCs on self-organized honeycomb-patterned films (honeycomb films) in order to establish a long-term culture for mVACs. The honeycomb films with highly regular porous structures can be prepared under humid casting conditions. These films can be prepared with ease, at a low cost and without any limitations pertaining to the availability of materials for the scaffold. As a result, mSVCs differentiated to mVACs and maintained their function for the secretion of adiponectin on the honeycomb films for at least 40 days. In addition, we investigated the influence of the pore size of the honeycomb films on mVAC behavior. We found that a honeycomb film with a pore size of 20 μm showed the highest mVAC function and optimum size for the long-term culture of mVACs. Thus, we established a long-term culture system for mVACs using the honeycomb films. We believe that this culture system will contribute to the understanding of the pathophysiology of mVACs and to the evaluation of drug candidates for the metabolic syndrome.

Calcium deficiency in the early stages after weaning is associated with the enhancement of a low level of adrenaline-stimulated lipolysis and reduction of adiponectin release in isolated rat mesenteric adipocytes

Dysregulation of visceral adipocytes increases the incidence of metabolic syndrome. Higher production of nonesterified fatty acid and changes in adipocytokine release may trigger insulin resistance. Many studies have suggested that calcium (Ca) deficiency is associated with insulin resistance; however, the mechanisms are poorly understood. We examined the effects of Ca deficiency on adrenaline-induced lipolysis and adipocytokine release in the early stages after weaning using freshly isolated adipocytes from mesenteric fat tissue of 3-week-old male Sprague-Dawley rats fed a normal-Ca (5 g/kg diet) or low-Ca (1 g/kg diet) diet for 4 weeks. The release rate of nonesterified fatty acid in the mesenteric adipocytes after stimulation with a low level of adrenaline (0.2 μg/mL) was much higher in the Ca-deficient group than in the control group. In contrast, adiponectin release in the mesenteric fat cells was lower in Ca-deficient rats. Leptin and tumor necrosis factor– α secretion showed a similar tendency without significant intergroup differences, and monocyte chemoattractant protein–1 release was not affected by Ca deficiency. We found that Ca deficiency reduced the average size of fat cells through a large increase in the number of cells slightly smaller than the average size, which may be associated with the changes in the properties of the mesenteric adipose tissue. Our present results suggest that a low intake of Ca in the early stages after weaning is associated with changes in the properties of mesenteric adipocytes, which may be linked to insulin resistance in the future.

Abstract 5042: Interferon-gamma Induced Adipose Inflammation Linked to the Impairment of Vascular Function in Type 2 Diabetic Mice

Interferon-gamma (IFN) is the hallmark cytokine of Th1 cells and plays a major role in immuno-mediated inflammation in type 1 diabetes. However, the role of IFN in initiating adipose inflammation and subsequent vascular dysfunction in type 2 diabetes remains to be determined. Accordingly, we hypothesized that IFN induces inflammatory cell infiltration and chemoattractant gene expression in mesenteric adipose tissue (MAT) and impairs vascular function of small mesenteric arteries (MA) of type 2 diabetic mice. To test this, we studied MAT inflammation, and vascular function of MA in control mice (m Lepr db ), diabetic mice (Lepr db ), m Lepr db treated with IFN, Lepr db treated with anti-IFN or anti-monocyte chemoattractant protein (MCP)-1. Acetylcholine (ACh)-induced vasodilation was impaired in Lepr db vs. m Lepr db , but sodium nitroprusside (SNP)-induced vasodilation was comparable. Both anti-IFN and anti-MCP-1 improved endothelial function in Lepr db , while IFN induced impaired vascular function in m Lepr db . Mesenteric bed weight and MAT adipocyte size were greatly elevated (P&lt;0.05) in Lepr db vs. m Lepr db . Immunohistochemical staining results revealed that CD3-positve T-lymphocytes, F4/80 and Mac-3 positive macrophage infiltration into MAT was markedly increased in Lepr db and IFN-treated m Lepr db . It showed reduced MAT macrophages infiltration in Lepr db treated with anti-IFN vs. Lepr db . Interestingly, Mac-3 positive macrophage infiltration into the adventitia of small mesenteric arteries was significantly increased in Lepr db and IFN-treated m Lepr db , suggesting the possible crosstalk between adipose inflammation and vascular dysfunction. Western blotting results showed that anti-IFN decreased MAT IFN and MCP-1 protein expression in Lepr db , while IFN and MCP-1 expression was elevated in IFN-treated m Lepr db . Anti-MCP-1 treatment only decreased MCP-1 expression in Lepr db without affecting IFN levels, indicating that IFN may act as an initiator of MAT inflammation and chemoattractant gene expression. These results suggest a role for IFN in the regulation of visceral adipose inflammatory response and vascular dysfunction in type 2 diabetes. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).

Influence of herring (Clupea harengus) and herring fractions on metabolic status in rats fed a high energy diet

Few dietary studies have looked beyond fish oil to explain the beneficial metabolic effects of a fish-containing diet. Our aim was to study whether addition of herring, or sub-fractions of herring, could counteract negative metabolic effects known to be induced by a high-fat, high-sugar diet. Rats were given six different diets: standard pellets; high energy diet with chicken mince (HiE control); high energy diet with herring mince (HiE herring); and high energy diet with chicken mince and either herring oil (HiE herring oil), herring press juice, PJ (HiE PJ) or herring low molecular weight PJ (HiE LMW-PJ). Factors associated with the metabolic syndrome were measured. There were no differences in energy intake or body weight between the groups, but animals fed high energy diets had a higher body fat content compared with the pellet group, although not statistically significant in all groups. Mesenteric adipocyte size was smaller in the HiE herring oil group compared with the HiE control. Glucose clamp studies showed that, compared with the pellet group, the HiE control and HiE herring diets, but not the HiE herring oil diet, induced insulin resistance. Addition of herring or herring oil to the high energy diet decreased total cholesterol levels, triacylglycerols and the atherogenic index compared with the HiE control group. The results suggest that addition of herring or herring oil counteracts negative effects on blood lipids induced by a high energy diet. The lipid component of herring thus seems to be responsible for these beneficial effects.

Physiological levels of insulin and IGF‐1 synergistically enhance the differentiation of mesenteric adipocytes.

Visceral adipose tissue, particularly mesenteric adipose tissue, is important in the pathogenesis of metabolic syndrome. Here, we present a physiologically relevant differentiation system of rat mesenteric-stromal vascular cells (mSVC) to mesenteric-visceral adipocytes (mVAC). We optimized the insulin concentration at levels comparable to those in vivo ( approximately 0.85 ng/ml) by including physiological concentrations of IGF-1. We found that the insulin-like growth factor (IGF-1) and insulin worked synergistically, since IGF-1 alone could induce CCAAT/enhancer binding protein alpha (C/EBPalpha) and adipocyte lipid binding protein (aP2) mRNA expression but not lipid droplet accumulation associated with maturation. Using real-time PCR analyses on 180 adipocyte-related genes, we identified a dramatic effect by IGF-1 plus insulin. We also demonstrated the state of insulin resistance at pathologically high insulin concentrations. This culture system will contribute to understanding the physiological differentiation process and the patho/physiology of mVAC.

Milk fermented byLactobacillus gasseriSBT2055 influences adipocyte size via inhibition of dietary fat absorption in Zucker rats

We have demonstrated previously that a diet containing skimmed milk (SM) fermented by Lactobacillus gasseri SBT2055 (LGSP) reduces adipocyte size in Sprague-Dawley rats. Two experiments were conducted to extend these observations in order to elucidate the mechanism involved. In experiment 1, lean and obese Zucker rats were fed a diet containing SM or LGSP for 4 weeks. The LGSP diet, compared with the SM diet, resulted in lowering of the mesenteric adipose tissue weight (23 %; P < 0.05), adipocyte sizes (28 %; P < 0.001) and serum leptin concentration (36 %; P < 0.05) in lean rats. Obese Zucker rats did not display such dietary effects. Only the number of smaller adipocytes was increased (P < 0.05) by the LGSP diet in the subcutaneous adipose tissue of obese rats. The LGSP diet significantly reduced the serum and hepatic cholesterol in rats. In addition, the LGSP diet led to an increased excretion of faecal fatty acids and total neutral faecal sterols in both rat strains. In experiment 2, Sprague-Dawley rats with permanent cannulation of the thoracic duct were fed either the SM or LGSP diets and their lymph was collected. The LGSP diet lowered the maximum transport rate of TAG and phospholipids. These results indicate that fermented milk regulates adipose tissue growth through inhibition at the stage of dietary fat absorption in lean Zucker rats.

Regulation of Lipoprotein Lipase by Fasting in Epididymal and Mesenteric Adipocytes of Rats

There are marked variations in the activity of lipoprotein lipase (LPL) among adipose depots. The aim of this study was to compare the mechanisms of 24 h of fasting on LPL regulation between epididymal (EPI) adipocytes and mesenteric (MES) adipocytes in rats. 1-Day fasting consistently decreased activities of heparin-releasable LPL, total extractable LPL and cellular LPL markedly in both EPI and MES fat pads. LPL activity in MES fat pads was relatively lower than in the EPI fat pads. Consistent with data on LPL activity, the levels of expression of LPL mRNA in both nutritional states were lower in MES than EPI adipose tissue and isolated adipocytes. The decreased LPL activity after 1 day of fasting in MES adipocytes was explained mainly by a 50% decrease in the relative abundance of LPL mRNA level and a parallel 50% decrease in relative rate of LPL synthesis. In contrast, fasting of 1 day in EPI adipocytes decreased total LPL activity by 47% but did not affect LPL mRNA level or relative rate of LPL synthesis. A decrease in overall protein synthesis contributed to the decreased LPL activity after 1 day fasting both in EPI and MES adipocytes. In MES adipocytes the decrease in LPL activity, LPL mRNA and LPL synthesis were comparable, but in EPI adipocytes the changes in LPL activity were substantially larger than the changes in LPL mRNA level and LPL synthesis. Therefore, fasting decreased fat cell size, LPL activity, LPL mRNA level and relative rate of LPL synthesis in rats, and these effects were more marked in the MES adipocytes. These results clearly demonstrate the regional variations in the metabolic response of adipose tissue and LPL functions to fasting.

Postnatal Testosterone Exposure Results in Insulin Resistance, Enlarged Mesenteric Adipocytes, and an Atherogenic Lipid Profile in Adult Female Rats: Comparisons with Estradiol and Dihydrotestosterone

Postnatal events contribute to features of the metabolic syndrome in adulthood. In this study, postnatally administered testosterone reduced insulin sensitivity and increased the mesenteric fat depot, the size of mesenteric adipocytes, serum levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, and the atherogenic index in adult female rats. To assess the involvement of estrogen and androgen receptors in these programming effects, we compared testosterone-exposed rats to rats exposed to estradiol or dihydrotestosterone (DHT). Estradiol-treated rats had lower insulin sensitivity than testosterone-treated rats and, like those rats, had enlarged mesenteric adipocytes and increased triglyceride levels. DHT also reduced insulin sensitivity but did not mimic the other metabolic effects of testosterone. All treated rats were probably anovulatory, but only those treated with testosterone had reduced testosterone levels. This study confirms our previous finding that postnatal administration of testosterone reduces insulin sensitivity in adult female rats and shows that this effect is accompanied by unfavorable changes in mesenteric fat tissue and in serum lipid levels. The findings in the estradiol and DHT groups suggest that estrogen receptors exert stronger metabolic programming effects than androgen receptors. Thus, insults such as sex hormone exposure in early life may have long-lasting effects, thereby creating a predisposition to disturbances in insulin sensitivity, adipose tissue, and lipid profile in adulthood.

Thiazolidinediones exhibit different effects on preadipocytes isolated from rat mesenteric fat tissue and cell line 3T3‐L1 cells derived from mice

The effects of PPAR-gamma agonists, thiazolidinediones (TZDs), on preadipocytes isolated from rat mesenteric adipose tissue and murine cell line 3T3-L1 were compared using an in vitro cell culture system. After each cell formed a confluent monolayer under appropriate medial conditions, pioglitazone or troglitazone was applied at 10 microM to each medium for cell maturation. We observed morphological changes in each cell, especially the accumulation of lipid droplets in the cytoplasm, during the culture periods. At the end of culture, DNA content, triglyceride (TG) content and glycerol-3-phosphate dehydrogenase (GPDH) activity were determined. Adiponectin concentrations in each culture medium were also measured during appropriate experimental periods. Application of TZDs increased the DNA content, TG accumulation and GPDH activity in the 3T3-L1 cells but not in the mesenteric adipocytes. Although TG accumulation was unchanged, the number of lipid particles was decreased and the size of lipid particles in the mesenteric adipocytes was increased by TZD application. Although the TZDs increased adiponectin release from the 3T3-L1 cells, adiponectin release from mesenteric adipocytes was suppressed (P<0.05). Thus, the effects of TZDs differed between the primary culture of mesenteric adipose cells and the line cell culture of 3T3-L1 cells. The source of adipocytes is an important factor in determining the action of TZDs in vitro, and particular attention should be paid when evaluating the effect of PPAR-gamma agonists on adipose tissues.

Mesenteric adipose tissue alterations resulting from experimental reactivated colitis

Adipose tissue secretes a large number of hormones that act either locally or at distant sites, modulating immune responses, inflammation, and many endocrine and metabolic functions. Abnormalities of fat in the mesentery have been long recognized in surgical specimens as characteristic features of Crohn's disease; however, the importance of this in chronic inflammatory disease is unknown. Additionally, adipocytes in depots that enclose lymph nodes or other dense masses of lymphoid tissue have many site-specific physiological properties. In this study, the alterations of mesenteric and perinodal mesenteric adipose tissue during experimental colitis, induced by repeated intracolonic trinitrobenzene sulfonic acid instillations, were evaluated, focusing on morphological and activity alterations and the adipocytokine production profile. After a 35-day protocol, the colitis animals presented greater mesenteric fat masses despite their lower body weights. Another adipose tissue depot, epididymal adipose tissue, was also evaluated and no change in mass was observed. The mesenteric adipocyte from colitis animals had a reduced diameter, normal PPAR-gamma-2 expression, and higher basal lipolysis and TNF-alpha production when compared to normal rats. Perinodal mesenteric adipocytes present normal diameters, downregulated levels of PPAR-gamma-2, higher basal lipolysis and TNF-alpha, and leptin and adiponectin production. The findings suggest that mesenteric adipose tissue has a site-specific response during experimental inflammation, where perinodal adipose tissue retains the ability to produce different adipocytokines. These substances may interfere in many lymph node aspects, while mesenteric adipose tissue produces substances that could contribute directly to aggravate the inflammatory process.

Fructose Consumption and Moderate Zinc Deficiency Influence Growth and Adipocyte Metabolism in Young Rats Prone to Adult-Onset Obesity

The effects of low zinc, high fructose diet on growth and adipocyte metabolism were examined in rats. At 28 days of age, animals were assigned to diets either adequate in zinc (30 ppm) with water (AZW) or fructose solution (AZF), or low in zinc (5 ppm) with water (LZW) or fructose solution (LZF). Body weight and food and fructose solution intake were measured three times a week. Blood samples were collected at baseline, 4 weeks, and 8 weeks, and energy expenditure was measured. The rats were killed at 12 weeks. Adipocytes were cultured in medium containing C14-glucose and physiological insulin concentrations. The animals in the LZF group consumed less energy and gained less weight than the other groups. Serum zinc concentrations were lower in the LZF than the AZF group. Energy expenditure over a 24-h period did not differ between groups; however, the respiratory quotient in the fed state was higher in the groups consuming fructose solution than in those consuming water. The mesenteric adipocytes from the animals in the LZF group utilized more glucose. Thus, the addition of fructose to a LZ diet reduced energy intake and growth and altered adipocyte fuel metabolism in young growing rats.

A New Rat Model Exhibiting Both Ovarian and Metabolic Characteristics of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. However, its etiology is unclear, and its management is often unsatisfactory or requires a diversified approach. Here, we describe a new rat PCOS model, the first to exhibit both ovarian and metabolic characteristics of the syndrome. Female rats received the nonaromatizable androgen dihydrotestosterone (DHT) or the aromatase inhibitor letrozole by continuous administration, beginning before puberty, to activate androgen receptors. Adult DHT rats had irregular cycles, polycystic ovaries characterized by cysts formed from atretic follicles, and a diminished granulosa layer. They also displayed metabolic features, including increased body weight, increased body fat, and enlarged mesenteric adipocytes, as well as elevated leptin levels and insulin resistance. All letrozole rats were anovulatory and developed polycystic ovaries with structural changes strikingly similar to those in human PCOS. Our findings suggest that the formation of a "hyperplastic" theca interna reflects the inclusion of luteinized granulosa cells in the cyst wall rather than true hyperplasia. We conclude that the letrozole model is suitable for studies of the ovarian features of human PCOS, while the DHT model is suitable for studies of both ovarian and metabolic features of the syndrome.

Depot-Specific Modulation of Rat Intraabdominal Adipose Tissue Lipid Metabolism by Pharmacological Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.