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1.
The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.  相似文献   

2.
Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of a variety of associated comorbidities (e.g., type 2 diabetes, nonalcoholic fatty liver disease, some immune‐related disorders). Although many studies have investigated the pathogenesis of overweight and obesity, multiple regulatory factors underlying the onset of obesity‐related metabolic disorders remain elusive. Macrophages contribute to modulation of obesity‐related inflammation and insulin resistance (IR); adipose tissue macrophages are particularly important in this context. Based on newly identified links between the chemokine system and obesity, macrophage polarization has become an essential target of new therapies for obesity‐related IR. The findings of multiple studies imply that variations in gut microbiota and its metabolites might contribute to the regulation of obesity and related metabolic disorders. Recently, several novel antidiabetic drugs, applied as treatment for weight loss, were shown to be effective for obesity‐induced IR and other comorbidities. The present review will discuss the properties and functions of macrophages in adipose tissue under conditions of obesity from three perspectives: the chemokine system, the gut microbiota, and antidiabetic drug application. It is proposed that macrophages might be a key therapeutic target for obesity‐induced complications.  相似文献   

3.

Context and Aims

Carboxylesterase 1 (CES1) appears to play an important role in the control of the metabolism of triglycerides and cholesterol in adipocytes and other cell types including hepatocytes. Therefore, it is relevant to gain insights into the genetic versus non-genetic mechanisms involved in the control of CES1 mRNA expression. Here, we investigated CES1 mRNA expression level in adipose tissue and its association with measures of adiposity and metabolic function in a population of elderly twins. Furthermore, the heritability of CES1 mRNA expression level in adipose tissue and the effect of CES1 gene duplication were assessed.

Methodology

A total of 295 monozygotic and dizygotic twin subjects (62–83 years) with (n = 48) or without (n = 247) type 2 diabetes mellitus were enrolled in the study. They were subjected to a standard oral glucose tolerance test and excision of abdominal subcutaneous fat biopsies during the fasting state. Levels of CES1 mRNA and copy number of the gene were assessed by quantitative PCR.

Results

CES1 mRNA expression level in adipose tissue was positively associated with body-mass index (P<0.001), homeostasis model assessment-insulin resistance (P = 0.003) and level of fasting glucose (P = 0.002), insulin (P = 0.006), and triglycerides (P = 0.003). The heritability for the expression of CES1 mRNA in adipose tissue was high. CES1 gene duplication was positively associated with insulin sensitivity (P = 0.05) as well as glucose tolerance (P = 0.03) and negatively associated with homeostasis model assessment-insulin resistance (P = 0.02). Duplication of CES1 was not linked to mRNA level of this gene (P = 0.63).

Conclusion

CES1 mRNA in adipose tissue appears to be under strong genetic control and was associated with measures of metabolic function raising the possibility of a potential role of this enzyme in the development of type 2 diabetes mellitus. Further studies are needed to understand the potential effect of CES1 gene duplication on adipocyte and whole-body metabolic functions.  相似文献   

4.
Murine norovirus (MNV) is prevalent in SPF mouse facilities in the United States, and we currently lack sufficient data to determine whether it should be eliminated. It is generally accepted that the virus does not cause clinical symptoms in immunocompetent mice. However, we previously reported that MNV infection alters the phenotype of a mouse model of bacteria-induced inflammatory bowel disease in part through its effects on dendritic cells. The tropism of MNV toward macrophages and dendritic cells makes MNV a potential intercurrent variable in murine models of macrophage-driven inflammatory diseases, such as obesity, insulin resistance, and atherosclerosis. Therefore, we determined whether MNV infection altered obesity and insulin resistance phenotypes in C57BL/6 mice, a widely used model of diet-induced obesity. We found that MNV did not alter weight gain, food intake, and glucose metabolism in this model, but it did induce subtle changes in lymphoid tissue. Further studies using other models of metabolic diseases are needed to provide additional information on the potential role this ‘subclinical’ virus might have on disease progression in mouse models of inflammatory diseases.Abbreviations: HFD, high-fat diet; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; MLN, mesenteric lymph node; MNV, murine norovirusMurine norovirus (MNV) is endemic in many SPF mouse colonies across North America,5 creating considerable potential for this virus to interfere with mouse models of human diseases. In addition, the presence of MNV in some mouse colonies and not in others may help explain phenotypic variability in mouse models across institutions. This virus is related to the human Norwalk virus that causes gastrointestinal inflammation in humans. Although MNV does not cause any overt illness in immunocompetent mice, significant inflammation and mortality can be induced in mice with abnormal innate immunity.7 Previously, we investigated the influence of MNV on the development of bacteria-induced inflammatory bowel disease in FVB.129P2-PAbcb1atm1Bor (Mdr1a−/−) mice.8 We found that infection with MNV accelerated the progression of inflammatory bowel disease in this mouse model when mice were coinfected with Helicobacter bilis. In addition, infection with MNV alone altered the immune response, probably through changes in dendritic cells.8 These findings suggest that MNV may induce subtle changes in immune responses even in immunocompetent mice, given that MNV is known to preferentially infect macrophages and dendritic cells.22Obesity has been defined as a disease of chronic inflammation, and in recent years, the prominent role that macrophages play in this process has been recognized.9,10,21,24 Obesity is a risk factor for various chronic diseases that share inflammation as a critical component of the disease process, such as metabolic syndrome, diabetes, and atherosclerosis.3 Because MNV has tropism for macrophages, we wished to determine whether MNV infection influences the development of obesity and insulin resistance in a widely used animal model of diet-induced obesity. C57BL/6 mice are the most frequently used ‘wild-type’ strain and are prone to develop insulin resistance as obesity develops during high-fat feeding.1 We hypothesized that MNV may accelerate inflammation by stimulating macrophage accumulation in adipose tissue, resulting in a more severe obesity or insulin resistance phenotype when mice are fed a high-fat diet.  相似文献   

5.
《Cell metabolism》2014,19(3):512-526
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6.
7.

Background

Recent understanding that insulin resistance is an inflammatory condition necessitates searching for genes that regulate inflammation in insulin sensitive tissues. 12/15-lipoxygenase (12/15LO) regulates the expression of proinflammatory cytokines and chemokines and is implicated in the early development of diet-induced atherosclerosis. Thus, we tested the hypothesis that 12/15LO is involved in the onset of high fat diet (HFD)-induced insulin resistance.

Methodology/Principal Findings

Cells over-expressing 12/15LO secreted two potent chemokines, MCP-1 and osteopontin, implicated in the development of insulin resistance. We assessed adipose tissue inflammation and whole body insulin resistance in wild type (WT) and 12/15LO knockout (KO) mice after 2–4 weeks on HFD. In adipose tissue from WT mice, HFD resulted in recruitment of CD11b+, F4/80+ macrophages and elevated protein levels of the inflammatory markers IL-1β, IL-6, IL-10, IL-12, IFNγ, Cxcl1 and TNFα. Remarkably, adipose tissue from HFD-fed 12/15LO KO mice was not infiltrated by macrophages and did not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. WT mice developed severe whole body (hepatic and skeletal muscle) insulin resistance after HFD, as measured by hyperinsulinemic euglycemic clamp. In contrast, 12/15LO KO mice exhibited no HFD-induced change in insulin-stimulated glucose disposal rate or hepatic glucose output during clamp studies. Insulin-stimulated Akt phosphorylation in muscle tissue from HFD-fed mice was significantly greater in 12/15LO KO mice than in WT mice.

Conclusions

These results demonstrate that 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding.  相似文献   

8.
9.
The early events that initiate inflammation in the adipose tissue during obesity are not well defined. It is unclear whether the recruitment of CD8 T cells to the adipose tissue during onset of obesity occurs through antigen-dependent or -independent processes. We have previously shown that interaction between NKG2D (natural-killer group 2, member D) and its ligand Rae-1ε is sufficient to recruit cytotoxic T lymphocytes to the pancreas and induce insulitis. Here, we tested whether NKG2D–NKG2D ligand interaction is also involved in obesity-induced adipose tissue inflammation and insulin resistance. We observed a significant induction of NKG2D ligand expression in the adipose tissue of obese mice, especially during the early stages of obesity. However, mice lacking NKG2D developed similar levels of insulin resistance and adipose tissue inflammation compared to control mice when placed on a high-fat diet. Moreover, overexpression of Rae-1ε in the adipose tissue did not increase immune cell infiltration to the adipose tissue either in the setting of a normal or high-fat diet. These results indicate that, unlike in the pancreas, NKG2D–NKG2D ligand interaction does not play a critical role in obesity-induced inflammation in the adipose tissue.  相似文献   

10.
目的:探讨小鼠胰岛素抵抗哮喘模型的建立方法,并进行评估。方法:C57BL/6J小鼠随机分为4组:正常对照组(HC)、哮喘组(NIRA)均给予普通饲料喂养;胰岛素抵抗组IRNA)、胰岛素抵抗+哮喘组(IRA)均给予高脂饲料(D12492)喂养。每周称重,第6-14周,每周检测各组小鼠空腹血糖(FPG)、空腹血清胰岛素(FINS)水平,计算稳态模型胰岛素抵抗评价指数(HOMA-IR)评估胰岛素抵抗程度;小鼠胰岛素抵抗模型建立成功后在其基础上诱导哮喘模型,NIRA组和IRA组小鼠给予卵清蛋白(OVA)致敏、激发;HC组和IRNA组小鼠给予生理盐水作为对照,末次激发24后,制作肺病理切片,计数肺泡灌洗液(BALF)中白细胞总数及分类,检测血清和BALF中相关炎性因子的水平,比较各组小鼠胰岛素抵抗指数与哮喘评价指标,评估模型。结果:(1)第9周末,IRNA组、IRA组小鼠的HOMA-IR值均2.5,表明胰岛素抵抗小鼠模型建立成功;(2)肺组织病理切片中,HC组、IRNA组小鼠肺组织无炎症改变,NIRA组、IRA组炎细胞浸润明显,尤以IRA组更甚。(3)与HC组比较,NIRA组(P0.01)、IRA组(P0.01)BALF中白细胞总数、嗜酸性粒细胞比例明显增高;(4)血清中抗OVA特异性Ig E(P0.01)和Ig G1(P0.05)水平显著升高;(5)血清和BALF中IL-4(P0.01)、IL-17(P0.05)的水平明显升高,且IRA组(P0.05)明显高于NIRA组;IFN-γ(P0.05)的水平明显降低,且IRA组(P0.05)明显低于NIRA组。结论:用高脂饲料喂养C57BL/6J小鼠9周,可建立稳定的胰岛素抵抗模型,从第10周开始用OVA致敏、激发诱发哮喘,可成功建立稳定的胰岛素抵抗哮喘小鼠模型,为进一步研究胰岛素抵抗与哮喘相关机制奠定基础。  相似文献   

11.
Insulin resistance (IR) is a villain role to the pathology of fatty liver diseases implicated in adipose tissue dysfunction, which is characterized by lipid droplets (LDs) accumulation and hypoxia-inducible factor 1α (HIF1α) related macrophage infiltration. HIF1α is required for its lipogenic actions in adipocytes, while and it regulates M1 and M2 polarization features of macrophages. Losartan has been shown to be an insulin sensitizer in obese states, actions involving in HIF1α signaling. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, GTT, ITT, and HOMA-IR were identified losartan alleviated IR signaling in obese mice. This alleviation may through inhibits HIF1α by suppressing STAT3-NF-κB signaling, which, in turn, revealed HIF1α-dependent decreases the angiogenesis pathway in adipose tissue, including regulation of VEGF and TGFβR2 levels. In white adipose tissue, a set of lipogenesis-related genes, Srebp1, Fas, and Scd-1 were markedly downregulated after losartan intervention, as well as reduced LDs size and LD-associated proteins, perilipin family proteins (PLINs) compared with obese mice. Losartan abolished macrophage infiltration with upregulation of M2 and inhibition of M1 macrophage markers in obese mice. Our data suggest that losartan attenuated obese-induced fatty liver, linked to alleviating inflammation in adipose tissues and a shift in M1/M2 macrophage balance. Furthermore, losartan might improve mitochondria biogenesis by upregulating SIRT1, PGC1α, UCP1, and mRNA of Tfam, Cd137, Tmem26, Ucp1 expression in white adipose tissue compared with the obese group. Taken together, losartan may improve IR and adipose dysfunction by inhibiting lipotoxicity and HIF1α pathways.  相似文献   

12.
Over the past two decades increases in obesity, due to high caloric intakes and immobilizing technologies, has led to a surge in type 2 diabetes. In obesity elevated circulating fatty acids set-off a pro-inflammatory cascade that increases the production of tumour necrosis factor-α (TNFα) from macrophages. Obesity is associated with blunted skeletal muscle fatty acid oxidation, accumulation of bioactive lipids and insulin resistance. The factors contributing to defects in fatty acid metabolism are not understood but new data demonstrates that increased TNFα in obesity increases protein phosphatase 2C (PP2C), which in turn suppresses the activity of AMP-activated protein kinase (AMPK), a critical regulator of energy metabolism 1. These data identify a novel mechanism by which inflammation in obesity is a precursor to defects in skeletal muscle fatty acid oxidation that generates a vicious cycle exacerbating the development of insulin resistance.  相似文献   

13.
Diet-induced weight gain causes changes in adipose tissue that alter blood monocytes and adipose tissue macrophages, increasing disease risk. The purpose of this study was to compare the effects of 24 wk of diet-induced weight gain on the percentages of blood monocytes and adipose tissue macrophages as well as the cell-surface expression of toll-like receptors 2 and 4 and leptin receptor, which are associated with inflammation and homing to adipose tissue. Crl:CD1(ICR) male mice were assigned to either a diet-induced weight gain (60% of calories from fat; n = 12) or control (10% of calories from fat; n = 13) group. After 24 wk of dietary treatment, whole blood and bilateral perigonadal fat pads were collected. Whole blood or SVF were separately labeled for monocytes (CD11b+CD14‑) or macrophages (CD11b+F4/80+) and receptor expression by using 3-color flow cytometry. Data were analyzed by using univariate ANOVA. Compared with control mice, those in the weight-gain group had greater body weight, fat mass, and percentages of monocytes and macrophages compared with CN. Regardless of cell type, monocytes and macrophages from mice in the weight-gain group expressed significantly less toll-like receptor 2 and leptin receptor than did control mice. The present study demonstrates that monocytes and macrophages are similarly affected by diet-induced weight gain. More research is needed to confirm how monocytes might be used as a proxy measure of macrophages.Abbreviations: gMFI, geometric mean fluorescence intensity; SVF, stromal vascular fraction; TLR, toll-like receptorDiet-induced weight gain causes changes in adipose tissue that contributes to increased disease risk via an elevation in systemic inflammation.1,13 Obese subjects have elevated concentrations of chemoattractants, which recruit naïve blood monocytes from the blood into adipose, where they mature into adipose tissue macrophages and ‘inflame’ adipose tissue.2,7,8,26 The principal recruitment signal for monocytes is elevated leptin and monocyte chemoattractant protein 1 and reduced adiponectin.4,28 Inflammation, as measured by an increase in proinflammatory cytokine (IL1β, IL6, and TNFα) production, is involved in the pathophysiology of cardiovascular disease and type 2 diabetes mellitus.9,11 Proinflammatory cytokine production in monocytes and macrophages is mediated by toll-like receptors (TLR). Of the 9 known TLR, TLR2 and TLR4 are involved in adipose tissue inflammation because they are responsive to leptin and other biomarkers associated with weight gain.3,5,14,23,24 Despite the known association of both monocytes and macrophages with inflamed adipose tissue, monocytes and macrophages in lean and obese mice have not been compared.Such a comparison would be advantageous because the collection of adipose tissue macrophages requires a terminal procedure, whereas blood monocytes can be harvested by using a nonlethal technique. We previously suggested that the use of nonlethal collection is desirable because it allows a researcher to collect longitudinal data over time and to reduce the number of animals that are required for a given experiment.7,14 Because blood monocytes may be a naïve version of adipose tissue macrophages, their measurement may provide a suitable proxy for the assessment of adipose tissue macrophages. With this knowledge, future studies might improve outcome measures related to diet-induced obesity, with fewer animals required for a given experiment. The purpose of the current study was to evaluate blood monocytes and their cell-surface receptors (leptin receptor, TLR2, and TLR4) as a possible proxy measure of adipose tissue macrophages in lean and obese mice.  相似文献   

14.
Epidemiological, clinical, and experimental animal studies suggest a strong correlation between insulin resistance and Alzheimer’s disease. In fact, type-2 diabetes is considered an important risk factor of developing Alzheimer’s disease. In addition, impaired insulin signaling in the Alzheimer’s disease brain may promote Aβ production, impair Aβ clearance and induce tau hyperphosphorylation, thereby leading to deterioration of the disease. The pathological prion protein, PrPSc, deposits in the form of extracellular aggregates and leads to dementia, raising the question as to whether prion pathogenesis may also be affected by insulin resistance. We therefore established high-fat diet-induced insulin resistance in tga20 mice, which overexpress the prion protein. We then inoculated the insulin-resistant mice with prions. We found that insulin resistance in tga20 mice did not affect prion disease progression, PrPSc deposition, astrogliosis or microglial activation, and had no effect on survival. Our study demonstrates that in a mouse model, insulin resistance does not significantly contribute to prion pathogenesis.  相似文献   

15.
The laboratory mouse is a key animal model for studies of adipose biology, metabolism and disease, yet the developmental changes that occur in tissues and cells that become the adipose layer in mouse skin have received little attention. Moreover, the terminology around this adipose body is often confusing, as frequently no distinction is made between adipose tissue within the skin, and so called subcutaneous fat. Here adipocyte development in mouse dorsal skin was investigated from before birth to the end of the first hair follicle growth cycle. Using Oil Red O staining, immunohistochemistry, quantitative RT-PCR and TUNEL staining we confirmed previous observations of a close spatio-temporal link between hair follicle development and the process of adipogenesis. However, unlike previous studies, we observed that the skin adipose layer was created from cells within the lower dermis. By day 16 of embryonic development (e16) the lower dermis was demarcated from the upper dermal layer, and commitment to adipogenesis in the lower dermis was signalled by expression of FABP4, a marker of adipocyte differentiation. In mature mice the skin adipose layer is separated from underlying subcutaneous adipose tissue by the panniculus carnosus. We observed that the skin adipose tissue did not combine or intermix with subcutaneous adipose tissue at any developmental time point. By transplanting skin isolated from e14.5 mice (prior to the start of adipogenesis), under the kidney capsule of adult mice, we showed that skin adipose tissue develops independently and without influence from subcutaneous depots. This study has reinforced the developmental link between hair follicles and skin adipocyte biology. We argue that because skin adipocytes develop from cells within the dermis and independently from subcutaneous adipose tissue, that it is accurately termed dermal adipose tissue and that, in laboratory mice at least, it represents a separate adipose depot.  相似文献   

16.
Liver X receptors (LXRs) play important roles in regulating cholesterol homeostasis, and lipid and energy metabolism. Therefore, LXR ligands could be used for the management of metabolic disorders. We evaluated rhein, a natural compound from Rheum palmatum L., as an antagonist for LXRs and investigated its anti-obesity mechanism in high-fat diet-fed mice. Surface plasmon resonance assays were performed to examine the direct binding of rhein to LXRs. LXR target gene expression was assessed in 3T3-L1 adipocytes and HepG2 hepatic cells in vitro. C57BL/6J mice fed a high-fat diet were orally administered with rhein for 4 weeks, and then the expression levels of LXR-related genes were analyzed. Rhein bound directly to LXRs. The expression levels of LXR target genes were suppressed by rhein in 3T3-L1 and HepG2 cells. In white adipose tissue, muscle and liver, rhein reprogrammed the expression of LXR target genes related to adipogenesis and cholesterol metabolism. Rhein activated uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) in wild-type mice, but did not affect UCP1 expression in LXR knockout mice. In HIB-1B brown adipocytes, rhein activated the UCP1 gene by antagonizing the repressive effect of LXR on UCP1 expression. This study suggests that rhein may protect against obesity and related metabolic disorders through LXR antagonism and regulation of UCP1 expression in BAT.  相似文献   

17.
A. M. Saxton  E. J. Eisen 《Genetics》1984,106(4):705-718
The hypothesis developed from single-gene mutant obese rodents that brown adipose tissue (BAT), through its thermogenic ability, is an important factor in the development of obesity, was tested in a randombred population of mice in which degree of adiposity is polygenically determined. Additive direct genetic parameters for measures of body size, lean, fatness and BAT at 6 wk of age were estimated under control and high-fat postweaning dietary regimens. Heritabilities were generally similar for the two diets. However, the lipid-free dry (LFD) component of BAT had a heritability estimate of 0.70 ± 0.26 on the control diet, but only 0.09 ± 0.20 on the high-fat diet. For all traits, genotype by diet interactions indicated that additive direct genetic rankings were not significantly different for the two diets. Based on estimates of genetic parameters in the control diet, selection for 6-wk body weight or 3- to 6-wk gain is expected to increase body size and adiposity. Selection for BAT weight is predicted to result in large, lean individuals. However, selection for the LFD content of BAT, generally believed to be a better indicator of thermogenic ability, is predicted to increase fatness as well as body size. Selection for LFD as a proportion of 6-wk body weight reduced the expected correlated response in fatness. It was concluded that BAT does not play a major role in determining the correlated response in obesity that is often found in populations selected for large body size.  相似文献   

18.
Objective: To determine the relationships between visceral and general adiposity, cardiovascular fitness, and markers of the insulin resistance syndrome in obese black and white teenagers. Research Methods and Procedures: Cross‐sectional survey of 81 obese 13‐ to 16‐year‐old youths. Visceral adipose tissue was measured with magnetic resonance imaging, and percentage body fat was measured with dual‐energy X‐ray absorptiometry. Cardiovascular fitness was assessed with a submaximal treadmill test. Fasting blood samples were analyzed for lipids/lipoproteins and insulin. Resting blood pressure was obtained using an automated cuff. Results: Visceral adipose tissue was significantly correlated with unfavorable levels of: triacylglycerol (r = 0.27, p < 0.05), total cholesterol (r = 0.27, p < 0.05), high‐density lipoprotein cholesterol (r = ?0.26, p < 0.05), the ratio of total cholesterol/high‐density lipoprotein cholesterol (r = 0.42, p < 0.01), low‐density lipoprotein cholesterol (r = 0.27, p < 0.05), apolipoprotein B (r = 0.38, p < 0.01), and systolic blood pressure (r = 0.30, p < 0.01). Multiple regression analyses revealed that visceral adipose tissue was more powerful than percentage body fat for explaining variance in lipoproteins (e.g., for the ratio of total cholesterol/high‐density lipoprotein cholesterol, r2 = 0.13, p < 0.01, and for systolic blood pressure, r2 = 0.07, p < 0.05). Ethnicity was the most powerful of the demographic predictors for blood lipids (r2 = 0.15 for triacylglycerol with lower levels in blacks; r2 = 0.10 for high‐density lipoprotein cholesterol with higher levels in blacks; r2 = 0.06 for the ratio of total cholesterol/high‐density lipoprotein cholesterol with lower levels in blacks). Cardiovascular fitness was not retained as a significant predictor of markers of the insulin resistance syndrome. Discussion: Some of the deleterious relationships between visceral adiposity and markers for the insulin resistance syndrome seen in adults were already present in these obese young people.  相似文献   

19.
Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10-4) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10-60) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10-9), BMI (5.4 x 10-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.  相似文献   

20.

Objective

Metabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury) and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase) inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle.

Methods

A full thickness burn (30% total body surface area) was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP) or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated.

Results

Burn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR), insulin receptor substrate (IRS)-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling), PTEN (a negative regulator of Akt-mediated signaling), protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277.

Conclusions

Our data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a pivotal role in burn-induced metabolic dysfunction and inflammatory response. Our study identifies FTase as a novel potential molecular target to reverse or ameliorate metabolic derangements in burn patients.  相似文献   

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