Correction to: Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge.
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ABSTRACT:
SUBMITTER: Ghosh S
PROVIDER: S-EPMC6643305 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Correction to: Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge.
Ghosh Sujoy S Taylor Jessica L JL Mendoza Tamra M TM Dang Thanh T Burk David H DH Yu Yongmei Y Kilroy Gail G Floyd Z Elizabeth ZE
Biology of sex differences 20190722 1
Following publication of the original article [1], the authors reported that additional file 1 was incorrect. The corrected additional file 1 is given below. ...[more]
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Project description:BackgroundThe obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age.MethodsBody composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA.ResultsSiah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels.ConclusionsThe most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females.
| S-EPMC6466809 | biostudies-literature
Project description:The goal of this experiment was to examine the sex-dependent effect of Siah2 in brown adipose tissue
2019-04-25 | GSE123990 | GEO
Project description:Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown.K14-VEGFR-3-Ig (sR3) mice that constitutively express soluble-VEGFR-3-Ig in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments.We show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity.These results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance.
| S-EPMC4314545 | biostudies-literature
Project description:The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.
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Project description:The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific peroxisome proliferative activated-receptor-? coactivator-1? (PGC-1?), a transcriptional coactivator of biogenesis, and BCL-2/ADENOVIRUS EIB 19-kDa interacting protein (BNIP3), a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2 production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild-type (WT), liver-specific PGC-1? heterozygote (LPGC-1?), and BNIP3 null mice were thermoneutral housed (29-31°C) and divided into three groups: sedentary-low-fat diet (LFD), 16 wk of (HFD), or 16 wk of HFD with VWR for the final 8 wk (HFD + VWR) (n = 5-7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group; however, HFD + VWR significantly increased maximal respiratory capacity only in WT and PGC-1? females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling control and reduced H2O2 production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1? and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD + VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1? or BNIP3.
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Project description:Obesity, hypertension, cardiovascular disease, and inflammation are closely associated with the rising incidence of diabetes mellitus. One pharmacological target that may have significant potential to lower the risk of obesity-related diseases is the angiotensin type 1 receptor (AT1R). We examined the hypothesis that the AT1R blocker valsartan reduces the metabolic consequences and inflammatory effects of a high-fat (Western) diet in mice. C57BL/6J mice were treated by oral gavage with 10 mg/kg per day of valsartan or vehicle and placed on either a standard chow or Western diet for 12 weeks. Western diet-fed mice given valsartan had improved glucose tolerance, reduced fasting blood glucose levels, and reduced serum insulin levels compared with mice fed a Western diet alone. Valsartan treatment also blocked Western diet-induced increases in serum levels of the proinflammatory cytokines interferon-gamma and monocyte chemotactic protein 1. In the pancreatic islets, valsartan enhanced mitochondrial function and prevented Western diet-induced decreases in glucose-stimulated insulin secretion. In adipose tissue, valsartan reduced Western diet-induced macrophage infiltration and expression of macrophage-derived monocyte chemotactic protein 1. In isolated adipocytes, valsartan treatment blocked or attenuated Western diet-induced changes in expression of several key inflammatory signals: interleukin 12p40, interleukin 12p35, tumor necrosis factor-alpha, interferon-gamma, adiponectin, platelet 12-lipoxygenase, collagen 6, inducible NO synthase, and AT1R. Our findings indicate that AT1R blockade with valsartan attenuated several deleterious effects of the Western diet at the systemic and local levels in islets and adipose tissue. This study suggests that AT1R blockers provide additional therapeutic benefits in the metabolic syndrome and other obesity-related disorders beyond lowering blood pressure.
| S-EPMC2836256 | biostudies-literature
Project description:This study investigates whether ladder climbing (LC), as a model of resistance exercise, can reverse whole-body and skeletal muscle deleterious metabolic and inflammatory effects of high-fat (HF) diet-induced obesity in mice. To accomplish this, Swiss mice were fed for 17 weeks either standard chow (SC) or an HF diet and then randomly assigned to remain sedentary or to undergo 8 weeks of LC training with progressive increases in resistance weight. Prior to beginning the exercise intervention, HF-fed animals displayed a 47% increase in body weight (BW) and impaired ability to clear blood glucose during an insulin tolerance test (ITT) when compared to SC animals. However, 8 weeks of LC significantly reduced BW, adipocyte size, as well as glycemia under fasting and during the ITT in HF-fed rats. LC also increased the phosphorylation of AktSer473 and AMPKThr172 and reduced tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL1-β) contents in the quadriceps muscles of HF-fed mice. Additionally, LC reduced the gene expression of inflammatory markers and attenuated HF-diet-induced NADPH oxidase subunit gp91phox in skeletal muscles. LC training was effective in reducing adiposity and the content of inflammatory mediators in skeletal muscle and improved whole-body glycemic control in mice fed an HF diet.
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Project description:Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.
| S-EPMC6349710 | biostudies-literature
Project description:Diet and/or exercise are cost effective interventions to treat obesity. However, it is unclear if the type of exercise undertaken can prevent the onset of obesity and if it can act through different effects on fat depots. In this study we did not allow obesity to develop so we commenced the high-fat diet (HFD) and exercise programs concurrently and investigated the effect of endurance exercise (END) and high-intensity interval training (HIIT) on changes in cellular adipogenesis, thermogenesis, fibrosis, and inflammatory markers in three different fat depots, on a HFD and a chow diet. This was to assess the effectiveness of exercise to prevent the onset of obesity-induced changes. Mice fed with chow or HFD (45% kcal fat) were trained and performed either END or HIIT for 10 weeks (3 x 40 min sessions/week). In HFD mice, both exercise programs significantly prevented the increase in body weight (END: 17%, HIIT: 20%), total body fat mass (END: 46%, HIIT: 50%), increased lean mass as a proportion of body weight (Lean mass/BW) by 14%, and improved insulin sensitivity by 22%. Further evidence of the preventative effect of exercise was seen significantly decreased markers for adipogenesis, inflammation, and extracellular matrix accumulation in both subcutaneous adipose tissue (SAT) and epididymal adipose tissue (EPI). In chow, no such marked effects were seen with both the exercise programs on all the three fat depots. This study establishes the beneficial effect of both HIIT and END exercise in preventing metabolic deterioration, collagen deposition, and inflammatory responses in fat depots, resulting in an improved whole body insulin resistance in HFD mice.
| S-EPMC8371352 | biostudies-literature
Project description:The ever-increasing incidence of obesity and related disorders impose serious challenges on public health worldwide. Brown adipose tissue (BAT) has strong capacity for promoting energy expenditure and has shown great potential in treating obesity. Exosomes are nanovesicles that share the characteristics of their donor cells. Whether BAT derived exosomes (BAT-Exos) might exert similar metabolic benefits on obesity is worthy of investigation. Methods: Obese mice were established by high-fat-diet (HFD) feeding and were treated with Seum-Exos or BAT-Exos isolated from young healthy mice. Blood glucose, glucose tolerance and blood lipids were tested in mice with indicated treatments. Histology examinations were performed on adipose tissue, liver and heart by HE staining and/or Oil Red O staining. Echocardiography was performed to evaluate cardiac function of mice. In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging and in vitro effects of exosomes were evaluated by cell metabolism analysis. Protein contents of BAT-Exos were analyzed by mass spectrometry. Results: The results showed that BAT-Exos reduced the body weight, lowered blood glucose and alleviated lipid accumulation in HFD mice independently of food intake. Echocardiography revealed that the abnormal cardiac functions of HFD mice were significantly restored after treatment with BAT-Exos. Cell metabolism analysis showed that treatment with BAT-Exos significantly promoted oxygen consumption in recipient cells. Protein profiling of exosomes demonstrated that BAT-Exos were rich in mitochondria components and involved in catalytic processes. Conclusions: Collectively, our study showed that BAT-Exos significantly mitigated the metabolic syndrome in HFD mice. Detailed elucidation of the reactive molecules and mechanism of action would provide new insights in combating obesity and related disorders.
| S-EPMC7381731 | biostudies-literature