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Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.

ABSTRACT: Adipose tissue macrophages (ATMs) play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet (HFD)-induced obesity has been shown to lead to ATM accumulation in rodents; however, the impact of hyperglycemia on ATM dynamics in HFD-fed type 2 diabetic models has not been studied. We previously showed that hyperglycemia induces the appearance of proinsulin (PI)-producing proinflammatory bone marrow (BM)-derived cells (PI-BMDCs) in rodents. We fed a 60% HFD to C57BL6/J mice to produce an obese type 2 diabetes model. Absent in chow-fed animals, PI-BMDCs account for 60% of the ATMs in the type 2 diabetic mice. The PI-ATM subset expresses TNF-? and other inflammatory markers, and is highly enriched within crownlike structures (CLSs). We found that amelioration of hyperglycemia by different hypoglycemic agents forestalled PI-producing ATM accumulation and adipose inflammation in these animals. We developed a diphtheria toxin receptor-based strategy to selectively ablate PI-BMDCs among ATMs. Application of the maneuver in HFD-fed type 2 diabetic mice was found to lead to near total disappearance of complex CLSs and reversal of insulin resistance and hepatosteatosis in these animals. In sum, we have identified a novel ATM subset in type 2 diabetic rodents that underlies systemic insulin resistance.

SUBMITTER: Buras ED

PROVIDER: S-EPMC4511209 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.

Buras Eric Dale ED Yang Lina L Saha Pradip P Kim Jongoh J Mehta Pooja P Yang Yisheng Y Hilsenbeck Susan S Kojima Hideto H Chen Wenhao W Smith C Wayne CW Chan Lawrence L

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20150507 8

Adipose tissue macrophages (ATMs) play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet (HFD)-induced obesity has been shown to lead to ATM accumulation in rodents; however, the impact of hyperglycemia on ATM dynamics in HFD-fed type 2 diabetic models has not been studied. We previously showed that hyperglycemia induces the appearance of proinsulin (PI)-producing proinflammatory bone marrow (BM)-derived cells (PI-BMDCs) in rodents. We fed a 60% HFD to C57BL6/J mice t ...[more]

PMID: 25953849

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Project description:BackgroundObesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice.MethodsA total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT.ResultsHFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT.ConclusionOur results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

Project description:The present study is to clarify the effect of insulin-producing cells (IPCs) derived from adipose tissue mesenchymal stem cells (AT-MSCs) on diabetic-induced impairments as the abnormalities of testicular tissues, oxidative stress of testes, and defects of spermatogenesis. Diabetes was stimulated by streptozotocin (STZ) injection in male adult Sprague Dawley (SD) rats. Diabetes was confirmed by taking two highly consecutive fasting blood sugar readings; more than 300 mg/dl; within one week. Five million of IPCs derived from AT-MSCs; encased in TheraCyte capsule; were then directly transplanted (one implant for each rat) subcutaneously in diabetic rats. Implants were maintained for 3 months and the fasting blood sugar of the transplanted rats was observed every month. At the end of the experiment; serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also estimated. The sperm parameters (count, motility, and abnormality) were recorded. In testicular tissue; GPX4, Bcl2, and Bax levels were evaluated, while oxidative stress and antioxidant enzymes activities were measured in the testes homogenate. Also, histopathological alterations were examined in the testes cross-section. In the results, it was found that IPCs treatment enhanced the serum testosterone, FSH, and LH levels. Diabetic-induced impairments in the sperm parameters were noticeably improved post-IPCs transplantation in the diabetic rats. Moreover, the treatment improved the diabetic-associated testicular oxidative stress. Also, it was recognized that the Bax expression decreased, while, GPX4 and Bcl2 expression increased in the treated rats. Meanwhile, the abnormalities showed in the histopathological studies of the hyperglycemic rat's testes were attenuated post-treatment. So, IPCs transplantation improved diabetes and consequently protected against hyperglycemia-induced testicular damages. Diabetes; STZ; stem cells; subcutaneous transplantation; TheraCyte capsule; testicular dysfunction

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Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.

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Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.

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