The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.

Objectives: Diabetes and dementia has been considered to have pathological relevance. Early diagnosis and treatment for Mild Cognitive Impairment (MCI) are important to stop it from advancing to dementia. We investigated the rate of MCI or dementia, correlation between cognitive dysfunction (CD) and background factor in diabetes patients, a valuable marker for diagnosis and effective diabetes treatment for prevention of CD. Approach and Results: We identified 161 patients aged ≥60 years, outpatient treatment at Kyushu University hospital from 2016/7 ∼ 2017/11. The Japanese versions of Montreal Cognitive Assessment (MoCA-J) and Mini-Mental State Examination (MMSE) were performed as screening. The patients who showed MMSE≤27 or MoCA-J≤25 had head MRI/SPECT, visited dementia specialist and were diagnosed with the disease type. The CD, screening results, diabetic clinical findings, contents of treatment and relative factors were analyzed by univariate or multivariate analysis. The subjects of investigation were aged 72.6±7.4 years, female 74/161 (46%), BMI 23.3±3.4, HbA1c 7.1±0.8%, duration14.4±10.6 years, insulin therapy 49/161(30.8%). Screening Results: MMSE{MCI22(13.7%), dementia1(0.6%)}/{ MoCA-J: MCI 44 (27.3%), dementia 6 (3.7%)}. 22 patients visited a dementia specialist, and diagnosed with Alzheimer’s dementia 2, MCI 15 and normal 5. The sensitivity of MCI in MMSE, MoCA-J were 46.7% and 93.3%, respectively. Exercise therapy showed significant inhibition of CD in correlation between MoCA-J and diabetes treatment. BMI, insulin history, sulfonylurea history, solitary life, CK, ASO were chosen by stepwise regression, which objective variable was MoCA-J. Age and BMI were significant objective variable by age correction. Conclusions: MMSE and MoCA-J showed significant correlation with treatment background of diabetes patients. MoCA-J is especially thought to be an eminent screening method for MCI in diabetes patients. Disclosure M. Okamoto: None. J. Itoh: None. N. Sonoda: None. Y. Maeda: None. M. Fujii: None. Y. Ogawa: Research Support; Self; AstraZeneca. Advisory Panel; Self; Gilead Sciences, Inc.. Research Support; Self; Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd..

Objectives: Polymerase delta interacting protein 2 (Poldip2) has previously been implicated in migration, proliferation and extracellular matrix (ECM) production in vascular smooth muscle cells. Thereby, regulation of Poldip2 protein expression is suggested to prevent the development and progression of diabetic macroangiopathy. We recently reported that Poldip2+/- mouse aortic smooth muscle cells (MASMs) exhibit higher β1-Integrin expression and activity of the PI3K/Akt/mTOR signaling pathway, leading to increased ECM protein synthesis. We further investigated the mechanism of Podlip2 in regulating the β1-Integrin expression. Approach and Results: Cell adhesion and cell signaling, below the focal adhesion, were investigated. Poldip2+/- MASMs (HET) showed both quicker cell attachment and detachment than Poldip2+/+ MASMs (WT). Paxillin, one of the components of focal adhesion, is expressed in all areas (from front to back) of lamellipodia in WT, on the other hand HET express the Paxillin only front area, which may induce weaker cell adhesion. The mature focal adhesion marker, Zyxin, expression is decreased in HET significantly. Intriguingly, the activity of RhoA is increased in HET and induced MRTF-A translocation from cytosol to nacreous. Conclusions: It is revealed that Poldip2 is positive regulator of Zyxin. HET has weak cell adhesion, and may induce Poldip2+/- MASMs exhibit higher β1-Integrin expression as a compensation against immature focal adhesion. Thus PI3K/Akt/mTOR signaling pathway is activated, leading to increased ECM protein synthesis. Translocation of MRTF-A from cytosol to the nucleus, may contribute to bind to transcriptional factor for Collagen I. This phenomenon is suggested as one more pathway, which Collagen I accumulates in HET. These findings have important implications for atherosclerotic vascular diseases such as diabetic macroangiopathy in which ECM accumulation plays a role. Disclosure M. Fujii: None. N. Sonoda: None. M. Okamoto: None. H. Morinaga: None. Y. Ogawa: Research Support; Self; AstraZeneca. Advisory Panel; Self; Gilead Sciences, Inc.. Research Support; Self; Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. K. Griendling: None.

The actin cytoskeleton is critical for form and function of vascular cells, serving mechanical, organizational and signaling roles. Because many cytoskeletal proteins are sensitive to reactive oxygen species, redox regulation has emerged as a pivotal modulator of the actin cytoskeleton and its associated proteins. Here, we summarize work implicating oxidants in altering actin cytoskeletal proteins and focus on how these alterations affect cell migration, proliferation and contraction of vascular cells. Finally, we discuss the role of oxidative modification of the actin cytoskeleton in vivo and highlight its importance for vascular diseases.

Objectives: Polymerase delta interacting protein 2 (Poldip2) has previously been implicated in migration, proliferation and extracellular matrix (ECM) production in vascular smooth muscle cells. To better understand the role of Poldip2 in ECM regulation, we investigated the mechanism responsible for collagen I accumulation in Poldip2(+/-) mouse aortic smooth muscle cells (MASMs).Approach and results: Protein degradation and protein synthesis pathways were investigated. Depletion of Poldip2 had no effect on proteasome activity, but caused a partial reduction in autophagic flux. However, the rate of collagen I degradation was increased in Poldip2(+/-) vs. Poldip2(+/+) MASMs. Conversely, activation of the PI3K/Akt/mTOR signaling pathway, involved in regulation of protein synthesis, was significantly elevated in Poldip2(+/-) MASMs as was beta 1-integrin expression. Suppressing mTOR signaling using Akt inhibitor or rapamycin and reducing beta 1-integrin expression using siRNA prevented the increase in collagen I production. While collagen I and fibronectin were increased in Poldip2(+/-) MASMs, overall protein synthesis was not different from that in Poldip2(+/+) MASMs, suggesting selectivity of Poldip2 for ECM proteins.Conclusions: Poldip2(+/-) MASMs exhibit higher beta 1-integrin expression and activity of the PI3K/Akt/mTOR signaling pathway, leading to increased ECM protein synthesis. These findings have important implications for vascular diseases in which ECM accumulation plays a role. (C) 2016 Elsevier Ltd. All rights reserved.

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic β-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic β-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.

ImmunotherapyVol. 6, No. 1 EditorialTargeting obesity, insulin resistance and Type 2 diabetes with immunotherapy: the challenges aheadMasakazu Fujii, Noriyuki Sonoda, Ryoichi Takayanagi & Tosyoshi InoguchiMasakazu Fujii* Author for correspondenceDepartment of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Search for more papers by this authorEmail the corresponding author at masakazu731079@yahoo.co.jp, Noriyuki SonodaDepartment of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan and Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanSearch for more papers by this author, Ryoichi TakayanagiDepartment of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanSearch for more papers by this author & Tosyoshi InoguchiDepartment of Internal Medicine & Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan and Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JapanSearch for more papers by this authorPublished Online:16 Dec 2013https://doi.org/10.2217/imt.13.142AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: apoptosis inhibitor of macrophageCTLA-4 Igmacrophage polarizationobesityType 2 diabetesReferences1 Lumeng CN, Bodzin JL, Saltiel AR. 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Cell Metab.11(6),479–492 (2010).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByImmunomodulator FTY720 improves glucose homeostasis and diabetic complications by rejuvenation of β ‐cell function in nonhuman primate model of diabetes2 February 2022 | Fundamental & Clinical Pharmacology, Vol. 36, No. 4Body mass index and response to abatacept in rheumatoid arthritis7 November 2016 | European Journal of Clinical Investigation, Vol. 46, No. 12 Vol. 6, No. 1 Follow us on social media for the latest updates Metrics Downloaded 114 times History Published online 16 December 2013 Published in print January 2014 Information© Future Medicine LtdKeywordsapoptosis inhibitor of macrophageCTLA-4 Igmacrophage polarizationobesityType 2 diabetesFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophage polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein α, peroxisome proliferator-activated receptor γ, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.

We and other investigators have reported that bilirubin and its precursor biliverdin may have beneficial effects on diabetic vascular complications, including nephropathy, via its antioxidant effects. Here, we investigated whether phycocyanin derived from Spirulina platensis, a blue-green algae, and its chromophore phycocyanobilin, which has a chemical structure similar to that of biliverdin, protect against oxidative stress and renal dysfunction in db/db mice, a rodent model for Type 2 diabetes. Oral administration of phycocyanin (300 mg/kg) for 10 wk protected against albuminuria and renal mesangial expansion in db/db mice, and normalized tumor growth factor-β and fibronectin expression. Phycocyanin also normalized urinary and renal oxidative stress markers and the expression of NAD(P)H oxidase components. Similar antioxidant effects were observed following oral administration of phycocyanobilin (15 mg/kg) for 2 wk. Phycocyanobilin, bilirubin, and biliverdin also inhibited NADPH dependent superoxide production in cultured renal mesangial cells. In conclusion, oral administration of phycocyanin and phycocyanobilin may offer a novel and feasible therapeutic approach for preventing diabetic nephropathy.

We appreciate Zelle et al.,1.Zelle D.M. Deetman N. Alkhalaf A. et al.Support for a protective effect of bilirubin on diabetic nephropathy in humans.Kidney Int. 2011; 79: 686Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar for their interest in our article2.Fujii M. Inoguchi T. Sasaki S. et al.Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase.Kidney Int. 2010; 78: 905-919Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar and for raising some insightful comments in their letter entitled ‘Support for a protective effect of bilirubin on diabetic nephropathy in humans’. As for the relationship between serum bilirubin and diabetic nephropathy, we first showed the lower prevalence of vascular complications, including nephropathy in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia, as well as reduced markers of oxidative stress and inflammation.3.Inoguchi T. Sasaki S. Kobayashi K. et al.Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes.JAMA. 2007; 298: 1398-1400Crossref PubMed Google Scholar Fukui et al.4.Fukui M. Tanaka M. Shiraishi E. et al.Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes.Kidney Int. 2008; 74: 1197-1201Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar also reported that serum bilirubin levels were associated with microalbuminuria and subclinical atherosclerosis in patients with type 2 diabetes. This letter by Zelle et al.1.Zelle D.M. Deetman N. Alkhalaf A. et al.Support for a protective effect of bilirubin on diabetic nephropathy in humans.Kidney Int. 2011; 79: 686Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar further supported the relationship between serum bilirubin and diabetic nephropathy in a case–control study. In the letter regarding the paper by Fukui et al.,4.Fukui M. Tanaka M. Shiraishi E. et al.Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes.Kidney Int. 2008; 74: 1197-1201Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Kassimatis and Moutzouris5.Kassimatis T.I. Moutzouris D.-A. Bilirubin as a predictor of albuminuria and atherosclerosis in type 2 diabetic patients: misleading data.Kidney Int. 2009; 75: 862Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar claimed that it was unwarranted to discuss the potential preventive and therapeutic application of bilirubin or its diagnostic utility as a new risk factor for diabetic nephropathy.5.Kassimatis T.I. Moutzouris D.-A. Bilirubin as a predictor of albuminuria and atherosclerosis in type 2 diabetic patients: misleading data.Kidney Int. 2009; 75: 862Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar In fact, these association studies do not necessarily implicate the causative role of bilirubin in the development of diabetic nephropathy. Therefore, we investigated whether bilirubin may protect against diabetic nephropathy in experimental animals in our article.2.Fujii M. Inoguchi T. Sasaki S. et al.Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase.Kidney Int. 2010; 78: 905-919Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Prospective studies are needed to confirm its diagnostic utility as a risk factor for diabetic nephropathy. In addition, we agree that further intervention studies are needed to explore the possibilities of compounds with similar properties to bilirubin, which may represent a new class of therapeutic agents that could protect against the development of diabetic nephropathy.

We examined the effects of adipose triglyceride lipase (ATGL) on the initiation of atherosclerosis. ATGL was recently identified as a rate-limiting triglyceride (TG) lipase. Mutations in the human ATGL gene are associated with neutral lipid storage disease with myopathy, a rare genetic disease characterized by excessive accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, shows massive TG accumulation in both coronary atherosclerotic lesions and the myocardium. Recent reports show that myocardial triglyceride content is significantly higher in patients with prediabetes or diabetes and that ATGL expression is decreased in the obese insulin-resistant state. Therefore, we investigated the effect of decreased ATGL activity on the development of atherosclerosis using human aortic endothelial cells. We found that ATGL knockdown enhanced monocyte adhesion via increased expression of TNFα-induced intercellular adhesion molecule-1 (ICAM-1). Next, we determined the pathways (MAPK, PKC, or NFκB) involved in ICAM-1 up-regulation induced by ATGL knockdown. Both phosphorylation of PKC and degradation of IκBα were increased in ATGL knockdown human aortic endothelial cells. In addition, intracellular diacylglycerol levels and free fatty acid uptake via CD36 were significantly increased in these cells. Inhibition of the PKC pathway using calphostin C and GF109203X suppressed TNFα-induced ICAM-1 expression. In conclusion, we showed that ATGL knockdown increased monocyte adhesion to the endothelium through enhanced TNFα-induced ICAM-1 expression via activation of NFκB and PKC. These results suggest that reduced ATGL expression may influence the atherogenic process in neutral lipid storage diseases and in the insulin-resistant state.

Accumulating evidence suggests that the intrarenal renin-angiotensin system may be involved in the progression of diabetic nephropathy. Chymase is a potent local angiotensin II-forming enzyme in several species, including humans and hamsters. However, the pathophysiological role of chymase is not fully understood. Here, we report a causal role of chymase in diabetic nephropathy and the therapeutic effectiveness of chymase inhibition. In the present study, renal chymase expression was markedly upregulated in streptozotocin-induced diabetic hamsters. Oral administration of a specific chymase inhibitor, TEI-F00806, completely ameliorated proteinuria, the overexpression of transforming growth factor-β and fibronectin in glomeruli, and renal mesangial expansion, by normalizing the increase in intrarenal angiotensin II levels in diabetic hamsters independently of blood pressure levels. In contrast, ramipril did not show such sufficient effects. These effects occurred in parallel with improvements in superoxide production and expression of NAD(P)H oxidase components [NAD(P)H oxidase 4 and p22(phox)] in glomeruli. This study showed for the first time that chymase inhibition may protect against elevated intrarenal angiotensin II levels, oxidative stress, and renal dysfunction in diabetes. These findings suggest that chymase offers a new therapeutic target for diabetic nephropathy.

We recently found a markedly lower prevalence of vascular complications, including kidney disease, in diabetic patients with Gilbert syndrome, a congenital form of hyperbilirubinemia, suggesting a beneficial effect of bilirubin (BIL) on diabetic nephropathy. To directly examine this, we determined whether hereditary hyperbilirubinemic Gunn j/j rats and biliverdin (BVD)-treated diabetic db/db mice were resistant to the development of renal disease. Both rodent models had less albuminuria and complete protection against the progression of mesangial expansion accompanied by normalization of transforming growth factor-beta 1 and fibronectin expression. Simultaneously, there was normalization of urinary and renal oxidative stress markers, and the expression of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunits in the kidney. In cultured vascular endothelial and mesangial cells, BIL and BVD significantly inhibited NADPH-dependent superoxide production, and both high glucose-and angiotensin II-induced production of reactive oxygen species. Collectively, our findings suggest that BIL and BVD may protect against diabetic nephropathy and may lead to novel antioxidant therapies for diabetic nephropathy. Kidney International (2010) 78, 905-919; doi:10.1038/ki.2010.265;published online 4 August 2010

We examined the prevalence of peripheral arterial disease (PAD) in Japanese diabetic patients with ankle–brachial index (ABI). Outpatients with diabetes (n = 4249) who were regularly visiting Kyushu University Hospital, its 17 related hospitals, Ryukyu University Hospital and its 6 related hospitals were enrolled in the Kyushu Prevention Study for Atherosclerosis from 2001 to 2003. At baseline, ABI was measured using a device “form PWV/ABI”. Valid information was available for 3906 diabetic patients (mean age: 60.8 years) including 1612 elderly patients (>65 years). Patients with a low ABI (<0.9) on either side or on both sides were considered to have PAD. The prevalence of PAD patients with ABI < 0.9 was 7.6% in all diabetic subjects. Elderly patients (>65 years) had a higher prevalence of PAD (12.7%) compared with younger patients (<65 years) (4.0%). In addition, the rate of patients who had been diagnosed accurately as having PAD before enrollment was low (24.4%). The prevalence of PAD was high in Japanese patients with diabetes, especially in elderly patients, in contrast to low rates of accurate diagnosis. Better diagnostic efforts and more intensive treatments are needed to improve quality of life and the overall prognosis of life in Japanese diabetic patients.