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It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. [ABSTRACT FROM AUTHOR]

Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Objective: Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-δ has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPARδ is atheroprotective; however, the role of PPARδ in renal function remains unclear. Here, we report the renoprotective effects of PPARδ activation in a model of streptozotocin-induced diabetic nephropathy.Research Design and Methods: Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and 3) diabetic mice treated with the PPARδ agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes.Results: GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPARδ activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression.Conclusions: These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPARδ agonists and support the concept that PPARδ agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of ∼10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 μm, where ACAM and γ-actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: An inflammatory process is involved in the mechanism of obesity-related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue., Research Design and Methods: We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1⁻(/)⁻) mice compared with wild-type (WT) mice fed HFD., Results: DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real-time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1⁻(/)⁻ mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1⁻(/) ⁻mice compared with WT mice fed HFD., Conclusions: These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance.

Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A(-/-)) mice. Diabetes was induced in SR-A(-/-) and wild-type (SR-A(+/+)) mice by streptozotocin injection. Diabetic SR-A(+/+) mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-beta at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A(-/-) mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A(-/-) mice compared with diabetic SR-A(+/+) mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A(+/+) mice and suppressed in diabetic SR-A(-/-) mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.