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Articles by S Schenk
Total Records ( 4 ) for S Schenk
  M Saberi , D Bjelica , S Schenk , T Imamura , G Bandyopadhyay , P Li , V Jadhar , C Vargeese , W Wang , K Bowman , Y Zhang , B Polisky and J. M. Olefsky
 

The transcription factor TORC2 [transducer of regulated cAMP-responsive element-binding protein (CREB) activity 2] is a major regulator of hepatic gluconeogenesis and is increased in hyperglycemic rodent models. Because chronic hyperglycemia and increased hepatic glucose production, via increased gluconeogenesis, is a key feature of type 2 diabetes, an effective in vivo method to efficiently knock down TORC2 could provide a potential therapy for treating hyperglycemia and type 2 diabetes. To assess this, primary mouse hepatocytes, high-fat diet (HFD)-fed mice, and Zucker diabetic fatty (ZDF) rats were treated with a siRNA against TORC2 (siTORC2), which was delivered via a novel lipid nanoparticle system, or control siRNA (siCON). Compared with siCON, administration of siTORC2 resulted in highly efficient, sustained (1–3 wk) knockdown of TORC2 and its gluconeogenic target genes phosphoenolpyruvate carboxykinase and glucose-6-phophatase in primary mouse hepatocytes and in the livers of HFD-fed mice. In mice, this knockdown was specific to the liver and did not occur in kidney, skeletal muscle, or adipose tissue. In HFD-fed mice, siTORC2 reduced in vivo gluconeogenic capacity, fasting hepatic glucose production, and hyperglycemia, and led to improved hepatic and skeletal muscle insulin sensitivity. siTORC2 treatment also improved systemic hyperglycemia in ZDF rats. In conclusion, these results demonstrate the importance of TORC2 in modulating HGP in vivo and highlight a novel, liver-specific siRNA approach for the potential treatment of hyperglycemia and type 2 diabetes.

  T Yoshizaki , S Schenk , T Imamura , J. L Babendure , N Sonoda , E. J Bae , D. Y Oh , M Lu , J. C Milne , C Westphal , G Bandyopadhyay and J. M. Olefsky
 

Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood. Here, we show that knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages broadly activates the JNK and IKK inflammatory pathways and increases LPS-stimulated TNF secretion. Moreover, gene expression profiles reveal that SIRT1 knockdown leads to an increase in inflammatory gene expression. We also demonstrate that SIRT1 activators inhibit LPS-stimulated inflammatory pathways, as well as secretion of TNF, in a SIRT1-dependent manner in RAW264.7 cells and in primary intraperitoneal macrophages. Treatment of Zucker fatty rats with a SIRT1 activator leads to greatly improved glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity during glucose clamp studies. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage proinflammatory state, fully consistent with the in vitro effects of SIRT1 in macrophages. In conclusion, these results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases.

  M Lu , D Patsouris , P Li , J Flores Riveros , J. M Frincke , S Watkins , S Schenk and J. M. Olefsky
 

Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNF-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects.

  M Lu , P Li , J Pferdekamper , W Fan , M Saberi , S Schenk and J. M. Olefsky
 

Recent findings denote an important contribution of macrophage inflammatory pathways in causing obesity-related insulin resistance. Inducible nitric oxide synthase (iNOS) is activated in proinflammatory macrophages and modestly elevated in insulin-responsive tissues. Although the benefits of systemic iNOS inhibition in insulin-resistant models have been demonstrated, the role of macrophage iNOS in metabolic disorders is not clear. In the current work, we used bone marrow transplantation (BMT) to generate mice with myeloid iNOS deficiency [iNOS BMT knockout (KO)]. Interestingly, disruption of iNOS in myeloid cells did not protect mice from high-fat diet-induced obesity and insulin resistance. When mice were treated with the iNOS inhibitor, N6-(1-Iminoethyl)-L-lysine hydrochloride (L-NIL), we observed a significant and comparable improvement of glucose homeostasis and insulin sensitivity in both wild-type and iNOS BMT KO mice. We further demonstrated that absence of iNOS in primary macrophages did not affect acute TLR4 signaling pathways and had only a modest and mixed effect on inflammatory gene expression. With respect to TNF treatment, iNOS KO macrophages showed, if anything, a greater inflammatory response. In summary, we conclude that iNOS inhibition in tissues other than myeloid cells is responsible for the beneficial effects in obesity/insulin resistance.

 
 
 
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