Defining Facilitative Leadership: A View from Inside the Mayor’s Office in Lawrence, KS,

This article combines practice and theory in describing the experiences of a mayor who also was a public administration faculty member

Knock-down of IL-1Ra in obese mice decreases liver inflammation and improves insulin sensitivity.

Interleukin 1 Receptor antagonist (IL-1Ra) is highly elevated in obesity and is widely recognized as an anti-inflammatory cytokine. While the anti-inflammatory role of IL-1Ra in the pancreas is well established, the role of IL-1Ra in other insulin target tissues and the contribution of systemic IL-1Ra levels to the development of insulin resistance remains to be defined. Using antisense knock down of IL-1Ra in vivo, we show that normalization of IL-1Ra improved insulin sensitivity due to decreased inflammation in the liver and improved hepatic insulin sensitivity and these effects were independent of changes in body weight. A similar effect was observed in IL1-R1 KO mice, suggesting that at high concentrations of IL-1Ra typically observed in obesity, IL-1Ra can contribute to the development of insulin resistance in a mechanism independent of IL-1Ra binding to IL-1R1. These results demonstrate that normalization of plasma IL-1Ra concentration improves insulin sensitivity in diet- induced obese mice

Knock-Down of IL-1Ra in Obese Mice Decreases Liver Inflammation and Improves Insulin Sensitivity

<div><p>Interleukin 1 Receptor antagonist (IL-1Ra) is highly elevated in obesity and is widely recognized as an anti-inflammatory cytokine. While the anti-inflammatory role of IL-1Ra in the pancreas is well established, the role of IL-1Ra in other insulin target tissues and the contribution of systemic IL-1Ra levels to the development of insulin resistance remains to be defined. Using antisense knock down of IL-1Ra in vivo, we show that normalization of IL-1Ra improved insulin sensitivity due to decreased inflammation in the liver and improved hepatic insulin sensitivity and these effects were independent of changes in body weight. A similar effect was observed in IL1-R1 KO mice, suggesting that at high concentrations of IL-1Ra typically observed in obesity, IL-1Ra can contribute to the development of insulin resistance in a mechanism independent of IL-1Ra binding to IL-1R1. These results demonstrate that normalization of plasma IL-1Ra concentration improves insulin sensitivity in diet- induced obese mice.</p></div

IL-1Ra ASO treatment results in increased energy expenditure.

<p>Oxygen consumption (A) and energy expenditure (B) were measured in CLAMS cages over a 48 hr period in week 4 of the study. core body temperature (C) in HFD-fed IL-1Ra ASO treated mice compared with control ASO treated mice. D) Activity is unchanged between groups. E) Quantitative PCR analysis of uncoupling protein 1 (UCP-1) in BAT. * p<0.05 compared to HFD-fed control treated group, n = 5 mice per group, ns, not significant.</p

IL1Ra ASO treatment reduces liver triglyceride and improved liver inflammation.

<p>A) Liver weight (g), B) H&E stain of liver. C) Liver triglyceride content after 6 weeks of IL-1Ra ASO or control ASO treatment in HFD fed mice. D) QPCR analysis of inflammatory gene expression in the liver of obese mice treated with IL-1Ra ASO or control ASO, results are normalized to beta actin mRNA and expressed relative to control ASO treatment. * p<0.05 compared to HFD-fed control treated group, n = 5−8 mice per group.</p

Antisense oligonucleotide (ASO) mediated knock-down of IL-1Ra transcript in vitro and in vivo using locked nucleic acids (LNAs).

<p>A) QPCR analysis of IL-1Ra mRNA expression after ASO treatment in Hepa 1–6 cells, each concentration was run in duplicate. B) QPCR analysis of IL-1Ra and IL-1β mRNA levels in liver and epididymal adipose (eWAT) from mice one week after IL-1Ra ASO administration. C) Blood glucose concentration in mice one week after IL-1Ra ASO treatment. D. QPCR analysis of IL-1Ra mRNA expression in liver and eWAT after 6 weeks of treatment of IL-1Ra ASO or control ASO. E. Plasma IL-1Ra concentration in obese mice treated with IL-1Ra ASO or control ASO for 6 weeks compared with aged matched lean control mice fed normal chow (NC). F. Analysis of liver enzyme levels after IL-1Ra ASO treatment in HFD-fed mice (ALT, alanine aminotransferase; AST, aspartate aminotransferase; GDH, glutamate dehydrogenase). *P<0.05 compared with control treated mice, QPCR results are normalized to beta actin mRNA and expressed relative to control treatment. Differences between groups were analyzed by one way ANOVA followed by Tukey post hoc tests, n = 5–8 mice per group, * p<0.05 compared to HFD-fed control treated group; ns, not significant.</p

G protein–coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice

Obesity-induced inflammation is a key component of systemic insulin resistance, which is a hallmark of type 2 diabetes. A major driver of this inflammation/insulin resistance syndrome is the accumulation of proinflammatory macrophages in adipose tissue and liver. We found that the orphan GPCR Gpr21 was highly expressed in the hypothalamus and macrophages of mice and that whole-body KO of this receptor led to a robust improvement in glucose tolerance and systemic insulin sensitivity and a modest lean phenotype. The improvement in insulin sensitivity in the high-fat diet–fed (HFD-fed) Gpr21 KO mouse was traced to a marked reduction in tissue inflammation caused by decreased chemotaxis of Gpr21 KO macrophages into adipose tissue and liver. Furthermore, mice lacking macrophage expression of Gpr21 were protected from HFD-induced inflammation and displayed improved insulin sensitivity. Results of in vitro chemotaxis studies in human monocytes suggested that the defect in chemotaxis observed ex vivo and in vivo in mice is also translatable to humans. Cumulatively, our data indicate that GPR21 has a critical function in coordinating macrophage proinflammatory activity in the context of obesity-induced insulin resistance