JCI early table of contents for June 1, 2012

June 1st, 2012
Improving obesity-induced insulin sensitivity

In recent years, a growing body of evidence has linked inflammation to the development of insulin resistance. In insulin resistance, the hormone insulin is less effective in promoting glucose uptake from the bloodstream into other tissues. Obesity is a major factor that contributes to insulin resistance, which can eventually lead to type 2 diabetes. Previous studies have shown that proinflammatory molecules found in fat tissue decreases sensitivity of tissues to insulin.

To identify drug targets that will improve insulin sensitivity, Dr. Olivia Osborn and her colleagues from the University of California in San Diego investigated the role of G protein-coupled receptor 21 (GPR21) in insulin resistance and energy homeostasis. The group compared mice without the gene encoding GPR21 to healthy control mice under normal and high-fat diet conditions. They discovered that mice lacking GPR21 had enhanced insulin sensitivity and increased energy expenditure independent of diet. This result was attributed to the reduced migration of inflammatory cells to the liver and fat tissue in the absence GPR21. Under normal diet, absence of GPR21 in the hypothalamus caused a modest decrease in body weight. This is the first study to demonstrate the negative impact of GPR21 on inflammation and insulin sensitivity. Their findings suggest that GPR21 inhibition may improve insulin resistance and enhance energy expenditure, making GPR21 inhibitors promising treatments for diabetes.


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


Jerrold Olefsky

Dept of Medicine, La Jolla, CA, USA

Phone: (858) 534-6651; Fax: (858) 534-6653; E-mail: jolefsky@ucsd.edu

View this article at: http://www.jci.org/articles/view/61953?key=dbc390c7fd2397640830


Keep metabolism in mind

Metabolic regulation requires activity in the brain that controls glucose balance and food uptake. The hormones insulin, which controls glucose uptake, and leptin, which regulates energy intake and energy expenditure, are critical for mediating energy balance and influence a number of activities in the brain. Dr. Joel Elmquist and colleagues at the University of Texas in Houston wanted to specifically determine which neurons in the brain are required for regulating energy balance. The research team knew that a transcription factor called FOXO1 controlled expression of many genes in response to insulin and leptin signaling. Using genetically modified mice that lack FOXO1 in a specific area of the brain called the ventral medial nucleus of the hypothalamus, they showed that these mice are lean because of increased energy expenditure. Further, these mice had higher sensitivity to insulin in muscle, and were unable to decrease energy expenditure in response to fasting. Their data shows that the action of FOXO1 in the ventral medial nucleus of the hypothalamus is critical for appropriate regulation of energy expenditure and normal glucose balance.


FOXO1 in the ventromedial hypothalamus regulates energy balance


Joel K. Elmquist

UT Southwestern Medical Center, Dallas, TX, USA

Phone: 214 648 2911; Fax: 214 648 5612; E-mail: joel.elmquist@utsouthwestern.edu

View this article at: http://www.jci.org/articles/view/62848?key=9c93a1c72137e21a5364


The right combination: overcoming drug resistance in cancer

Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed resistance to these drugs and are therefore no longer responsive to drug treatment. In a recent research article published in the Journal of Clinical Investigation, Goutham Narla and colleagues at Case Western Reserve University sought to better understand the molecular players in the EGFR signaling pathway in hopes of finding new drug targets for EGFR-associated cancers. Using cancerous human lung tissue and a mouse model of EGFR-associated lung cancer, The Narla team discovered that two tumor suppressor genes, KLF6 and FOXO1, function to disrupt overactive EGFR signaling. After treating the cancerous lung tissue and cancer-prone mice with an FDA-approved drug called trifluoperazine hydrochloride (TFP), which increases the activity of FOXO1, they restored the effectiveness of the anti-EGFR drug erlotinib and reduced tumor growth. Their work identified new drug targets for EGFR-associated cancers and suggests that combinatorial drug therapy regimens may improve treatment outcome.


Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response


Goutham Narla

Case Western Reserve University and University Hospitals, Cleveland, OH, USA

Phone: 3472550885; E-mail: Goutham.Narla@mssm.edu

View this article at: http://www.jci.org/articles/view/62058?key=9eb9f31baf7df0c3365e


Finding new treatment options in inflammatory brain diseases

A team of scientist, led by Dr. Azeb Tadesse Argaw from the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, have identified a promising avenue for treating inflammatory brain diseases like multiple sclerosis. When the barrier that protects the brain, known as the blood brain barrier (BBB), becomes weak and permeable, it can lead to brain inflammation, edema and neurotoxicity. In a previous study, the group discovered that inflammatory mediators involved in brain lesion development induced angiogenic proteins in the astrocytes. This finding led them to investigate the impact of a protein that stimulates angiogenesis, vascular endothelial growth factor-A (VEGF-A), on brain permeability and inflammation. In this study, the team generated mice that have inactivated VEGF-A proteins in the astrocytes. This mouse model showed reduced BBB breakdown, decreased inflammatory cell infiltration, and increased mobility following administration of a paralytic agent. Next, the group evaluated the efficacy of a few agents in diminishing the negative effects of VEGF-A on the BBB. They discovered that systemic inhibition of endothelial nitric oxide synthase (eNOS) abolished the effects of VEGF-A on BBB breakdown. Additionally, they found that treatment with a selective eNOS inhibitor reduced drug-induced paralysis in mice. These exciting results indicate that blocking VEGF-A is an effective strategy for treating inflammatory brain diseases. Importantly, eNOS inhibitors can be given peripherally to reduce the harmful effects of VEGF-A on the brain.


Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease


Gareth John

Mount Sinai School of Medicine, New York, NY, USA

Phone: 212 241 8142; Fax: ; E-mail: gareth.john@mssm.edu

View this article at: http://www.jci.org/articles/view/60842?key=f54bc2cb8432c10cbd88


Tumor growth and chemoresistance are promoted by ribosomal associated protein RACK

In cells, ribosomes are responsible for translating genetic information, in the form of messenger RNA, to proteins. Coordinated translation initiation is coupled with cell cycle progression and cell growth, but excessive ribosome synthesis and translation initiation can promote cancer. Hepatocellular carcinoma is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. Dr. Jianxin Gu and colleagues at Fudan University in Shanghai, China found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in hepatocellular carcinoma. Aberrant expression of RACK1 contributed to chemoresistance as well as to tumor growth of hepatocellular carcinoma, effects that depended on ribosome localization of RACK1. The group went on to show that ribosomal RACK1 promoted preferential translation of the potent factors involved in growth and survival. Their results imply that RACK1 may function as an internal factor involved in the growth and survival of hepatocellular carcinoma and suggest that targeting RACK1 may be an efficacious strategy for hepatocellular carcinoma treatment.


Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma


Jianxin Gu

Gene Research Center, Shanghai Medical College, Fudan University, Shanghai, , CHN

Phone: 8621-54237704; E-mail: jxgu@shmu.edu.cn

View this article at: http://www.jci.org/articles/view/58488?key=b32b824a1904ce6fbd34


Glucocorticoids regulate immunologic fitness

Glucocorticoids (GCs) are commonly used to treat autoimmunity, but their normal roles in the immune system are not well known. Noting that GCs are naturally made in the thymus, the site where immune cells called T cells originate, Dr. Jonathan Ashwell and his group at the National Cancer Institute studied the role of GCs in T cell development and activation. They designed a mouse line in which the gene encoding the GC receptor (GR) is deleted in immature T cells. They found that the GR-deficient T cells could not respond appropriately to antigen-induced signaling. T cells generate a diverse repertoire of TCR to respond to foreign antigens in the body. Mittelstadt's group concluded that the defects were due to a shift in the TCR repertoire because they found that GR-deficient T cells responded normally when they forced to express a TCR with a fixed specificity. They demonstrated alterations in the TCR repertoire genetically, reporting a difference in the usage of particular TCR-encoding gene segments between GR-deficient and wild-type cells. The TCR repertoire is selected in the thymus where immature T cells that recognize the body's own proteins are selected against and killed. In the GR-deficient thymus, the numbers of T cells late in the maturation pathway were reduced, suggesting unusually high numbers of T cells were previously eliminated. The group concluded that the GCs in the thymus prevent inappropriate killing of T cells during development, thus providing a sufficient and diverse TCR repertoire.


Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness


Jonathan David Ashwell

National Institutes of Health, Bethesda, MD, USA

Phone: 301-496-4931; Fax: 301-402-4844; E-mail: jda@pop.nci.nih.gov

View this article at: http://www.jci.org/articles/view/63067?key=24fae67ed3776d86f2e0


Breathing abnormalities uncovered in mouse model of Leigh Syndrome

Leigh syndrome is a progressive neurodegenerative disorder affecting 1 in 40,000 live births. In up to 75% of cases, patient death is caused by respiratory arrest, but the molecular mechanisms behind breathing abnormalities are unclear.

Mutations in Leigh syndrome patients have been reported to occur in components of the mitochondrial complex I, which plays a vital role in cellular energy production, though how these mutations contribute to the development of disease is unknown. Researchers from the Howard Hughes Medical Institute at University of Washington, led by Dr. Richard Palmiter, have developed a mouse model with the hallmarks of Leigh syndrome, including progressive neurodegeneration, behavioral changes, and respiratory apnea. The researchers found that loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, resulted in compromised activity of mitochondrial complex 1 and causes a fatal progressive encephalopathy. Using magnetic resonance imaging and immunohistochemistry, the researchers located signs of neuroinflammation in a specialized region of the brain known as the dorsal brainstem vestibular nucleus (VN). Selective inactivation of Ndufs4 in the VN resulted in breathing abnormalities and premature death in mice. Restoration of Ndufs4 using gene therapy in the VN corrected breathing deficits and prolonged the lifespan of knockout mice. This genetic murine model of Leigh syndrome provides new insights into the disease, indicating that compromised mitochondrial function within the VN of the brain contributes to respiration abnormalities.


Fatal breathing dysfunction in a mouse model of Leigh Syndrome


Richard D. Palmiter

University of Washington, Seattle, WA, USA

Phone: 206.543.6064; Fax: 206-543-0858; E-mail: palmiter@uw.edu

View this article at: http://www.jci.org/articles/view/62923?key=69fce563f91f65906283

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