JCI table of contents: Jan. 18, 2007

Obesity is one of the main risk factors for developing type II diabetes. Previous studies have shown that mice lacking a protein known as SH2B1 throughout their body are obese and develop diabetes. However, researchers from the University of Michigan have now shown that replacing SH2B1 only in the brain of these mice rescues them from obesity, indicating that targeting SH2B1 in the brain might be a new avenue of research for the development of treatments for obesity and type II diabetes.

In the study, which appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, Liangyou Rui and colleagues show that SH2B1 is expressed in many tissues related to obesity, including the brain, liver, pancreas, and fat tissue. Replacing SH2B1 in only the brain of mice lacking SH2B1 prevented the mice from becoming obese. It also prevented the mice from developing obesity after being fed a high-fat diet, indicating that SH2B1 in the brain is required to regulate body weight and fat content. This study therefore implicates SH2B1 in the brain as a potential target for the treatment of obesity and type II diabetes, two of the most pressing health problems in the developed world today.

TITLE: Neuronal SH2B1 is essential for controlling energy and glucose homeostasis

AUTHOR CONTACT:

Liangyou Rui
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 615-7544; Fax: (734) 647-9523; E-mail: ruily@umich.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29417

Autophagy is a cellular process that enables cells to turnover their contents, something that they do frequently. Autophagy is initiated in tumor cells by chemotherapy and radiation, but it is not known if this contributes to tumor cell death or helps tumor cells survive the anti-cancer therapy. However, in a study using a mouse model of B cell lymphomas, researchers from the University of Pennsylvania have now shown that autophagy represents a survival mechanism for tumor cells treated with agents that initiate tumor cell death by a process known as apoptosis.

In the study, which appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, Craig Thompson and colleagues show that in a tumor in which apoptosis was induced by activation of p53 expression, autophagy was observed only in tumor cells not undergoing apoptosis. If mice were unable to initiate autophagy, increased numbers of tumor cells undergoing apoptosis were detected. Furthermore, if these mice were treated with the chemotherapeutic agent cyclophosphamide, tumor cell apoptosis and tumor regression was increased and tumor recurrence was substantially delayed. This study has clinical implications as it indicates that adjunct treatment with inhibitors of autophagy might increase the efficacy of apoptosis-inducing chemotherapeutics in human patients with cancer.

TITLE: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma

AUTHOR CONTACT:

Craig B. Thompson
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 746-5515; Fax: (215) 746-5511; E-mail: craig@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28833

ENDOCRINOLOGY: The more mutations the worse the disease in idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is an inherited genetic disorder that results in impaired sexual development due to a deficiency in a sex hormone known as GnRH. Although individuals are thought to inherit IHH by having just one gene defect (in any one of a number of genes), not all the evidence supports this hypothesis, for example, not all family members with a given gene defect have the same symptoms.

In a study that appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, Nelly Pitteloud and colleagues from Massachusetts General Hospital in Boston show that in two separate families with distinct forms of IHH (Kallman syndrome and normosmic IHH, respectively) different combinations of several gene defects result in different disease symptoms. In the first family, the individual with the most severe phenotype had mutations in two different genes (FGFR1 and NELF). By contrast, his parents and siblings with only one or other of the mutations exhibited less severe disease. Similarly, in the second family, the most severely affected individual had 2 mutations in her GNRHR genes and 1 mutation in her FGFR1 gene, whereas the less severely affected family members did not have all 3 genetic mutations. This study indicates that IHH is not caused by a defect in a single gene, something that has implications for the genetic counseling of IHH.

TITLE: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism

AUTHOR CONTACT:

Nelly Pitteloud
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 724-1830; Fax: (617) 726-5357; E-mail: npitteloud@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29884

Infection with Pseudomonas aeruginosa is a major problem for patients in hospital, who are at increased risk of infection because they often have a weakened immune system, as well as individuals with cystic fibrosis. One of the things that makes P. aeruginosa so virulent is the expression of a number of proteins that function as a type III secretion system. In a study that appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, researchers from the University of California at San Francisco, have identified Cbl-b as a protein that helps protect mice from infection with P. aeruginosa by targeting one of the components of the type III secretion system, ExoT.

Joanne Engel and colleagues found that in cultured human cells, ExoT was targeted for destruction by the host protein Cbl-b. More importantly, ExoT was shown to be important for bacterial dissemination in mice infected with P. aeruginosa and mice lacking Cbl-b were more susceptible to both intranasal and systemic infection with P. aeruginosa than wild-type mice. This study therefore identifies Cbl-b as a component of early host defense against infection with P. aeruginosa, an observation that could help develop new strategies for the treatment of individuals infected with this major opportunistic pathogen.

TITLE: The ubiquitin ligase Cbl-b limits Pseudomonas aeruginosa exotoxin T–mediated virulence

AUTHOR CONTACT:

Joanne Engel
University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 476-7355; Fax: (415) 476-9364; E-mail: Jengel@medicine.ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28792

Cystic fibrosis (CF) is caused by mutations in a gene that encodes a protein known as CFTR. More than 1000 different disease-causing mutations in CFTR have been identified, and although the overall effect of each mutation is to decrease CFTR expression at the cell surface, it is not known for every one of these mutations what the molecular defect is that causes the decreased cell surface expression of CFTR. Now, researchers from the University of North Carolina at Chapel Hill have shown that one specific mutation in CFTR (the S13F mutation) prevents CFTR from interacting with proteins known as filamins, which are essential for maintaining CFTR at the cell membrane.

In the study, which appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, Sharon Milgram and colleagues show that when expressed in cultured human cell lines, S13F mutant CFTR is not maintained at the cell surface and is degraded more rapidly than normal CFTR. Furthermore, normal CFTR interacts with proteins known as filamins, whereas S13F mutant CFTR does not. Having identified that filamins are important for maintaining cell surface expression of CFTR it will be necessary to determine how filamins interact with other proteins involved in maintaining CFTR at the cells surface. This might provide insight into how further CF-causing mutations in CFTR cause disease.

TITLE: Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR

AUTHOR CONTACT:

Sharon L. Milgram
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Phone: (919) 966-9792; Fax: (919) 966-1856; E-mail: milg@med.unc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30376