JCI early table of contents for Dec. 10, 2012

December 10, 2012

Brown fat transplants help mice lose weight

Brown fat is a specialized tissue in mammals that is used to generate heat (thermogenesis). While white fat is associated with increased body mass, brown fat is associated with a lower body mass index (BMI) and consumes large amounts of energy. Researchers have long been intrigued by the idea of brown fat transplant as a therapeutic tool to combat obesity. In this issue of the Journal of Clinical Investigation, researchers led by Laurie Goodyear at the Joslin Diabetes Center in Boston, performed brown fat transplants in mice to determine if this intervention could treat obesity. Using mice fed either a normal diet or a high-fat diet, Goodyear and colleagues demonstrated that brown fat transplants significantly decreased body weight and improved insulin sensitivity and glucose metabolism. Additionally, the transplanted brown fat secreted hormones, including IL-6, which mediated metabolic effects throughout the body. This study establishes brown fat as an important regulator of metabolism and suggests that this tissue could be an important therapeutic target in the treatment of obesity-related diseases.

Brown adipose tissue regulates glucose homeostasis and insulin sensitivity

Laurie Goodyear
Joslin Diabetes Center, Boston, MA, USA
Phone: 617-732-2573; E-mail: laurie.goodyear@joslin.harvard.edu

View this article at: http://www.jci.org/articles/view/62308?key=cedba4d6317782f11bf4

Researchers identify therapeutic targets in neurofibromatosis

Neurofibromatosis-1 (NF1) is an inherited disorder caused by mutations in the NF1 gene that result in the formation of nervous tissue tumors (neurofibromas) in the skin, subcutaneous tissue, and the cranial and spinal root nerves. Additionally, NF1 patients are predisposed to juvenile myelomonocytic leukemia (JMML), myeloproliferative disorders, and malignant peripheral nerve sheath tumors (MPNST). NF1 encodes a protein that serves as a negative regulator of a signaling pathway composed of RAS, RAF, MEK, and ERK proteins, known as MAPK signaling cascades. Cells expressing mutated NF1 exhibit hyperactivation of these signaling pathways. In this issue of the Journal of Clinical Investigation, three independent groups of researchers report that MAPK hyperactivation is a critical mediator of disease pathogenesis in neurofibromatosis. Researchers led by Wade Clapp at Indiana University found that disruption of ERK signaling blocked the development of JMML in NF1 mutant mice. Similarly, Kevin Shannon and colleagues at the University of California, San Francisco, determined that inhibition of the MAPK signaling cascade component, MEK, reduced the growth of NF1-associated peripheral nerve tumors in mice. MEK inhibition was also shown to ameliorate NF1-associated murine myeloproliferative disorders by Nancy Ratner's research group at Cincinnati Children's Hospital Medical Center. Taken together, these studies demonstrate that hyperactivation of MEK and ERK underlies NF1-associated disorders and provide a rationale for testing MEK and ERK inhibitors in neurofibromatosis patients.

Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require ERK

D. Wade Clapp
Indiana University, Indianapolis, IN, USA
Phone: 317-278-9290; Fax: 317-274-8679; E-mail: dclapp@iupui.edu

View this article at: http://www.jci.org/articles/view/66167?key=df59be6c98451e691eb2


Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice

Kevin Shannon
UCSF, San Francisco, CA, USA
Phone: 415-476-7932; E-mail: shannonk@peds.ucsf.edu

View this article at: http://www.jci.org/articles/view/63193?key=235f142b51523aa39d08


MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors

Nancy Ratner
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Phone: 513-636-9469; Fax: 513-636-3549; E-mail: nancy.ratner@cchmc.org

View this article at: http://www.jci.org/articles/view/60578?key=c334a1be90808f7eb294

Gene regulatory network links obesity and inflammation

Obesity is associated with chronic inflammation, but the mechanisms that mediate this inflammation are not entirely clear. In this issue of the Journal of Clinical Investigation, researchers led by Nicolas Venteclef of the Institute of Cardiometabolism and Nutrition in Paris, identified a protein complex that blocks the expression of genes that are associated with obesity-related inflammation. They found that the GPS2/SMRT complex was significantly reduced in fat cells from obese patients, but expression increased after gastric bypass surgery-induced weight loss, coincident with a reduction in the expression of inflammatory markers. This study identifies a regulatory network that promotes obesity-related inflammation in humans.

GPS2/SMRT corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation

Nicolas Venteclef
University Pierre et Marie Curie-Paris 6, Paris, FRA
Phone: 33-142-346-956; E-mail: nicolas.venteclef@upmc.fr

View this article at: http://www.jci.org/articles/view/64052?key=b914f2bfed3ec913f6b2

Researchers identify inflammatory mediators associated with kidney stones

Calcium oxalate crystals, otherwise known as kidney stones, can cause kidney damage in addition to severe pain. In this issue of the Journal of Clinical Investigation, researchers led by Hans Joachim Anders at the Klinikum der Universität München in Munich, Germany, identified the inflammatory pathways that are activated by kidney stones and characterized the molecular mechanisms that lead to kidney damage in mice. They found that the protein IL-1β was primarily responsible for inducing damage, suggesting that blocking the activity of this protein might help protect the kidneys of patients with kidney stones.

Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion


Shrikant Ramesh Mulay

Klinikum der Universität München, Medizinische Poliklinik, Munich, DEU

Phone: 49-892-180-758-55; E-mail: Shrikant_Ramesh.Mulay@med.uni-muenchen.de

View this article at: http://www.jci.org/articles/view/63679?key=443f299f0873997b6568

Mutant photoreceptors shed light on the pathology of retinitis pigmentosa

Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes visual impairment and, eventually, blindness. RP is caused by mutations in the light-detecting photoreceptor rhodopsin. Most RP patients have mutations in both copies of the rhodopsin gene (autosomal dominant); however, it is possible to carry only a single mutated copy (autosomal recessive). In this issue of the Journal of Clinical Investigation, researchers led by Kryzsztof Palczewski at Case Western Reserve University engineered mice with a single mutated copy of the rhodopsin gene and compared them to mice with two mutated copies. The mice with a single mutated copy had delayed-onset, milder retinal degeneration. Additionally, they exhibited disorganized retinal structures and altered photoreceptor positioning. Interestingly, the mutant rhodopsin functioned normally, demonstrating that rhodopsin positioning was critical to its function. This study demonstrates that positioning of rhodopsin in the retina is critical to its function and indicates that RP is caused by structural changes in the retina rather than a dysfunctional rhodopsin.

Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization

Krzysztof Palczewski
Case Western Reserve University, Cleveland, OH, USA
Phone: 216-368-4631; E-mail: kxp65@case.edu

View this article at: http://www.jci.org/articles/view/66176?key=e8ce723539c73155eb4c

Immune system responses determine HIV's ability to escape detection

The body responds to infectious agents such as bacteria and viruses by identifying proteins that are specific to these agents, known as epitopes, and using them to generate immune cells that will selectively recognize and destroy infected cells. HIV escapes immune detection by accumulating mutations in epitopes that are recognized by T cells, a type of immune cell that can kill virus-infected cells. These mutations prevent T cell recognition and allow the virus to survive. In this issue of the Journal of Clinical Investigation, researchers led by Nilu Goonetilleke at Oxford University measured T cell responses in 17 patients during different stages of HIV-1 infection. These studies allowed Goonetilleke and colleagues to correlate T cell responses with the length of time it took the virus to escape immune detection and provide insight into how T cells respond to and influence HIV during the early stages of infection. The results of these studies may have implications for HIV vaccine design.

Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

Nilu Goonetilleke
Weatherall Institute of Molecular Medicine, Oxford, GBR
Phone: 44-1865-222-145; E-mail: nilu.goonetilleke@ndm.ox.ac.uk

View this article at: http://www.jci.org/articles/view/65330?key=2fe7ea2833c648b7c2f3

Researchers identify immune cells that contribute to the development of multiple sclerosis

Multiple sclerosis (MS) is characterized by the infiltration of the central nervous system (CNS) by immune cells. A particular type of immune cell, Tc17, has been found in MS lesions in humans, but it is unclear what role these cells play in disease pathogenesis. In this issue of the Journal of Clinical Investigation, researchers led by Magdalena Huber at the University of Marburg in Germany used a mouse model of MS to determine the role of Tc17 cells. They found that Tc17 cells help Th17 immune cells to invade the CNS by secreting the protein IL-17. Without Tc17 cells, the Th17 cells did not accumulate in the CNS, preventing the development of MS. This study demonstrates that Tc17 cells help initiate MS by allowing immune cells to reach the CNS and suggests that therapies targeting Tc17 cells might be helpful in treating early MS.

IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis

Magdalena Huber
University of Marburg, Marburg, DEU
Phone: 49-64-215-866-455; E-mail: magdalena.huber@staff.uni-marburg.de

View this article at: http://www.jci.org/articles/view/63681?key=c1ceb5e75a1bd5004508

Estrogen receptor activity is dependent on bone tissue type

Bone mass is determined by the balance of two opposing activities: bone removal by osteoclasts and bone formation by osteoblasts. Additionally, there are two types of bone tissue: cancellous bone makes up the spongy interior, while cortical bone forms the hard outer portion of the bone. Estrogens help maintain both types of bone and the estrogen receptor ERα is known to regulate the maintenance of cancellous bone, but ERα's role in the maintenance of cortical bone is unclear. In this issue of the Journal of Clinical Investigation, researchers led by Stavros Manalogos at the University of Arkansas for Medical Sciences determined the role of ERα in mouse osteoblasts. They found that ERα stimulated expansion in the outer, fibrous layer of the bone, known as the periosteum, and prevented removal of the cortical bone. These results demonstrate that ERα plays a context-dependent role in bone formation.

Estrogen Receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual

Stavros Manolagas
University of Arkansas for Medical Sciences, Little Rock, AR, USA
Phone: 501-686-5130; Fax: 501-686-8148; E-mail: manolagasstavros@uams.edu

View this article at: http://www.jci.org/articles/view/65910?key=243925d25e1b2ac2cf40


JCI Journals

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