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Public release date: 25-Jun-2012[ | E-mail |
Share ] Contact: Sarah Jackson
press_releases@the-jci.org
Journal of Clinical Investigation
METABOLISM
The skinny on what makes us fat
Obesity is a disorder in which fat cells grow larger and accumulate. Certain proteins, called WNT family proteins, function to prevent fat cell formation. However, the activity of WNT proteins can be inhibited by secreted frizzled-related proteins (SFRPs), thus leading to fat cell generation. One of these SFRPs, SFRP5, is highly expressed during fat cell generation and increases during obesity. Dr. Ormond MacDougald and colleagues at the University of Michigan sought to determine the mechanism of SFRP5-mediated obesity and found that mice lacking SFRP5 were resistant to diet-induced obesity, despite having similar numbers of fat cells as control mice. The results from a transplantation experiment wherein fat tissue was transferred from SFRP5-deficient mice into obesity-prone mice demonstrated that the mechanism of SFRP5-mediated inhibition of fat cell generation is specific to the tissue itself and not dependent on the surrounding environment. The team also found that SFRP5-deficient mice showed increased metabolic activity compared to control mice. These findings, which were discussed in a commentary by Alexander Rauch and Susanne Mandrup at the University of Southern Denmark, shed light on the mechanism of SFRP5-mediated obesity and identify the WNT signaling pathway as a potential therapeutic target to counteract obesity.
TITLE:
Regulation of adipocyte mitochondrial biogenesis and metabolism by secreted frizzled-related protein 5 and WNT signaling
AUTHOR CONTACT:
Ormond MacDougald
University of Michigan, Ann Arbor, MI, USA
Phone: (734) 647-7721; Fax: 734 232-8175; E-mail: macdouga@umich.edu
ACCOMPANYING COMMENTARY
TITLE:
Lighting the fat furnace without SFRP5
AUTHOR CONTACT:
Susanne Mandrup
University of Southern Denmark, Odense, DNK
Phone: +45 6550 2340; Fax: ; E-mail: s.mandrup@bmb.sdu.dk
MICROBIOLOGY
Inflammatory bacterial deposits remain after antibiotic treatment
Lyme disease is caused by the bacterial spirochete B. burgdorferi, which is transmitted to humans through tick bites. The disease typically begins with a skin rash and is followed by fever, joint pain, and other flu-like symptoms. If diagnosed early, Lyme disease can be successfully treated with antibiotics; however, up to 25% of patients experience arthritis-like symptoms after treatment. The cause of this condition, termed antibiotic refractory Lyme arthritis, is currently unknown. In the current issue of the JCI, researchers led by Dr. Linda Bockenstedt at Yale University reported on a fluorescent form of B. burgdorferi spirochetes used to determine what happens to the bacteria during and after antibiotic treatment. Using a special type of microscopy to examine the joints and cartilage in living mice, the researchers found that the number of spirochetes diminished quickly during antibiotic treatment and that live spirochetes were entirely eradicated by the time the treatment was completed. Despite being unable to detect live spirochetes after treatment, the researchers detected a fluorescent signal in the joints of the infected mice, which they attributed to bacterial debris. This debris could not cause an infection, but was still be detected by antibodies and elicited an inflammatory immune response. In a related commentary, Alan Barbour of the University of California Irvine notes the important ramifications of discovering non-viable and non-transmissible bacterial remnants following antibiotic treatment and the implications for antibiotic-refractory Lyme arthritis. Further studies will be required to determine if B. burgdorferi debris can cause arthritis in humans, as mice do not develop chronic Lyme arthritis.
TITLE:
Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy
AUTHOR CONTACT:
Linda K. Bockenstedt
Yale University School Of Medicine, New Haven, CT, USA
Phone: 203-785-2453; Fax: 203-785-7053; E-mail: linda.bockenstedt@yale.edu
ACCOMPANYING COMMENTARY
TITLE:
Remains of infection
AUTHOR CONTACT:
Alan G. Barbour
University of California Irvine, Irvine, CA, USA
Phone: 949-824-5626; Fax: ; E-mail: abarbour@uci.edu
INFECTIOUS DISEASE
Oxidative stress fuels Trypanosoma cruzi infection in mice
Trypanosoma cruzi is a parasitic flagellate protozoa that causes Chagas disease. Dr. Claudia Paiva and colleagues at the Universidade Federal of Rio de Janeiro in Brazil report on how oxidative damage produced by immune cells contributes to the parasite burden. Using a mouse model of T. cruzi infection, they report that induction of a protein called NRF2 and heme-oxygenase-1 (HO-1) mounted antioxidant defenses during infection that enhanced infection . Further, several antioxidants reduced parasite burden in immune cells, while pro-oxidants promoted parasite populations. In a related commentary, Dr. Norma Andrews notes that this report sheds light on an unresolved issue in the field and suggests that oxidative stress may facilitate parasite access to iron. The Paiva team work indicates that oxidative stress contributes to parasite persistence in host tissues and open a new avenue for the development of anti-T. cruzi drugs.
TITLE:
Oxidative stress fuels Trypanosoma cruzi infection in mice
AUTHOR CONTACT:
Claudia Paiva
UFRJ, Rio de Janeiro, BRA
Phone: (21)22700990; Fax: (21)25608340; E-mail: cnpaiva@iname.com
ACCOMPANYING COMMENTARY
TITLE:
Oxidative stress and intracellular infections: more iron to the fire
AUTHOR CONTACT:
Norma Andrews
Yale U Sch Med, New Haven, CT, USA
Phone: 203-737-2410; Fax: 203-737-2630; E-mail: norma.andrews@yale.edu
CARDIOLOGY
Keeping the beat: regulating the cardiac conduction system
Heart rate is controlled by the cardiac conduction system, which produces electrical impulses the heart and stimulates muscle contractions that pump blood. Defects in the cardiac conduction system result in the serious and often fatal cardiac conduction system disease. While current treatment options are limited, an improved understanding of the molecular basis of cardiac conduction could improve the development of new therapies. Dr. Ivan Moskowitz and colleages at the University of Chicago tested a hypothesis that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature cardiac conduction. They found that mice lacking TBX5 from the mature ventricular conduction system had severe defects in cardiac conduction including loss of fast conduction, arrhythmias, and sudden death. They went on to show that TBX5 binds to regulatory elements in important cardiac genes, including a sodium channel encoded by Scn5a. Their results provide important understanding the molecular pathology of cardiac conduction system disease.
TITLE:
A Tbx5-Scn5a Molecular Network Modulates Function of the Adult Murine Cardiac Conduction System
AUTHOR CONTACT:
Ivan Moskowitz
The University of Chicago, Chicago, IL, USA
Phone: 773 834 0462; Fax: 773 834 2132; E-mail: imoskowitz@peds.bsd.uchicago.edu
ACCOMPANYING ARTICLE
TITLE:
Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer
AUTHOR CONTACT:
Vincent Christoffels
Academic Medical Center, Amsterdam, NLD
Phone: +31 20 5667821; Fax: +31 20 6976177; E-mail: v.m.christoffels@amc.uva.nl
ENDOCRINOLOGY
Neutralizing antibody improves hyperparathyroidism but increases mortality
Chronic kidney diseasemineral and bone disorder is associated with hyperparathyroidism and elevations in serum levels of the phosphaturic hormone FGF23 To better understand the role of FGF23 in the development of chronic kidney diseasemineral and bone disorder, Dr. Victoria Shalhoub and colleagues at Amgen Inc. developed a specific antibody to neutralize FGF23 in a rat model of the disease. Neutralization of FGF23 reduced hyperparathyroidism, including decreased parathyroid hormone, increased vitamin D, increased serum calcium, and normalized bone-formation rate. However, they also observed dose-dependent increases in serum phosphate and aortic calcification associated with increased risk of mortality treated rats. Thus, mineral disturbances caused by neutralization of FGF23 limited the efficacy of FGF23 antibody therapy and likely contributed to the increased mortality observed in the rat model.
TITLE:
FGF23 neutralization improves chronic kidney diseaseassociated hyperparathyroidism yet increases mortality
AUTHOR CONTACT:
Victoria Shalhoub
Amgen Inc, Thousand Oaks, CA, USA
Phone: 1(805) 6301059; E-mail: vickishalhoub@yahoo.com
ACCOMPANYING COMMENTARY
TITLE:
Fibroblast growth factor 23: friend or foe in uremia?
AUTHOR CONTACT:
Orson Moe
UT Southwestern Medical Center, Dallas, TX, USA
Phone: 214 648 7993; Fax: 214 648 2071; E-mail: Orson.Moe@utsouthwestern.edu
NEUROBIOLOGY
Biochemical cause of neuromuscular disorder revealed
Congenital myasthenic syndromes are neuromuscular disorders that can be caused by defects in acetylcholine receptor (AChR) function. By studying point mutations in patients with myasthenic syndromes, Dr. Xin-Ming Shen and colleagues at the Mayo Clinic in Rochester, MN uncovered unsuspected functional significance of specific amino acids in AChR. Their results indicate that an identified amino acid in the AChR? subunit is contributes to the response of the AChR to the neurotransmitter acetylcholine and that mutation of this residue underlies the neuromuscular defects observed.
TITLE:
Key role of myasthenic syndrome mutant residue in loop-C of AChR ?-subunit in initial coupling of binding to gating
AUTHOR CONTACT:
Xin-Ming Shen
Mayo Clinic, Rochester, MN, USA
Phone: 507-284-5102; E-mail: shen.xinming@mayo.edu
ACCOMPANYING COMMENTARY
TITLE:
Pharmacogenomics: mapping monogenic mutations to direct therapy
AUTHOR CONTACT:
Palmer Taylor
UCSD, LaJolla, , USA
Phone: 858-534-1366; Fax: ; E-mail: pwtaylor@ucsd.edu
[ | E-mail | Share ] ?
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Public release date: 25-Jun-2012[ | E-mail |
Share ] Contact: Sarah Jackson
press_releases@the-jci.org
Journal of Clinical Investigation
METABOLISM
The skinny on what makes us fat
Obesity is a disorder in which fat cells grow larger and accumulate. Certain proteins, called WNT family proteins, function to prevent fat cell formation. However, the activity of WNT proteins can be inhibited by secreted frizzled-related proteins (SFRPs), thus leading to fat cell generation. One of these SFRPs, SFRP5, is highly expressed during fat cell generation and increases during obesity. Dr. Ormond MacDougald and colleagues at the University of Michigan sought to determine the mechanism of SFRP5-mediated obesity and found that mice lacking SFRP5 were resistant to diet-induced obesity, despite having similar numbers of fat cells as control mice. The results from a transplantation experiment wherein fat tissue was transferred from SFRP5-deficient mice into obesity-prone mice demonstrated that the mechanism of SFRP5-mediated inhibition of fat cell generation is specific to the tissue itself and not dependent on the surrounding environment. The team also found that SFRP5-deficient mice showed increased metabolic activity compared to control mice. These findings, which were discussed in a commentary by Alexander Rauch and Susanne Mandrup at the University of Southern Denmark, shed light on the mechanism of SFRP5-mediated obesity and identify the WNT signaling pathway as a potential therapeutic target to counteract obesity.
TITLE:
Regulation of adipocyte mitochondrial biogenesis and metabolism by secreted frizzled-related protein 5 and WNT signaling
AUTHOR CONTACT:
Ormond MacDougald
University of Michigan, Ann Arbor, MI, USA
Phone: (734) 647-7721; Fax: 734 232-8175; E-mail: macdouga@umich.edu
ACCOMPANYING COMMENTARY
TITLE:
Lighting the fat furnace without SFRP5
AUTHOR CONTACT:
Susanne Mandrup
University of Southern Denmark, Odense, DNK
Phone: +45 6550 2340; Fax: ; E-mail: s.mandrup@bmb.sdu.dk
MICROBIOLOGY
Inflammatory bacterial deposits remain after antibiotic treatment
Lyme disease is caused by the bacterial spirochete B. burgdorferi, which is transmitted to humans through tick bites. The disease typically begins with a skin rash and is followed by fever, joint pain, and other flu-like symptoms. If diagnosed early, Lyme disease can be successfully treated with antibiotics; however, up to 25% of patients experience arthritis-like symptoms after treatment. The cause of this condition, termed antibiotic refractory Lyme arthritis, is currently unknown. In the current issue of the JCI, researchers led by Dr. Linda Bockenstedt at Yale University reported on a fluorescent form of B. burgdorferi spirochetes used to determine what happens to the bacteria during and after antibiotic treatment. Using a special type of microscopy to examine the joints and cartilage in living mice, the researchers found that the number of spirochetes diminished quickly during antibiotic treatment and that live spirochetes were entirely eradicated by the time the treatment was completed. Despite being unable to detect live spirochetes after treatment, the researchers detected a fluorescent signal in the joints of the infected mice, which they attributed to bacterial debris. This debris could not cause an infection, but was still be detected by antibodies and elicited an inflammatory immune response. In a related commentary, Alan Barbour of the University of California Irvine notes the important ramifications of discovering non-viable and non-transmissible bacterial remnants following antibiotic treatment and the implications for antibiotic-refractory Lyme arthritis. Further studies will be required to determine if B. burgdorferi debris can cause arthritis in humans, as mice do not develop chronic Lyme arthritis.
TITLE:
Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy
AUTHOR CONTACT:
Linda K. Bockenstedt
Yale University School Of Medicine, New Haven, CT, USA
Phone: 203-785-2453; Fax: 203-785-7053; E-mail: linda.bockenstedt@yale.edu
ACCOMPANYING COMMENTARY
TITLE:
Remains of infection
AUTHOR CONTACT:
Alan G. Barbour
University of California Irvine, Irvine, CA, USA
Phone: 949-824-5626; Fax: ; E-mail: abarbour@uci.edu
INFECTIOUS DISEASE
Oxidative stress fuels Trypanosoma cruzi infection in mice
Trypanosoma cruzi is a parasitic flagellate protozoa that causes Chagas disease. Dr. Claudia Paiva and colleagues at the Universidade Federal of Rio de Janeiro in Brazil report on how oxidative damage produced by immune cells contributes to the parasite burden. Using a mouse model of T. cruzi infection, they report that induction of a protein called NRF2 and heme-oxygenase-1 (HO-1) mounted antioxidant defenses during infection that enhanced infection . Further, several antioxidants reduced parasite burden in immune cells, while pro-oxidants promoted parasite populations. In a related commentary, Dr. Norma Andrews notes that this report sheds light on an unresolved issue in the field and suggests that oxidative stress may facilitate parasite access to iron. The Paiva team work indicates that oxidative stress contributes to parasite persistence in host tissues and open a new avenue for the development of anti-T. cruzi drugs.
TITLE:
Oxidative stress fuels Trypanosoma cruzi infection in mice
AUTHOR CONTACT:
Claudia Paiva
UFRJ, Rio de Janeiro, BRA
Phone: (21)22700990; Fax: (21)25608340; E-mail: cnpaiva@iname.com
ACCOMPANYING COMMENTARY
TITLE:
Oxidative stress and intracellular infections: more iron to the fire
AUTHOR CONTACT:
Norma Andrews
Yale U Sch Med, New Haven, CT, USA
Phone: 203-737-2410; Fax: 203-737-2630; E-mail: norma.andrews@yale.edu
CARDIOLOGY
Keeping the beat: regulating the cardiac conduction system
Heart rate is controlled by the cardiac conduction system, which produces electrical impulses the heart and stimulates muscle contractions that pump blood. Defects in the cardiac conduction system result in the serious and often fatal cardiac conduction system disease. While current treatment options are limited, an improved understanding of the molecular basis of cardiac conduction could improve the development of new therapies. Dr. Ivan Moskowitz and colleages at the University of Chicago tested a hypothesis that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature cardiac conduction. They found that mice lacking TBX5 from the mature ventricular conduction system had severe defects in cardiac conduction including loss of fast conduction, arrhythmias, and sudden death. They went on to show that TBX5 binds to regulatory elements in important cardiac genes, including a sodium channel encoded by Scn5a. Their results provide important understanding the molecular pathology of cardiac conduction system disease.
TITLE:
A Tbx5-Scn5a Molecular Network Modulates Function of the Adult Murine Cardiac Conduction System
AUTHOR CONTACT:
Ivan Moskowitz
The University of Chicago, Chicago, IL, USA
Phone: 773 834 0462; Fax: 773 834 2132; E-mail: imoskowitz@peds.bsd.uchicago.edu
ACCOMPANYING ARTICLE
TITLE:
Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer
AUTHOR CONTACT:
Vincent Christoffels
Academic Medical Center, Amsterdam, NLD
Phone: +31 20 5667821; Fax: +31 20 6976177; E-mail: v.m.christoffels@amc.uva.nl
ENDOCRINOLOGY
Neutralizing antibody improves hyperparathyroidism but increases mortality
Chronic kidney diseasemineral and bone disorder is associated with hyperparathyroidism and elevations in serum levels of the phosphaturic hormone FGF23 To better understand the role of FGF23 in the development of chronic kidney diseasemineral and bone disorder, Dr. Victoria Shalhoub and colleagues at Amgen Inc. developed a specific antibody to neutralize FGF23 in a rat model of the disease. Neutralization of FGF23 reduced hyperparathyroidism, including decreased parathyroid hormone, increased vitamin D, increased serum calcium, and normalized bone-formation rate. However, they also observed dose-dependent increases in serum phosphate and aortic calcification associated with increased risk of mortality treated rats. Thus, mineral disturbances caused by neutralization of FGF23 limited the efficacy of FGF23 antibody therapy and likely contributed to the increased mortality observed in the rat model.
TITLE:
FGF23 neutralization improves chronic kidney diseaseassociated hyperparathyroidism yet increases mortality
AUTHOR CONTACT:
Victoria Shalhoub
Amgen Inc, Thousand Oaks, CA, USA
Phone: 1(805) 6301059; E-mail: vickishalhoub@yahoo.com
ACCOMPANYING COMMENTARY
TITLE:
Fibroblast growth factor 23: friend or foe in uremia?
AUTHOR CONTACT:
Orson Moe
UT Southwestern Medical Center, Dallas, TX, USA
Phone: 214 648 7993; Fax: 214 648 2071; E-mail: Orson.Moe@utsouthwestern.edu
NEUROBIOLOGY
Biochemical cause of neuromuscular disorder revealed
Congenital myasthenic syndromes are neuromuscular disorders that can be caused by defects in acetylcholine receptor (AChR) function. By studying point mutations in patients with myasthenic syndromes, Dr. Xin-Ming Shen and colleagues at the Mayo Clinic in Rochester, MN uncovered unsuspected functional significance of specific amino acids in AChR. Their results indicate that an identified amino acid in the AChR? subunit is contributes to the response of the AChR to the neurotransmitter acetylcholine and that mutation of this residue underlies the neuromuscular defects observed.
TITLE:
Key role of myasthenic syndrome mutant residue in loop-C of AChR ?-subunit in initial coupling of binding to gating
AUTHOR CONTACT:
Xin-Ming Shen
Mayo Clinic, Rochester, MN, USA
Phone: 507-284-5102; E-mail: shen.xinming@mayo.edu
ACCOMPANYING COMMENTARY
TITLE:
Pharmacogenomics: mapping monogenic mutations to direct therapy
AUTHOR CONTACT:
Palmer Taylor
UCSD, LaJolla, , USA
Phone: 858-534-1366; Fax: ; E-mail: pwtaylor@ucsd.edu
[ | E-mail | Share ] ?
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
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