JCI table of contents: Aug. 9, 2007

The thyroid gland has an important role in determining how much energy the body burns. Thyroid gland functions are regulated by a hormone known as thyroid-stimulating hormone (TSH). Increased levels of TSH, as well as increased signaling through the receptor for TSH, result in hyperthyroidism (characterized by weight loss because the body increases the amount of energy it burns) and goiter.

Signals downstream of the receptor for TSH had been thought to be mediated mainly by a protein complex known as Gs. But now, a study that appears online on August 9, in advance of publication in the September print issue of the Journal of Clinical Investigation, indicates that in mice Gq/G11-mediated signaling has an essential role in transmitting TSH-induced signals and therefore in regulating thyroid gland function. This makes Gq and G11 potential new targets for the treatment of hyperthyroidism and goiter.

In the study, Stefan Offermanns and colleagues from the University of Heidelberg, Germany, generated mice lacking the alpha-subunits of both Gq and G11 only in cells of the thyroid gland. These mice had reduced thyroid gland function and many had symptoms similar to individuals with hypothyroidism. In addition, the thyroid gland in these mice was unresponsive to the proliferative effects of TSH and a goitrogenic diet. The authors therefore suggest that inhibiting Gq and G11, or the molecules activated downstream of these G proteins, might be of therapeutic benefit for individuals with diseases characterized by increased thyroid gland function and/or growth.

TITLE: Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development

AUTHOR CONTACT:
Stefan Offermanns
University of Heidelberg, Heidelberg, Germany.
Phone: 49-6221-54-8246; Fax: 49-6221-54-8549; E-mail: Stefan.Offermanns@pharma.uni-heidelberg.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30380

The prevalence of heart failure continues to increase in the Western world, making it one of the biggest killers in this region. It is characterized by loss of the muscle cells of the heart (cardiomyocytes). Although this loss is generally considered to occur mostly through a process known as apoptotic cell death, a new study appearing online on August 9, in advance of publication in the September print issue of the Journal of Clinical Investigation, indicates that cell death by necrosis also has a role in the cardiomyocyte loss that accompanies heart failure in mice.

In the study, Jeffery Molkentin and colleagues from Cincinnati Children’s Hospital Medical Center, show that in mice increased Ca2+ influx in cardiomyocytes causes the cells to die by necrosis and the mice to die of heart failure. Necrotic cell death and heart failure were enhanced by agonists of beta-adrenergic receptors and abrogated by inhibitors of beta-adrenergic receptors. They were also abrogated in mice lacking cyclophilin D, which is the regulator of the mitochondrial permeability pore. This demonstration that Ca2+- and mitochondrial-dependent necrotic cardiomyocyte death is a cellular event that contributes to heart failure in mice, led the authors to conclude that heart failure is a pleiotropic disease that involves both apoptotic and necrotic cardiomyocyte death.

TITLE: Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure

AUTHOR CONTACT:
Jeffery D. Molkentin
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: (513) 636-3557; Fax (513) 636-5958; E-mail: jeff.molkentin@cchmc.org.

Steven R. Houser
Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 707-3278; Fax: (215) 707-0170; E-mail: srhouser@temple.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31060

Changes in the size, shape, and function of the heart (cardiac remodeling) contribute to the onset and progression of heart failure. Adverse cardiac remodeling occurs in mice engineered to have sustained inflammation in the heart (MHCsTNF mice) and is accompanied by increased death of the muscle cells of the heart (cardiomyocytes) by a process known as apoptosis and decreased cardiomyocyte expression of the anti-apoptotic protein Bcl-2.

In a study that appears online on August 9 in advance of publication in the September print issue of the Journal of Clinical Investigation, Douglas Mann and colleagues from Baylor College of Medicine, Houston, do not observe adverse cardiac remodeling in MHCsTNF mice engineered to constitutively express Bcl-2 in their cardiomyocytes. However, although cardiomyocyte apoptosis was decreased, it was not completely eliminated. Further analysis revealed that Bcl-2 inhibited only one pathway of apoptosis activated by the sustained inflammatory response — the intrinsic apoptotic pathway of cell death. The extrinsic apoptotic pathway of cell death proceeded unchecked. These data led the authors to suggest that the extent of cardiomyocyte apoptosis is a critical factor in determining whether or not adverse cardiac remodeling occurs.

TITLE: TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways

AUTHOR CONTACT:
Douglas L. Mann
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-0285; Fax: (713) 798-0270; E-mail: dmann@bcm.tmc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=29134

Tumor suppressor proteins are so called because their functions oppose the development of cancer. Studies in mice indicate that the protein PU.1 is a tumor suppressor. Mice lacking a specific portion of the DNA (known as the upstream regulatory element; URE) that controls the level of expression of the PU.1 gene develop acute myeloid leukemia (AML). When researchers from Harvard Medical School, Boston, analyzed the equivalent URE in humans they found that a subset of individuals with AML had a genetic mutation known as a SNP that decreased the ability of this region of DNA to enhance PU.1 gene expression.

In the study, which appears online on August 9 in advance of publication in the September print issue of the Journal of Clinical Investigation, Daniel Tenen and colleagues show that the SNP decreased the ability of a protein known as SATB1 to bind the URE and promote PU.1 gene expression. Expression of the PU.1 gene was therefore much decreased. This effect was observed specifically in the precursors of immune cells known as myeloid cells. This study raises the possibility that genetic mutations in UREs might have a critical role in the development of cancer.

TITLE: A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia

AUTHOR CONTACT:
Daniel G. Tenen
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 667-5561; Fax: (617) 667-3299; E-mail: dtenen@bidmc.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30525

In simple terms, individuals become obese if they eat more calories than they burn. However, the molecular pathways that control feeding behavior and cellular energy expenditure are highly complex and not completely understood.

In a study that appears online on August 9 in advance of publication in the September print issue of the Journal of Clinical Investigation, Clay Semenkovich and colleagues from Washington University School of Medicine, St. Louis, show that mice lacking a protein known as FAS in beta-islet cells in the pancreas and in the region of the brain known as the hypothalamus are lean because they eat less and move around more than normal mice. These effects on behavior were associated with decreased signaling in the hypothalamus through a protein known as PPAR-alpha. Administration of a PPAR-alpha agonist into the hypothalamus increased the amount mice lacking FAS specifically in the beta-islet cells and in the hypothalamus ate but did not increase the amount normal mice ate. This study therefore identifies FAS-mediated activation of PPAR-alpha as a molecular pathway controlling feeding behavior in mice.

TITLE: Brain fatty acid synthase activates PPAR-alpha to maintain energy homeostasis

AUTHOR CONTACT:
Clay F. Semenkovich
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314)-362-4454; Fax: (314)-362-7641; E-mail: csemenko@wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31183