Papers by Tadahiro Kitamura
American journal of physiology. Endocrinology and metabolism, Jan 15, 2014
Skeletal muscle is a reservoir of energy in the form of protein, which is degraded under cataboli... more Skeletal muscle is a reservoir of energy in the form of protein, which is degraded under catabolic conditions, resulting in the formation of amino acids and ammonia as a byproduct. The expression of FOXO1, a forkhead-type transcription factor, increases during starvation and exercise. In agreement, transgenic FOXO1-Tg mice that overexpress FOXO1 in skeletal muscle exhibit muscle atrophy. The aim of this study was to examine the role of FOXO1 in amino acid metabolism. The mRNA and protein expressions of glutamine synthetase (GS) were increased in skeletal muscle of FOXO1-Tg mice. Fasting induced FOXO1 and GS expression in wild-type mice but hardly increased GS expression in muscle-specific FOXO1 knockout (FOXO1-KO) mice. Activation of FOXO1 also increased GS mRNA and protein expression in C2C12 myoblasts. Using a transient transfection reporter assay, we observed that FOXO1 activated the GS reporter construct. Mutation of a putative FOXO1-binding consensus sequence in the downstream ...
Bookmarks Related papers MentionsView impact
Nature Genetics, 2002
Bookmarks Related papers MentionsView impact
Diabetes, 2015
Insulin signaling in liver blunts glucose production and stimulates triglyceride biosynthesis. Fo... more Insulin signaling in liver blunts glucose production and stimulates triglyceride biosynthesis. FoxO1 is required for cAMP induction of hepatic glucose production, and is permissive for insulin's ability to suppress this process. Moreover, FoxO1 ablation results in unchecked lipogenesis. In this study, we investigated the pleiotropic actions of FoxO1 on glucose and lipid metabolism. To this end, we reconstituted FoxO1 function in mice with a liver-specific deletion of Foxo1 using targeted knock-in of an allele encoding a DNA binding-deficient FoxO1 mutant (L-DBD). Chow-reared L-DBD mice showed defects in hepatic glucose production but normal liver triglyceride content despite increased rates of de novo lipogenesis and impaired fatty acid oxidation in isolated hepatocytes. Gene expression studies indicated that FoxO1 regulates expression of glucokinase via a cell-nonautonomous co-regulatory mechanism while its regulation of glucose-6-phosphatase proceeds via a cell-autonomous action as a direct transcriptional activator. These conclusions support a differential regulation of hepatic glucose and lipid metabolism by FoxO1 based on the mechanism by which it alters expression of key target genes involved in each process.
Bookmarks Related papers MentionsView impact
The Journal of Cell Biology, 2003
Bookmarks Related papers MentionsView impact
PLoS ONE, 2009
Bookmarks Related papers MentionsView impact
Neuroscience Research, 2011
Bookmarks Related papers MentionsView impact
Neuroscience Research, 2009
Bookmarks Related papers MentionsView impact
Nature Medicine, 2006
Bookmarks Related papers MentionsView impact
Molecular and Cellular Biology, 2006
Bookmarks Related papers MentionsView impact
Molecular and Cellular Biology, 2009
An understanding of the mechanisms that govern pancreatic endocrine cell ontogeny may offer strat... more An understanding of the mechanisms that govern pancreatic endocrine cell ontogeny may offer strategies for their somatic replacement in diabetic patients. During embryogenesis, transcription factor FoxO1 is expressed in pancreatic progenitor cells. Subsequently, it becomes restricted to beta cells and to a rare population of insulin-negative juxtaductal cells (FoxO1+ Ins(-)). It is unclear whether FoxO1+ Ins(-) cells give rise to endocrine cells. To address this question, we first evaluated FoxO1's role in pancreas development using gain- and loss-of-function alleles in mice. Premature FoxO1 activation in pancreatic progenitors promoted alpha-cell formation but curtailed exocrine development. Conversely, FoxO1 ablation in pancreatic progenitor cells, but not in committed endocrine progenitors or terminally differentiated beta cells, selectively increased juxtaductal beta cells. As these data indicate an involvement of FoxO1 in pancreatic lineage determination, FoxO1+ Ins(-) cells were clonally isolated and assayed for their capacity to undergo endocrine differentiation. Upon FoxO1 activation, FoxO1+ Ins(-) cultures converted into glucagon-producing cells. We conclude that FoxO1+ Ins(-) juxtaductal cells represent a hitherto-unrecognized pancreatic cell population with in vitro capability of endocrine differentiation.
Bookmarks Related papers MentionsView impact
Molecular and Cellular Biology, 2008
Bookmarks Related papers MentionsView impact
Journal of Clinical Investigation, 2004
Bookmarks Related papers MentionsView impact
Journal of Clinical Investigation, 2004
The role of different tissues in insulin action and their contribution to the pathogenesis of dia... more The role of different tissues in insulin action and their contribution to the pathogenesis of diabetes remain unclear. To examine this question, we have used genetic reconstitution experiments in mice. Genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis. We show that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescues insulin receptor knockout mice from neonatal death, prevents diabetes in a majority of animals, and normalizes adipose tissue content, lifespan, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells are rescued from neonatal death, but develop lipoatrophic diabetes and die prematurely. These data indicate, surprisingly, that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes.
Bookmarks Related papers MentionsView impact
Journal of Clinical Investigation, 2001
Type 2 diabetes is characterized by the inability of insulin to suppress glucose production in th... more Type 2 diabetes is characterized by the inability of insulin to suppress glucose production in the liver and kidney. Insulin inhibits glucose production by indirect and direct mechanisms. The latter result in transcriptional suppression of key gluconeogenetic and glycogenolytic enzymes, phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6p). The transcription factors required for this effect are incompletely characterized. We report that in glucogenetic kidney epithelial cells, Pepck and G6p expression are induced by dexamethasone (dex) and cAMP, but fail to be inhibited by insulin. The inability to respond to insulin is associated with reduced expression of the forkhead transcription factor Foxo1, a substrate of the Akt kinase that is inhibited by insulin through phosphorylation. Transduction of kidney cells with recombinant adenovirus encoding Foxo1 results in insulin inhibition of dex/cAMP-induced G6p expression. Moreover, expression of dominant negative Foxo1 mutant results in partial inhibition of dex/cAMP-induced G6p and Pepck expression in primary cultures of mouse hepatocyes and kidney LLC-PK1-FBPase(+) cells. These findings are consistent with the possibility that Foxo1 is involved in insulin regulation of glucose production by mediating the ability of insulin to decrease the glucocorticoid/cAMP response of G6p.
Bookmarks Related papers MentionsView impact
Journal of Clinical Investigation, 2002
Bookmarks Related papers MentionsView impact
Journal of Clinical Investigation, 2002
Bookmarks Related papers MentionsView impact
Journal of Clinical Investigation, 2007
Bookmarks Related papers MentionsView impact
Gastroenterology, 2007
Bookmarks Related papers MentionsView impact
FEBS Letters, 2014
Androgen reduces fat mass, although the underlying mechanisms are unknown. Here, we examined the ... more Androgen reduces fat mass, although the underlying mechanisms are unknown. Here, we examined the effect of testosterone on heat production and mitochondrial biogenesis. Testosterone-treated mice exhibited elevated heat production. Treatment with testosterone increased the expression level of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), ATP5B and Cox4 in skeletal muscle, but not that in brown adipose tissue and liver. mRNA levels of genes involved in mitochondrial biogenesis were elevated in skeletal muscle isolated from testosterone-treated male mice, but were down-regulated in androgen receptor deficient mice. These results demonstrated that the testosterone-induced increase in energy expenditure is derived from elevated mitochondrial biogenesis in skeletal muscle.
Bookmarks Related papers MentionsView impact
Endocrinology, 2008
Bookmarks Related papers MentionsView impact
Uploads
Papers by Tadahiro Kitamura