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Featured researches published by Nobuharu Fujii.


Journal of Clinical Investigation | 2001

Role of AMP-activated protein kinase in mechanism of metformin action

Gaochao Zhou; Robert W. Myers; Ying Li; Yuli Chen; Xiaolan Shen; Judy Fenyk-Melody; Margaret Wu; John Ventre; Thomas W. Doebber; Nobuharu Fujii; Nicolas Musi; Michael F. Hirshman; Laurie J. Goodyear; David E. Moller

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformins beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformins inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.


Diabetes | 2007

Skeletal Muscle Adaptation to Exercise Training AMP-Activated Protein Kinase Mediates Muscle Fiber Type Shift

Katja S.C. Röckl; Michael F. Hirshman; Josef Brandauer; Nobuharu Fujii; Lee A. Witters; Laurie J. Goodyear

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by ∼40% in transgenic mice expressing a muscle-specific AMPKα2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (γ1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKα2-inactive mice. Sedentary γ1TG mice showed a ∼25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a ∼65% increase in hexokinase II protein in wild-type mice but not in AMPKα2-inactive mice. Hexokinase II was significantly elevated in sedentary γ1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein.


Journal of Biological Chemistry | 2005

AMP-activated Protein Kinase α2 Activity Is Not Essential for Contraction- and Hyperosmolarity-induced Glucose Transport in Skeletal Muscle

Nobuharu Fujii; Michael F. Hirshman; Erin M. Kane; Richard C. Ho; Lauren E. Peter; Matthew M. Seifert; Laurie J. Goodyear

To examine the role of AMP-activated protein kinase (AMPK) in muscle glucose transport, we generated muscle-specific transgenic mice (TG) carrying cDNAs of inactive α2 (α2i TG) and α1 (α1i TG) catalytic subunits. Extensor digitorum longus (EDL) muscles from wild type and TG mice were isolated and subjected to a series of in vitro incubation experiments. In α2i TG mice basal α2 activity was barely detectable, whereas basal α1 activity was only partially reduced. Known AMPK stimuli including 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), rotenone (a Complex I inhibitor), dinitrophenol (a mitochondrial uncoupler), muscle contraction, and sorbitol (producing hyperosmolar shock) did not increase AMPK α2 activity in α2i TG mice, whereas α1 activation was attenuated by only 30–50%. Glucose transport was measured in vitro using isolated EDL muscles from α2i TG mice. AICAR- and rotenone-stimulated glucose transport was fully inhibited in α2i TG mice; however, the lack of AMPK α2 activity had no effect on contraction- or sorbitol-induced glucose transport. Similar to these observations in vitro, contraction-stimulated glucose transport, assessed in vivo by 2-deoxy-d-[3H]glucose incorporation into EDL, tibialis anterior, and gastrocnemius muscles, was normal in α2i TG mice. Thus, AMPK α2 activation is essential for some, but not all, insulin-independent glucose transport. Muscle contraction- and hyperosmolarity-induced glucose transport may be regulated by a redundant mechanism in which AMPK α2 is one of multiple signaling pathways.


Proceedings of the Nutrition Society | 2004

Regulation of glucose transport by the AMP-activated protein kinase

Nobuharu Fujii; William G. Aschenbach; Nicolas Musi; Michael F. Hirshman; Laurie J. Goodyear

The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated during exercise and muscle contraction as a result of acute decreases in ATP:AMP and phosphocreatine:creatine. Physical exercise increases muscle glucose uptake, enhances insulin sensitivity and leads to fatty acid oxidation in muscle. An important issue in muscle biology is to understand whether AMPK plays a role in mediating these metabolic processes. AMPK has also been implicated in regulating gene transcription and, therefore, may function in some of the cellular adaptations to training exercise. Recent studies have shown that the magnitude of AMPK activation and associated metabolic responses are affected by factors such as glycogen content, exercise training and fibre type. There have also been conflicting reports as to whether AMPK activity is necessary for contraction-stimulated glucose transport. Thus, during the next several years considerably more research will be necessary in order to fully understand the role of AMPK in regulating glucose transport in skeletal muscle.


Biochemical and Biophysical Research Communications | 2000

Exercise induces isoform-specific increase in 5'AMP-activated protein kinase activity in human skeletal muscle.

Nobuharu Fujii; Tatsuya Hayashi; Michael F. Hirshman; Jeremy T. Smith; Susan A. Habinowski; Lennart Kaijser; James Mu; Olle Ljungqvist; Morris J. Birnbaum; Lee A. Witters; Anders Thorell; Laurie J. Goodyear


American Journal of Physiology-cell Physiology | 2004

Cloning and characterization of mouse 5′-AMP-activated protein kinase γ3 subunit

Haiyan Yu; Nobuharu Fujii; Michael F. Hirshman; Jason M. Pomerleau; Laurie J. Goodyear


Diabetes Research and Clinical Practice | 2007

Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle: –Insight from analysis of a transgenic mouse model–

Nobuharu Fujii; Matthew M. Seifert; Erin M. Kane; Lauren E. Peter; Richard C. Ho; Schuyler Winstead; Michael F. Hirshman; Laurie J. Goodyear


Biochemical and Biophysical Research Communications | 2007

Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle

Richard C. Ho; Nobuharu Fujii; Lee A. Witters; Michael F. Hirshman; Laurie J. Goodyear


Biochemical and Biophysical Research Communications | 2006

JNK1 deficiency does not enhance muscle glucose metabolism in lean mice

Carol A. Witczak; Michael F. Hirshman; N. Jessen; Nobuharu Fujii; Matthew M. Seifert; Josef Brandauer; Gökhan S. Hotamisligil; Laurie J. Goodyear


Biochemical and Biophysical Research Communications | 2004

cDNA cloning and functional characterization of a novel splice variant of c-Cbl-associated protein from mouse skeletal muscle ☆

Oscar Alcazar; Richard C. Ho; Nobuharu Fujii; Laurie J. Goodyear

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Laurie J. Goodyear

Brigham and Women's Hospital

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Richard C. Ho

Brigham and Women's Hospital

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Matthew M. Seifert

Brigham and Women's Hospital

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Erin M. Kane

Brigham and Women's Hospital

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Haiyan Yu

Brigham and Women's Hospital

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Lauren E. Peter

Brigham and Women's Hospital

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