Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 16, Pages 4563-4573Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01914-08
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Funding
- NIH [R01 DK60839, P01 DK56116]
- Physiology Core [P30 DK57521, R37CA49152]
- FIRB [RBIN047PZY]
- Heart and Stroke Foundation of Canada and Canadian Diabetes Association
- NIH NRSA
- Grants-in-Aid for Scientific Research [21390067] Funding Source: KAKEN
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PTP1B(-/-) mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that alpha 1 and alpha 2 AMPK activity are elevated and acetylcoenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha 2, but not alpha 1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron-but not muscle-specific PTP1B(-/-) mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B(-/-) mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.
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