Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues.
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 alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, 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.
Xue
Bingzhong
B
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Pulinilkunnil
Thomas
T
Murano
Incoronata
I
Bence
Kendra K
KK
He
Huamei
H
Minokoshi
Yasuhiko
Y
Asakura
Kenji
K
Lee
Anna
A
Haj
Fawaz
F
Furukawa
Noboru
N
Catalano
Karyn J
KJ
Delibegovic
Mirela
M
Balschi
James A
JA
Cinti
Saverio
S
Neel
Benjamin G
BG
Kahn
Barbara B
BB
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D004789:Enzyme Activation; D007031:Hypothalamus / Q000201:enzymology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000201:enzymology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014018:Tissue Distribution
D007527:Isoenzymes; D055372:AMP-Activated Protein Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1