Scientists have revealed that weight maintenance is more complicated than the old "calories in, calories out" adage and connections between known regulators of body mass may be the key to treat obesity and metabolic disorders.
A team of researchers led by the University of Pennsylvania School of Veterinary Medicine's Kendra K. Bence had earlier highlighted the important role of the enzyme protein tyrosine phosphatase 1B (PTP1B) in regulating body weight and showed that PTP1B acts to counter the action of the hormone leptin, which is produced by fat cells and suppresses appetite. When mice have been bred to lack PTP1B, they remain lean even when they have unlimited access to high-fat food.
Looking for other proteins with this sequence, they turned up tropomyosin receptor kinase B (TrkB), a receptor in the brain that binds to a molecule called brain-derived neurotrophic factor (BDNF).
To see if PTP1B does in fact act upon TrkB, the researchers first performed a series of experiments on neuronal cells in culture. They found that boosting expression of PTP1B suppressed BDNF and TrkB activity. Conversely, inhibiting PTP1B activity enhanced the activity of the BDNF-TrkB signaling pathway. The researchers also used biochemical assays to confirm that PTP1B physically interacts with TrkB.
The researchers gave animals bred to lack PTP1B a dose of BDNF in their brains, an action that, in normal mice, reduces appetite. Lacking PTP1B didn't change this fact. But these mice did differ from normal mice in one important way: their core temperature. The genetically altered mice had higher core temperatures after a dose of BDNF than normal mice, an effect that correlates with increased energy expenditure - calories out - and thus causes weight loss.
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It was found that because BDNF is known to play a more general role in brain function, PTP1B too may be influencing more than obesity and metabolism. Trk receptors, for example, are overrepresented in neuroblastoma, a cancer of the nerve cells that often affects children.
Bence added that this is the first time that anyone has linked PTP1B with BDNF and TrkB in vivo and it was interesting to see that the effect on weight regulation seems to be through impacting core temperature and not food consumption.
The study was published in the Journal of Biological Chemistry.
