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Why Do Patients on TZD’s Gain Weight?

According to a new study, TZDs activates sensors on a brain cells that increase hunger….

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The researchers discovered that sensors found in the brain that detect free circulating energy and help use sugars are located on brain cells that control eating behavior. These hunger-stimulating cells found at the base of the hypothalamus are known as agouti-related protein (AgRP) cells, and they contain peroxisome proliferator-activated receptor (PPARs) sensors. Activation of these PPARs sensors triggers: food hoarding, food intake, and the production of more AgRP.

The study was an animal study done on Siberian hamsters and mice. Outcomes measures included: (1) PPAR-gamma agonism or antagonism effects after the administration of rosiglitazone (ROSI) and/or GW9662 injections in rodents; (2) if food deprivation (FD) co-increases AgRP and PPAR-gamma expression; (3) if intraperitoneally administered ROSI increase AgRP and neuropeptide Y (NPY); (4) if PPAR-gamma antagonism blocks FD-induced increases in AgRP and NPY; and (5) if PPAR-gamma modulations affects plasma ghrelin.

The authors found that activation of AgRP made the rodents immediately hungry, so hungry that it would wake a rodent from its slumber to go eat. Researchers found that activating these receptors makes the rodents eat more and store more food for later, while blocking them makes them eat less and store less food for later (even in situations where the mice been deprived of food). ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increase in AgRP and NPY. There was no effect on plasma ghrelin.

Besides the fact that the study was done on animals, the authors noted other limitations. One limitation was that there is limited access to the brain by ROSI IV injection, but the results showed peripheral ROSI to affect FD-induced behavior and brain function –showing CNS action.

Practice Pearls:

  • AgRP are hunger-triggering cells found at the base of the hypothalamus that contains PPAR-gamma senor receptors.
  • Trigger of these PPAR-gamma senor receptors leads to: food hoarding, food intake, and the production of more AgRP.
  • TZDs are PPAR-gamma agonist that can triggers these digestive behaviors.

Garretson JT. Peroxisome Proliferator-activated Receptor gamma Controls Ingestive Behavior, AgRP, and NPY mRNA in the Arcuate Hypothalamus. Journal of Neuroscience. 2015; 35(11): 4571-81