Preventing Obesity and Diabetes in Mice by Blocking the Production of Peripheral Serotonin

Peripheral serotonin plays an important role in metabolism. Inhibiting the production of peripheral serotonin in mice on a high-fat diet helps prevent weight gain, insulin resistance, and the accumulation of fat in the liver by enhancing the metabolic activity of brown adipose tissue.

Citation

Crane J.D., Palanivel R., Mottillo E.P., Bujak A.L., Wang H., Ford R.J., Collins A., Blümer R.M., Fullerton M.D., Yabut J.M., Kim J.J., Ghia J., Hamza S.M., Morrison K.M., Schertzer J.D., Dyck J.R.B., Khan W.I., Steinberg G.R., "Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis," Nature Medicine, 21, 2, (2015).

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What is this research about?

Serotonin is a signalling molecule found in a huge variety of animal species. When the molecule exists outside of the body's central nervous system (peripheral serotonin), it is regulated by the expression of a gene called tryptophan hydroxylase 1 (Tph1). Prior research indicates that increased levels of peripheral serotonin and increased expression of Tph1 is linked to obesity. The purpose of this research is to examine how genetically deleting or chemically inhibiting the Tph1 gene affects the metabolism of male mice that are fed a high-fat diet. The hypothesis is that decreasing the expression of Tph1, and thus decreasing peripheral serotonin levels, can help prevent weight-gain and insulin resistance in the male mice. 

What did the researchers do?

For all of their experiments the researchers used male mice that were fed a high-fat diet. In the first experiment the researchers compared the energy intake and energy expenditure of mice that had the Tph1 gene deleted to mice that had the Tph1 gene present. They did this by using metabolic cages that could measure daily food intake, physical activity levels, and oxygen consumption. In the second experiment, comparing the same mice as in the first, the researchers measured the uptake of a molecule called fluorodeoxyglucose to understand which tissues are involved in the changes in oxygen consumption. Subsequently, they measured serotonin levels in the determined tissue. In the third experiment, using only mice that had Tph1 deleted, the researchers implanted serotonin pellets in some of the mice and placebo pellets in the other mice. They measured and compared body mass, white adipose tissue weight, blood glucose levels, glucose tolerance, insulin sensitivity, oxygen uptake and heat generation, in order to understand if serotonin is what mediates the metabolic changes in mice with Tph1 deleted. Subsequent experiments were conducted to understand the mechanism by which serotonin mediates these metabolic changes through a molecule called mitochondrial uncoupling protein 1 (UCP1), and whether chemically inhibiting the Tph1 gene would have the same metabolic effects that were seen in the experiments using mice that had the Tph1 gene deleted. Finally, in the last experiment, the researchers chemically inhibited Tph1 in mice that had the gene expressing UCP1 deleted and in mice that had the gene  expressing UCP1 present. They compared body mass, liver weight, fat levels, glucose tolerance, oxygen uptake, and heat generation in these mice to understand if, ultimately, the metabolic effects of Tph1 deletion or inhibition are dependent on increased UCP1 levels. 

What did the researchers find?

Comparing mice on a high-fat diet that had the Tph1 gene present to those that had the Tph1 gene deleted, the researchers found that the latter:

  • Gained significantly less weight
  • Had lower fat levels, lower fat accumulation in the liver, lower adipose tissue inflammation, lower blood glucose levels
  • Had improved glucose tolerance and insulin sensitivity
  • Had greater oxygen consumption, despite having similar food intake and daily activity as the mice with Tph1 present
  • Had greater uptake of fluorodeoxyglucose and elevated UCP1 levels and oxygen consumption in interscapular brown adipose tissue

Similar effects were seen in mice that had Tph1 chemically inhibited.  The researchers found that decreased serotonin levels mediated these metabolic effects by inducing an increased production of UCP1. The researchers concluded that chemical inhibition or genetic deletion of Tph1 can reverse and prevent obesity, insulin resistance, and non-alcoholic fatty liver disease. 

How can you use this research?

This research may be of interest to academics, health professionals, and everyday people concerned with health issues such as obesity, diabetes, and non-alcoholic fatty liver disease. Although the study was conducted using mice, this research helps us understand the metabolic processes that contribute to the aforementioned health concerns. Ultimately, this research provides insight into a way that we can potentially reverse and prevent obesity, diabetes, and non-alcoholic fatty liver disease by reducing peripheral serotonin and increasing the metabolic activity of brown adipose tissue. 

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