iScience: Losing this protein will make the appetite strong

Obesity is an increasingly serious public health problem.

"Fundamentally speaking, obesity is caused by an imbalance between food intake and energy expenditure," said Dr.

In this study, scientists created mice that were unable to produce XRN1 protein in a subset of forebrain neurons

At 6 weeks of age, the scientists noticed that mice without XRN1 in their brains began to gain weight rapidly and became obese at 12 weeks of age

When they monitored the feeding behavior, the research team found that the mice without XRN1 ate almost twice as much food per day as the control mice

In order to study what caused the rats to overeating, the scientists measured the level of leptin in the blood, which is a hormone that suppresses hunger

The scientists also found that 5-week-old mice developed resistance to insulin

"We believe that the increase in blood sugar and insulin levels is due to a lack of response to leptin," explained Dr.

Then, the scientists checked whether obesity is also caused by rats that consume less energy

"For some reason, this means that without XRN1, rats cannot effectively use fat as fuel," said Dr.

Once the rats reach 12 weeks of age, their energy expenditure will be less than that of the control rats

"In general, we believe that the overeating caused by leptin resistance is the main reason these mice become obese," said Dr.

In order to further study how the lack of XRN1 leads to leptin resistance and increased appetite, the scientists observed whether the activity of appetite-regulating genes in the hypothalamus has changed

XRN1 plays a vital role in gene activity because it participates in the last step of messenger RNA (mRNA) degradation

In the hypothalamus, the scientists found that the level of mRNA used to make agoui-related peptide (AgRP) in obese mice increased, leading to an increase in the protein content of AgRP

"This is just speculation, but we believe that the increase in this protein and the abnormal activation of neurons that produce this protein may be the cause of leptin resistance in these mice," said Dr.

However, the exact mechanism by which the loss of XRN1 leads to increased activation of AgRP neurons remains unclear
.
XRN1 is only removed in a specific subset of forebrain neurons, and AgRP neurons are not among them
.
This suggests that another neuron that does lose XRN1 may be involved and may mistakenly send signals to AgRP neurons and maintain their activity
.

In the next step, the laboratory hopes to cooperate with neuroscience research units to find out exactly how XRN1 affects the activity of hypothalamic neurons to regulate appetite
.

"Determine which neurons and proteins in the brain are involved in appetite regulation, and fully determine how resistance to leptin is caused, which may eventually lead to targeted treatments for obesity," said Dr.
Yanagiya
.

Journal Reference :

1. Shohei Takaoka, Akiko Yanagiya, Haytham Mohamed Aly Mohamed, Rei Higa, Takaya Abe, Ken-ichi Inoue, Akinori Takahashi, Patrick Stoney, Tadashi Yamamoto.
   Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis .
   iScience , 2021; 24 ( 10): 103151 DOI: 10.
   1016/j.
   isci.
   2021.
   103151