Among the many interesting scientific advances we are seeing around obesity and how it might best be tackled, one hormone central to the regulation of appetite routinely rears its head. Called leptin, a new study has revealed some of the molecular machinery behind its functioning, and shown how the loss of a key protein can drive insatiable appetites and obesity in mice.
Leptin is a hormone produced by fat cells that carries out a range of functions in the body, chief among them being the regulation of appetite. It does by communicating with the brain region called the hypothalamus to let the person know they've had enough to eat, but this relationship can break down in people with obesity.
While the higher amount of fat cells in the body means higher levels of leptin, this doesn't necessarily mean better suppression of appetite. The leptin signals can fail to have the desired effect in these cases, with the leptin receptors in the brain not activating as they should, leading the person to overeat and continue to gain weight. This is known as leptin resistance.
Scientists aren't exactly sure why a high-fat diet or overeating causes leptin resistance, but a team from the Okinawa Institute of Science and Technology has shed new light on the issue via experiments in mice. These rodents were engineered to be lacking a protein found in neurons in the forebrain, where the hypothalamus is found, called XRN1.
At the age of six weeks, mice lacking the XRN1 protein began to quickly gain weight and at the age of 12 weeks, had become obese, with fat accumulating in their adipose tissue and in the liver. Observing the behavior of these mice along with a control group, those without XRN1 were found to be eating almost twice the amount each day.
“This finding was really surprising,” says study author Dr. Shohei Takaoka. “When we first knocked out XRN1 in the brain, we didn’t know exactly what we would find, but this drastic increase in appetite was very unexpected.”
To dig into the reasons why these mice were eating more, the scientists measured levels of leptin in their blood, which were found to be abnormally high compared to the controls. In line with our understanding around leptin resistance, rather than suppressing their appetite, these higher concentrations of the hormone appeared to be doing little to prevent the rodents from overeating.
Next, the scientists investigated whether any changes were occurring in the activity of genes within the hypothalamus that regulate appetite. XRN1 is known to be implicated in gene activity, helping degrade mRNA that is then used to build certain proteins. The researchers found that the obese mice possessed higher levels of mRNA used to build a protein called Agouti-related peptide (AgRP), known to be one of the most powerful stimulators of appetite.
“It’s still only speculation, but we think that an increase of this protein, and abnormal activation of the neuron that produces it, might be the cause of leptin resistance in these mice,” says study author Dr. Akiko Yanagiya. “Leptin normally suppresses activity of the AgRP neuron, but if loss of XRN1 results in this neuron remaining highly active, it could override the leptin signal.”
Along with these observations of leptin resistance, the scientists also found the mice lacking XRN1 developed resistance to insulin, the hormone that regulates glucose levels in the blood. This hallmark of diabetes was seen at just five weeks old, and the levels of glucose and insulin continued to rise significantly alongside the increasing leptin levels.
“We think that the levels of glucose and insulin rose due to the lack of response to leptin,” explains Dr. Yanagiya. “Leptin resistance meant that the mice kept eating, keeping the level of glucose in the blood high, and therefore increasing insulin in the blood.”
Part of the research included studying the energy expenditure of the mice, to see whether the obese mice were using less energy. This involved placing the rodents in special cages to measure their metabolic rate, which revealed no difference between the groups of mice at the age of six weeks. This did reveal, however, that the mice lacking XRN1 were using mainly carbohydrates for energy, while the control group were using a combination of carbohydrates and fat.
“For some reason, this means that without XRN1, the mice cannot use fat as a fuel effectively,” said Dr. Yanagiya. “Why this occurs though, we still don’t know.”
For their next steps, the scientists hope to explore these mechanisms further in order to understand how XRN1, or the lack of it, influences the neuronal activity in the hypothalamus and has downstream effects on appetite suppression.
“Identifying which neurons and proteins in the brain are involved in regulating appetite, and fully determining how resistance to leptin is caused, could eventually lead to a targeted treatment for obesity,” said Dr. Yanagiya.
The research was published in the journal iScience.
