In a recently conducted study, researchers have found a new mechanism to regulate obesity. Senior author of the research, Makoto Fukuda said, “It’s well known that the brain is involved in the development of obesity, but how a high-fat diet changes the brain so it triggers the accumulation of body fat is still unclear.”
The team involved, studied Rap1 gene, which is expressed in different tissues, including the brain where it is involved in functions like memory and learning. Not a lot was known on the role of the gene in energy balance. The scientists selectively deleted the Rap1 gene in a group of neurons in the hypothalamus to explore the effects. With two groups of mice; they genetically engineered one group to lack the Rap1 gene, while the other had a functional gene.
The mice in both groups were then fed a high-fat diet in which 60 per cent of the calories came from fat. While the control mice with a working Rap1 gene gained weight, the mice without, had markedly reduced body weight and less body fat. However, when both the groups were fed a normal diet, both showed similar weights and body fat.
“We observed that the mice lacking Rap1 were not physically active. However, they ate less and burned more body fat than mice with Rap1. These observations were associated with the hypothalamus producing more of a hormone that reduces appetite, called POMC, and less of hormones that stimulate appetite, called NPY and AgRP,” Fukuda said. The team was also interested to study whether leptin changed in mice lacking the gene. The ‘satiety hormone’, Leptin produced by fatty tissue, helps regulate body weight by inhibiting appetite. Obese people however, do not respond to leptin’s signals of satiety, and the blood levels of leptin are higher than those in non-obese people. Leptin resistance is a hallmark of human obesity.
"When we administered ESI-05 to obese mice, we restored their sensitivity to leptin on a level similar to that in mice eating a normal diet. The mice ate less and lost weight," Fukuda said. The new mechanism shows how the brain can affect the development of obesity triggered by consuming a high-fat diet. Consuming a high-fat diet results in changes in the brain that increase Rap1 activity, which in turn leads to a decreased sensitivity to leptin, and this sets the body on a path to obesity.
