A tiny RNA molecule, or microRNA, called miR-128-1 helps to regulate metabolism and could be a treatment target in obesity and related conditions, a study in mice suggests.
These findings also shed new light on how certain human traits have evolved.
The study, “A MicroRNA Linking Human Positive Selection and Metabolic Disorders,” was published in the journal Cell and was conducted by researchers at institutions in the U.S. and Europe.
A genetic variant in chromosome 2 known as 2q21.3 appeared and spread throughout human populations in Europe thousands of years ago. In fact, this variant has been considered a classic example of positive selection, where a genetic change makes a person more fit to survive, and is more likely to be passed along to future generations.
Researchers have long thought that the reason why 2q21.3 provides a survival advantage is because this genetic change confers the ability to produce lactase — an ability that is otherwise lost in infancy. Lactase is needed to digest lactose, a sugar commonly found in milk. Scientists reasoned that the ability to drink milk throughout life was a survival advantage, as it gave people access to more sources of nutrition when food was scarce.
But milk spoils quickly, so most populations learned to make dairy products, such as cheese and yoghurt, as a means of preservation. When milk is processed into these products, most of the lactose is removed.
“Hence, individuals among herding populations, even those with moderate lactose intolerance, should have been able to consume stored milk products during most famines,” the investigators wrote.
Further suggesting that something in chromosome 2 other than 2q21.3 might provide a survival advantage, this specific variant has been linked to an increased risk of obesity and type 2 diabetes.
The researchers had previously identified miR-128-1 in the same region as 2q21.3. As a microRNA, it is involved in gene regulation. Specifically, they found that miR-128-1 regulated blood cholesterol levels, and suspected that it might play a wider role in metabolism.
“We had discovered that miR-128-1 was present in the same chromosome neighborhood as lactase, and the fact that the locus [gene spot] is also linked to metabolic diseases smelled to us like there might be a connection of the microRNA to human evolutionary adaptation to famine,” Anders Näär, PhD, the study’s senior author and a professor at UC Berkeley, said in a university press release.
To test this, the researchers silenced the function of miR-128-1 in two models of obesity: a diet-induced model, where mice were fed a high-fat diet, and an established model of genetic obesity, where mice are unable to produce leptin, a hormone that helps suppress hunger and regulates energy balance.
In both models, blocking miR-128-1 led to significantly greater energy expenditure, as well as reductions in weight gain and fat accumulation. Targeting the microRNA also protected from insulin resistance, a precursor to type 2 diabetes
Comparable results were seen in genetically engineered mice that lacked miR-128-1 entirely. Compared to mice with functional miR-128-1, these mice had significantly less weight gain and fat accumulation.
“The results were quite striking. They show that a microRNA acting as a master regulator of the energy storage programs in many metabolically active organs may contribute to metabolic diseases such as obesity and type 2 diabetes linked to nutritional overabundance,” Näär said.
These results suggest that miR-128-1 helps to promote a “thrifty” metabolism — essentially, allowing the body to store more energy reserves.
This could explain why the 2q21.3 was positively selected in ancient times: the presence of miR-128-1 would have made individuals more likely to survive famine — but because they had more bodily stores of energy, not just because they could digest milk.
While such metabolic efficiency may have been beneficial long ago, in modern times — when cheap, calorie-dense foods are often easy to access — the same differences may predispose individuals toward obesity.
“Hence, miR-128-1 may represent a therapeutic target for the treatment of metabolic diseases such as obesity and [type 2 diabetes],” the researchers concluded.
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