Problems With MRP4 Gene Raises Obesity Risk, Mouse Study Suggests
Suppressing the activity of a cellular transporter called multidrug resistance protein 4 (Mrp4) results in more fat tissue, less energy expenditure, and insulin resistance, according to a study in mice.
These findings suggest that lower-than-normal Mrp4 levels can increase the risk of developing metabolic diseases such as obesity and type 2 diabetes, and spot the Mrp4 gene as a new genetic factor of such conditions, researchers said.
The study, “Multidrug resistance‐associated protein 4 (Mrp4) is a novel genetic factor in the pathogenesis of obesity and diabetes,” was published in The FASEB journal and conducted by researchers in the U.S.
Obesity, caused by complex interactions between genetics and diet, is associated with an increased risk of insulin resistance and type 2 diabetes. (Insulin resistance refers to impaired cell response to insulin, and can lead to type 2 diabetes.)
The increasing global rates of obesity and diabetes highlight a greater need to identify new factors involved in the formation of fat cells, or adipogenesis, “which will provide better knowledge for the exploration of novel therapeutic for treating metabolic diseases,” the scientists wrote.
Mrp4 belongs to the ABC transporters superfamily that is known to transport signaling molecules and chemicals (including medications) out of the cell. In people, variations in the gene coding for Mrp4 have been linked to diabetes-associated kidney disease and altered medication metabolism.
Previous studies showed that Mrp4 protein levels are increased in metabolic tissues such as the liver and kidney in mouse models of obesity and diabetes, suggesting this protein may contribute to the development of these conditions. However, the potential role of Mrp4 in fat tissue is unknown.
Researchers evaluated the effects of suppressing Mrp4’s activity in fat tissue of mice, and in lab-grown mouse and human cells used as cellular models of adipogenesis.
First, the team assessed Mrp4 levels in fat tissue, as well as fat tissue cells and mass, in mice genetically modified to lack the Mrp4 gene and in normal, control mice.
In controls, Mrp4 levels were found to be higher in fat tissue relative to muscle tissue, and in the liver (involved in fat metabolism). In turn, mice lacking Mrp4 were visibly obese, with higher body fat and fat-to-body weight ratio, as well as enlarged fat cells compared with control mice.
In addition, blood levels of the leptin hormone — which regulates hunger and energy balance — were significantly increased in Mrp4-deficient mice. However, the animals showed no changes in food intake and had lesser spontaneous physical activity and energy expenditure, suggesting that they developed leptin resistance, the research team said.
Loss of Mrp4 was also found to impair the mice’s glucose (sugar) metabolism and to promote insulin resistance. Notably, all these features are hallmarks of obesity and diabetes.
In agreement, when researchers pharmacologically blocked the activity of Mrp4 in cellular models, there was an increase in the levels of adipogenesis-related genes, in the number of fat cells, and in fat accumulation within cells.
“Lack of Mrp4 increases the risk of development of metabolic diseases as evidenced by increased [fat] tissue weight, insulin resistance, decreased glucose clearance, and energy expenditure observed in [Mrp4-deficient] mice,” the researchers wrote.
Further analyses of mouse fat tissue revealed that Mrp4’s loss significantly changed the activity of genes involved in several molecular pathways, including those related to metabolism and adipogenesis.
In particular, the team found that absence of Mrp4 function increased the levels of cAMP (an adipogenesis-inducing molecule) within cells, and dropped the levels of prostaglandin E2 (an adipogenesis-suppressing molecule). Both molecules are known to be transported by Mrp4.
These findings suggest that “altered transport of cAMP and prostaglandin E2 (PGE2) in the absence of Mrp4 may play a significant role in the development of a metabolic disease [profile] and regulation of adipogenesis,” the team wrote.
“Our findings indicate that Mrp4 is a novel genetic factor in the [development] of metabolic diseases such as obesity and diabetes,” the researchers concluded.
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