Uncovering new strategies to fight obesity is a key focus for researchers, given that the condition is a growing public health concern. Now, a new study sheds light on how the renin-angiotensin system – the hormone system that regulates blood pressure – may also promote excess weight gain. The discovery offers a potential target for obesity treatment.
Senior study author Justin Grobe, Ph.D., assistant professor of pharmacology at the University of Iowa, and colleagues published their findings in the journal Cell Reports.
While the role of the renin-angiotensin system (RAS) in blood pressure control is well established, previous studies have indicated the RAS is also involved in energy balance and metabolism, suggesting the hormone system influences weight.
According to Grobe and colleagues, whether RAS promotes weight gain or weight loss depends on where in the body it is active. For example, if the RAS is highly active in the brain, it increases energy expenditure by boosting resting metabolism, which leads to weight loss.
However, If peripheral RAS activity is increased – that is, if there are high levels of the RAS hormone angiotensin circulating in the rest of the body – it reduces resting metabolism, causing weight gain. Heightened peripheral RAS is often found in obese individuals.
“At a very simplistic level, you can think of the brain RAS as the gas pedal on metabolism and the peripheral (circulating) RAS as the brake, with angiotensin as the driver,” explains Grobe.
For their study, Grobe and colleagues set out to investigate the mechanisms by which the peripheral RAS dampens resting metabolism, with the aim of bringing us closer to a strategy that could halt this process.
The team analyzed mice that had been genetically modified to have excessively heightened RAS activity in the brain.
Compared with control mice, the genetically modified mice had greater resting metabolic rate and weight loss, even though they had the same diet and physical activity levels.
- Obesity affects around 78.6 million adults in the United States
- Obesity raises the risk of heart disease, stroke, type 2 diabetes, and some types of cancer
- In 2008, medical costs for obesity totaled $147 billion.
On analyzing the fat tissue of both groups of mice, the researchers found that the subcutaneous fat on the hips of the genetically modified mice showed increased heat production – or thermogenesis – while visceral fat surrounding the internal organs did not.
Subcutaneous fat refers to fat that is directly under the skin, and it is considered by some health professionals as a “healthy” fat. Visceral fat, however, which is stored deep in the abdominal area, is considered an “unhealthy” fat, raising the risk of obesity-related diseases, such as diabetes and heart disease.
Next, the team activated a receptor called angiotensin II type 2 (AT2) in the subcutaneous fat cells of the mice. AT2 is normally activated when the peripheral RAS is increased.
After the AT2 receptor was activated, the researchers found the mice gained weight, despite experiencing no changes in diet or food intake.
In detail, they found that AT2 activation lowers the production of a protein called UCP1 in subcutaneous fat cells, which is key for non-shivering thermogenesis. Lower UCP1 levels impair fat cells’ ability to generate heat, the team notes.
“If the fat cell is the thermogenic tissue (generating heat by burning calories), you can either have a bigger engine or you can push the gas pedal harder to create a larger effect,” explains Grobe. “Our study shows that angiotensin is modulating the size of the engine (amount of UCP1), not how hard the gas pedal is being pushed.”
Overall, the researchers say their findings suggest that increased peripheral RAS activity – through increased angiotensin levels – promotes obesity through AT2 activation and impaired thermogenesis.
“In multiple ways, activation of the AT2 receptor [by increasing the peripheral RAS] is interfering with the capacity of the cell to make heat.
It is very consistent with the clinical observation that peripheral angiotensin goes up during obesity. This is probably at least one of the mechanisms by which that excess angiotensin is perpetuating obesity. Because it is telling the body to slow down its metabolism as the body gets bigger.”
Justin Grobe, Ph.D.
The authors say this increased understanding of how the RAS affects weight gain could pave the way for new treatments for obesity and its related complications.