Targeting an enzyme in fat cells drives rapid weight loss in obese mice
One hormone we are seeing implicated more and more in obesity research goes by the name of leptin, and scientists continue to demonstrate how changing the way the body responds to it might lead to improved health. A new study has shown how targeting an enzyme within fat cells can alter sensitivity to leptin and in turn drive rapid weight loss in obese mice, while also improving overall metabolic health.
Leptin is a hormone that fat cells produce and plays a key role in regulating our appetite, by communicating with the brain to let us know we've had enough to eat. Someone with a larger proportion of fat cells will therefore have higher amounts of leptin, but the communication with the brain can break down in people with obesity, causing them to overeat and continue to gain weight. This is known as leptin resistance, and scientists have been investigating how this hallmark of obesity might be addressed.
“When this role of leptin was first discovered, people thought it would be the silver bullet to treating obesity,” said Işin Çakir, lead author of the study. “If leptin can lower food intake and increase energy burning, then more leptin should help lower obesity. But that turned out not to be the case.”
Over the past few years we have seen some promising inroads made in this area, uncovering the role key proteins play in leptin resistance, along with hormones in the gut. This latest research from scientists at the University of Michigan centers on an enzyme in fat calls called histone deacetylase 6 (HDAC6), which, with a compound, they were able to inhibit in obese mice on high-fat diets.
This improved the rodent brain's ability to sense leptin, and within just a few weeks, led to a decrease in body weight of almost 25 percent. The scientists note that this came almost entirely from the loss of fat tissue, with only a small part of the decline coming from a loss of lean muscle mass. Further, the treatment didn't bring about a decline in energy expenditure like a lower food intake might do, with the mice also exhibiting improvements in liver health and glucose intolerance, lowering their risk of diabetes.
The scientists also treated lean mice with the same compound, but this didn't lead to any loss in body mass, nor were these effects observed in obese mice genetically engineered to be lacking leptin. This suggests that for the HDAC6 inhibitors to drive weight loss, high levels of leptin must already be present in the body. But significant questions remain around whether this would work in humans.
One issue the scientists are working to address is the toxicity that occurs when most HDAC6 inhibitors break down in the human body, which makes them unsafe for use in treating diabetes and obesity. The team is now working on versions that lack these toxic portions but can still have the same inhibitory effects against HDAC6.
“There are a lot of compounds that have been shown to reduce obesity in mice but don’t have the same effect in humans, or that might reduce weight in humans but are not safe,” said Çakir. “Obviously, the most important questions are: Is HDAC6 inhibition going to have the same effect in humans, and is it going to be safe? And a lot more research is needed before we will have answers to those questions.”
The research was published in the journal Nature Metabolism.
Source: University of Michigan