The study key points
- In response to hunger, the nerve signalling molecule neuropeptide Y (NPY) increases food intake while decreasing energy production.
- A new mouse research indicates that blocking an NPY receptor increases heat production in fat tissue.
- The drug decreased weight gain by about 40% in animals fed a high-fat diet.
- Since the drug does not tend to cross the blood-brain barrier, it is unlikely to have a negative impact on mood, unlike other weight-loss medications.
Obesity prevalence has more than tripled globally since 1975, according to the World Health Organization (WHO).
According to the WHO, 39 percent of all adults worldwide were overweight in 2016, and 13% were obese. Diabetes, cardiovascular disease, and certain cancers are all linked to these conditions.
People can achieve and maintain a healthy weight by changing their exercise and dietary habits. However, for a variety of reasons, taking these measures successfully can be difficult, and some people resort to appetite-suppressing drugs.
Various drugs that suppress appetite by acting directly on neurotransmitter systems in the brain have been withdrawn from the market over the years due to negative side effects, especially in the areas of mood and heart function.
Dr. Yanchuan Shi, who heads the neuroendocrinology group at the Garvan Institute of Medical Research in Sydney, Australia, says, “Most current prescribed therapies are aimed at lowering food intake by targeting the central nervous system.”
“However, these may have major psychological or cardiovascular side effects, resulting in the withdrawal of over 80% of these drugs from the market,” she adds.
Dr. Shi and his colleagues decided to see if there was a new way to lose weight without damaging the central nervous system. Their findings were published in the journal Nature Communications.
Preserving energy stores
The researchers focused on NPY, a nerve signalling molecule. It aids many animals, including mice and humans, in surviving in environments where food scarcity is normal.
By minimising heat production in a form of fat tissue called brown adipose tissue, NPY increases food intake while conserving energy reserves.
However, in an environment where people have easy access to food and do not get enough exercise, NPY can make losing weight especially difficult.
Prof. Herbert Herzog, head of the Garvan Institute’s Eating Disorders Lab, explains, “NPY is a metabolism regulator that plays a critical role during states of low energy supply, where it helps store fat as a survival mechanism.”
“However, these beneficial effects today will worsen current diet-induced weight gain, contributing to obesity and metabolic disease.”
Dr. Shi, Prof. Herzog, and colleagues looked at how a drug called BIBO3304 affected mice and human fat cells from obese people. The drug inhibits a form of NPY cell receptor known as Y1 that is present in fat tissue and other body tissues.
Since BIBO3304 does not cross the blood-brain barrier, it is unlikely to have a negative impact on mood.
Increase in heat production
The mice were fed a high-fat diet with or without BIBO3304 for 7 weeks.
They discovered that mice who were given the drug gained 40% less weight. This was due to increased heat production in the animals’ brown adipose tissue and a reduction in total fat mass, according to the researchers.
“The Y1 receptor acts as a ‘brake’ for heat generation in the body. In our study, we found that blocking this receptor in fat tissues transformed the ‘energy-storing’ fat into ‘energy-burning’ fat, which switched on heat production and reduced weight gain.”
– Dr. Yanchuan Shi.
Surprisingly, the scientists found that overweight tissue from obese mice and humans had higher activity of the Y1 receptor genes than tissue from people who were healthy weight.
When NPY binds to Y1, it raises food consumption and decreases energy production, which may explain why losing weight is so difficult.
When the researchers used BIBO3304 on fat cells from people with obesity, the cells triggered the same heat-generating genes that had been activated in the mice.
This indicates that the drug, or similar molecules, might function in people the same way they do in mice.
The authors discovered that blocking Y1 has many knock-on effects, including improved glucose metabolism, in addition to reducing weight gain in mice.
Since Y1 constricts blood vessels, blocking it with BIBO3304 can cause blood vessels to widen, lowering blood pressure.
Dr. Shi told NCCMED that blocking this receptor could cause vasodilation, which could be beneficial in the context of hypertension. However, more research is needed to confirm this.
BIBO3304 also promotes bone cell formation, which may help preserve bone density and prevent osteoporosis in older people, according to the researchers.
Dr. Shi admitted that the research did not explicitly assess whether the drug could help obese people lose weight. Rather, it showed that BIBO3304 could keep mice from gaining weight.
“While we didn’t test the method in obesity models, obesity is a state of energy oversupply caused by fat accumulation,” she explained. “As a result, our research suggests that a treatment like BIBO3304 may aid in the treatment of obesity by raising energy expenditure through fat burning, resulting in weight loss.”
It’s also worth noting that mouse and human metabolisms vary significantly. Keith Frayn, emeritus professor of human metabolism at the University of Oxford in the United Kingdom, said:
I don’t place a lot of weight on studies in small rodents, especially in this field. Small rodents have a much greater capacity than do humans for up-regulating thermogenesis [increasing their heat generation]. So we cannot assume that these studies in mice will translate to humans until they are tested.”