According to the World Health Organization (WHO), the prevalence of obesity worldwide has more than tripled since 1975.
In 2016, the WHO estimates, 39% of all adults worldwide were overweight, and 13% had obesity. These conditions are associated with diabetes, cardiovascular disease, and some cancers.
Changing exercise and dietary habits can help people reach and maintain a healthy weight. However, taking these steps effectively can be challenging for many reasons, and some people also look to appetite-suppressing medication.
Over the years, various drugs that suppress the appetite by acting directly on neurotransmitter systems in the brain have been withdrawn from the market due to adverse effects, particularly involving mood and the function of the heart.
“Most current prescribed treatments are aimed at reducing food intake by targeting the central nervous system,” says Dr. Yanchuan Shi, who leads the neuroendocrinology group at the Garvan Institute of Medical Research, in Sydney, Australia.
“However, these can have significant psychiatric or cardiovascular side effects, which have resulted in over 80% of these medications being withdrawn from the market,” she notes.
Dr. Shi and colleagues wanted to test a new way of reducing weight gain without affecting the central nervous system. Their research has been published in Nature Communications.
Conserving energy stores
The team focused on a nerve signaling molecule called NPY. It helps many animals, including mice and humans, survive conditions in which food shortages are commonplace.
NPY increases food intake and conserves energy stores by reducing heat generation in a type of fat tissue called brown adipose tissue.
In an environment where people have ready access to food and do not get sufficient exercise, however, NPY may make it particularly difficult to lose weight.
“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,” says Prof. Herbert Herzog, head of the Eating Disorders Lab at the Garvan Institute.
“Today, however, these advantageous effects can exacerbate existing diet-induced weight gain, leading to obesity and metabolic disease.”
Dr. Shi, Prof. Herzog, and colleagues investigated the effects of a drug called BIBO3304 on mice and human fat cells from people with obesity. The drug blocks a type of cell receptor for NPY called Y1 that is found in fat tissue and other tissues in the body.
Crucially, BIBO3304 cannot cross the blood-brain barrier, so it is unlikely to adversely affect mood.
Increased heat generation
For 7 weeks, the researchers fed mice a high-fat diet, with or without BIBO3304.
They found that the mice given the drug gained 40% less weight. This, the team discovered, resulted from increased heat generation in the animals’ brown adipose tissue and reduced overall fat mass.
“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.
Interestingly, the scientists discovered that the fat tissue from both mice and humans with obesity had higher activity of the genes for the Y1 receptor than tissue from individuals with a healthy weight.
This may partly explain why losing weight can be so difficult, given that NPY increases food intake and reduces energy output when it binds to Y1.
When the researchers applied BIBO3304 to fat cells from people with obesity, the cells switched on the same genes involved in heat generation as those that had been activated in the mice.
This suggests that the drug, or similar molecules, could work in the same way in people as it does in mice.
In addition to reducing weight gain in mice, the authors discovered that blocking Y1 has several knock-on effects, including improving glucose metabolism.
As Y1 contracts blood vessels, blocking Y1 with BIBO3304 may widen blood vessels, a process called vasodilation, which lowers blood pressure.
“We predict that blocking this receptor could cause vasodilation that may be beneficial in the context of hypertension, but further study needs to be done to confirm this,” Dr. Shi told Medical News Today.
The researchers had previously shown that BIBO3304 also stimulates bone cell growth, which could help maintain bone density, preventing osteoporosis in older people.
Dr. Shi acknowledged that the study did not directly test whether the drug could promote weight loss in people with obesity. Rather, it demonstrated that BIBO3304 could prevent weight gain in mice.
“While we didn’t test the approach in models of obesity, obesity is, similarly, a condition of energy oversupply due to the accumulation of fat,” she said. “Therefore, our study suggests that a treatment like BIBO3304 could help treat obesity by increasing energy expenditure through the burning of fat, leading to weight loss.”
It is also worth noting that metabolism in mice and humans differs in important ways. Keith Frayn, emeritus professor of human metabolism at the University of Oxford, in the United Kingdom, told MNT:
“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.”