Could a drug that turns up the heat in fat tissue treat obesity?

  • In times of acute stress, a nerve signaling molecule called NPY boosts food intake and reduces energy output.
  • A new study in mice suggests that a drug that blocks a receptor for NPY increases heat generation in fat tissue.
  • In animals fed a high-fat diet, the drug reduced weight gain by around 40%.
  • The drug does not appear to cross the blood-brain barrier, so unlike other weight loss drugs it is unlikely to adversely affect mood.

According to the World Health Organization (WHO), the prevalence of obesity worldwide has more than tripled since 1975.

The WHO estimate that in 2016, 39% of all adults in the world had overweight and 13% had obesity.

The conditions are associated with diabetes, cardiovascular disease, and some cancers.

Exercise and a healthful diet can help people to lose weight and avoid weight gain, but for many, shedding the pounds and then keeping them off is a struggle.

Over the years, numerous drugs that suppress appetite by acting directly on neurotransmitter systems in the brain have been withdrawn from the market due to adverse effects, particularly on the heart and mood.

“Most current prescribed treatments are aimed at reducing food intake by targeting the central nervous system,” says Dr Yan-Chuan 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have significant psychiatric or cardiovascular side effects, which have resulted in over 80% of these medications being withdrawn from the market,” she adds.

Dr Yan-Chuan Shi and her colleagues wanted to discover a way to reduce weight gain without affecting the central nervous system.

Conserving energy stores

They focused on a nerve signaling molecule called neuropeptide Y (NPY) that helps many animals, including mice and humans, to 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 known as 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 for people 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 Professor Herbert Herzog, head of the Eating Disorders Lab at Garvan.

“Today, however, these advantageous effects can exacerbate existing diet-induced weight gain, leading to obesity and metabolic disease.”

Dr Shi, Prof. Herzog, and their colleagues investigated the effects of a drug called BIBO3304 on mice and on human fat cells from individuals with obesity.

The drug blocks a type of cell receptor for NPY called Y1 that is found in fat tissue and elsewhere in the body.

Crucially, BIBO3304 cannot cross the blood-brain, so it is unlikely to adversely affect mood.

Increased heat generation

The researchers fed mice a high-fat diet for 7 weeks, either with or without BIBO3304.

They found that the mice given the drug gained 40% less weight as a result of increased heat generation in their 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. Yan-Chuan Shi.

Interestingly, the scientists discovered that fat tissue from both mice and humans with obesity contained more of the Y1 receptor than tissue from individuals with a normal 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 human fat cells from individuals with obesity, the cells switched on the same genes involved in heat generation as those that were activated in mice.

This suggests that the drug, or similar molecules, could work in the same way in people as it does in mice.

The research has been published in Nature Communications.

Added benefits

In addition to reducing weight gain in mice, the authors discovered that blocking Y1 has several knock-on effects, including improving glucose metabolism.

BIBO3304 also widened blood vessels, known as “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 have previously shown that BIBO3304 also stimulates bone cell growth, which could help to maintain bone density to prevent osteoporosis in older people.

Dr. Shi acknowledged that the study did not directly test whether the drug could promote weight loss in obesity. Rather, it demonstrated that BIBO3304 could prevent weight gain.

“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 the metabolism of mice and humans differs in important respects.

Keith Frayn, emeritus professor of human metabolism at the University of Oxford in the United Kingdom, told Medical News Today:

“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.”

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