Turning up body heat may provide a safer treatment for obesity

DARLINGHURST, Australia — Researchers in Australia are turning up the heat on obesity, literally. Unlike weight loss drugs which can have adverse side-effects, their study finds gene therapy may hold the key to safer obesity treatments.

A team from the Garvan Institute of Medical Research says blocking a certain genetic receptor in fat cells can raise heat production, thereby increasing fat metabolism. Study authors add that this treatment would avoid targeting a patient’s central nervous system, like other drugs do. Instead, this approach to weight loss focuses on the Y1 receptor in the molecule neuropeptide Y (NPY).

“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,” explains co-senior author Dr. Yan-Chuan Shi, leader of the Neuroendocrinology Group at Garvan, in a media release.

“Most of the current medications used to treat obesity target the brain to suppress appetite and can have severe side effects that limit their use. Our study reveals an alternative approach that targets the fat tissues directly, which may potentially be a safer way to prevent and treat obesity.”

Linking the Y1 receptor to obesity

Obesity is a major public health issue around the world. As of 2018, over 40 percent of the adult population in the United States classifies as obese. Nearly one in five children are also obese, according to the same estimates from the CDC. Previous studies have revealed how being overweight or obese can lead to severe health complications, including diabetes, heart disease, and even cancer.

In the new report, Dr. Shi’s group studied the role Y1 receptors play when it comes to fat storage and metabolic health. NPY molecules typically release these receptors when they think the body is starving. This helps to reduce energy usage and increases fat storage.

To their surprise, researchers also discovered Y1 receptors are released in greater numbers in the fat tissue of obese people. After this revelation, the team tried blocking Y1 receptors using the experimental treatment BIBO3304 on obese mice.

“In our study, we found that mice that were administered BIBO3304 and fed a high-fat diet gained about 40% less body weight over seven weeks than mice on a high-fat diet alone. This significant reduction of body weight gain was caused by an increase in body heat generation and reduction in fat mass,” Dr. Shi reports.

Following their success with the mice, study authors tested BIBO3304 to human fat cells from obese patients. The treatment began switching on the same genes which produced more heat in mice cells. Researchers believe targeting the Y1 receptor pathway in humans will likely result in the same higher fat metabolism and weight loss seen in mice.

Avoiding the dangers of common weight loss drugs

Study authors explain that NPY plays a critical role in human biology as a metabolism regulator. The molecule acts as a survival mechanism when people are displaying low energy.

“Today however, these advantageous effects can exacerbate existing diet-induced weight gain, leading to obesity and metabolic disease,” notes co-senior author Professor Herbert Herzog, head of the Eating Disorders Lab at Garvan.

The team adds one of the key takeaways from this study is the discovery that BIBO3304 does not cross the blood-brain barrier. This means the genetic changes to the Y1 receptors don’t reach the brain and focuses specifically on peripheral tissues.

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

“Our study is crucial evidence that blocking Y1 receptors in peripheral tissues without affecting the central nervous system is effective at preventing obesity by increasing energy expenditure. It reveals a new therapeutic approach that is potentially safer than current medications that target appetite,” adds Prof. Herzog.

In addition to providing a safer weight loss therapy, researchers say targeting the NPY-Y1 receptor system can also stimulate bone cell growth, strengthen cardiovascular function, and improve insulin resistance.

The study appears in the journal Nature Communications.