A New Approach to Obesity Treatment: Increasing Body Heat Production

A receptor that helps conserve energy when food is scarce may be key to a safer approach to treating diet-induced obesity, research from the Garvan Institute of Medical Research has shown.

In a study using experimental models and adipose tissue biopsies from obese people, the team found that blocking a specific receptor in the molecule neuropeptide Y (NPY), which helps our bodies regulate heat production, can increase lipid metabolism and prevent weight gain .

“The Y1 receptor acts as a ‘brake’ for heat generation in the body. In our study, we found that blocking this receptor in adipose tissues converts the “energy storing” fat into “energy burning” fat, which turns on heat production and reduces weight gain, ”says Dr. Yan-Chuan Shi, head of the Neuroendocrinology Group in Garvan and co-senior author of the paper published in Nature Communications.

“Most of the drugs currently used to treat obesity target the brain to suppress appetite and can have serious side effects that limit their use. Our study reveals an alternative approach that targets adipose tissue directly and may be a safer way to prevent and treat obesity. “

Dr.  Yan-Chuan Shi.

Co-senior author Dr. Yan-Chuan Shi. Photo credit: Garvan Institute

Y1 receptor linked to obesity

Obesity and overweight are major public health problems, affecting an estimated two-thirds of all adults in Australia. The condition can lead to serious medical complications, including diabetes, cardiovascular disease, and some cancers. While lifestyle changes are essential for weight loss, for some, medication is a crucial additional treatment option.

The study’s authors looked at Y1 receptors controlled by the NPY molecule, which is released in the body during starvation conditions to reduce energy consumption and increase fat storage. Surprisingly, the team discovered that Y1 receptors were produced in higher concentrations in the fat tissue of obese people.

The team then blocked the Y1 receptor using the experimental treatment BIBO3304 in a mouse model of obesity.

“In our study, we found that mice given BIBO3304 on a high fat diet gained about 40% less body weight over seven weeks than mice given a high fat diet alone. This significant decrease in body weight gain was caused by an increase in body heat production and a decrease in fat mass, ”says Dr. Shi.

“When we applied BIBO3304 to human fat cells isolated from obese individuals, we found that the cells turned on the same genes involved in heat generation as those in mice, suggesting that targeting the Y1 receptor pathway is the Similarly, it can increase fat metabolism and reduce weight gain in humans, ”adds Dr. Shi added.

Obesity at the source

“NPY is a metabolic regulator that plays a crucial role in low energy conditions and helps store fat as a survival mechanism. Today, however, these beneficial effects can exacerbate existing diet-related weight gain and lead to obesity and metabolic disorders, ”said co-senior author Professor Herbert Herzog, director of the Garvan Eating Disorders Laboratory.

The researchers say that a key component of the study was to show that the experimental treatment, BIBO3304, did not cross the blood-brain barrier and that the anti-obesity effects of blocking the Y1 receptor pathways were not through the brain, but tissue appeared specifically only in peripheral areas.

“Most of the treatments currently prescribed aim to reduce food intake by targeting the central nervous system. However, these can have significant psychiatric or cardiovascular side effects, which has resulted in over 80% of these drugs being withdrawn from the market, ”says Dr. Shi.

“Our study is critical evidence that blocking Y1 receptors in peripheral tissues is effective in preventing obesity by increasing energy expenditure without affecting the central nervous system. It shows a new therapeutic approach that is potentially safer than current drugs that target appetite, ”says Professor Herzog.

“Our team and other groups have identified other potential benefits in fighting the NPY-Y1 receptor system, including stimulating bone cell growth and improving cardiovascular function and insulin resistance,” he added. “We hope that the publication of our results will generate increased interest in research into BIBO3304 and related compounds as potential treatments for obesity and other health conditions.”

Reference: May 11, 2021, Nature Communications.
DOI: 10.1038 / s41467-021-22925-3

This research was supported by the National Health & Medical Research Council of Australia and a grant from the Diabetes Australia Research Program.

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