The results of studies led by scientists at the Garvan Institute of Medical Research suggest how a receptor that helps to conserve energy when food is scarce may be the key to the development of safer approaches to treating diet-induced obesity. The research, using experimental models and fat tissue biopsies from obese individuals, revealed that blocking a specific receptor of neuropeptide Y (NPY), a molecule that helps our body regulate its heat production, could increase fat metabolism and prevent weight gain.

“The Y1 receptor acts as a ‘brake’ for heat generation in the body,” explained Yan-Chuan Shi, PhD, leader of the Neuroendocrinology Group at Garvan. “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 … 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.”

Shi is senior author of the team’s published paper in Nature Communications, which is titled, “Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.”

Obesity is caused by an imbalance between food intake and energy expenditure  (EE). Overweight and obesity represent a major public health issue, and in Australia an estimated two thirds of all adults are affected, the Garvan Institute notes. Obesity can lead to severe medical complications, including diabetes, cardiovascular disease and some cancers, and while lifestyle changes are essential to weight loss, medication is a crucial adjunct treatment option for some. However, the team continued, with the exception of bariatric surgery, current therapies targeting the modulation of food intake (FI) haven’t proven effective in reducing and maintaining fat mass and body weight.

“One of the main reasons for this is that therapies targeting central appetite control also influences a variety of anxiety-related behaviors and emotionality that can lead to severe side effects that diminish the efficacy of such interventions,” the authors stated. And as Shi explained, “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.”

Co-senior author Dr Yan-Chuan Shi [Garvan Institute]
One of the most powerful controllers of feeding and energy homeostasis regulation is neuropeptide Y (NPY), which is released in the body under conditions of starvation to help reduce energy expenditure and increase fat storage. The molecule is widely expressed in the central nervous system, and acts through signaling via the Y1, Y2, Y4, Y5 and y6 receptors. “Importantly, however, NPY and its Y-receptors are also prominently expressed in the periphery …” the authors commented.

 

“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,” noted co-senior author Herbert Herzog, PhD, 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.”

For their reported study, the authors investigated Y1 receptors (Y1R) controlled by NPY. Previous studies, including research that suggested partial knockdown of Y1R signaling inhibition in peripheral tissues had beneficial effects on fat mass and lipid oxidation, led the authors to hypothesize that “ … blocking Y1R signaling in peripheral tissues may ameliorate diet-induced obesity (DIO) and improve whole-body glucose metabolism.”

Surprisingly, the team discovered that Y1 receptors were produced at higher levels in the fat tissue of obese individuals, and in the fat tissues of obese mice, “… suggesting a functional link between Y1R signaling and the development of obesity,” they wrote.  They then blocked the Y1 receptor using the experimental treatment BIBO3304 in a mouse model of obesity. BIBO3304 is a peripheral-only acting Y1R selective antagonist, that doesn’t cross the blood-brain barrier, so any effects would be through its actions on Y1R signaling in peripheral tissues, and not via signaling in the brain.

“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,” Shi reported. “This significant reduction of body weight gain was caused by an increase in body heat generation and reduction in fat mass.” Interestingly, studies in obese mice fed a high fat diet also indicated that selective peripheral antagonism of Y1R led to measurable improvements in glucose homeostasis.

Through additional experiments the researchers also showed that selectively deleting Y1R from adipocytes also protected against diet-induced obesity. And when they applied BIBO3304 to human fat cells isolated from obese individuals, these human cells began switching on the same genes involved in producing heat, as those that were switched on in the obese mice, “ … which suggests that targeting the Y1 receptor pathway may similarly increase fat metabolism and reduce weight gain in humans,” Shi added.

The collective studies demonstrated that development of obesity is promoted by signaling through Y1R in the periphery, “… since selective antagonism of peripheral Y1R or deletion of adipose tissue Y1R prevents the development of high-fat DIO,” the investigators concluded. The results demonstrated that periphery specific antagonism of Y1R signaling using BIBO3304 prevents DIO by stimulating EE and whole-body thermogenesis. “The marked rise in EE can be explained by an increase in thermogenesis in BAT [brown adipose tissue] as well as substantial WAT [white adipose tissue] browning, leading to the increased body and BAT temperature … Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.”

“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,” said Herzog.

“Our team and other groups have revealed further potential benefits in targeting the NPY-Y1 receptor system, including the stimulation of bone cell growth, and improvement in cardiovascular function and insulin resistance. We hope that the publication of our findings will lead to increased interest for exploring BIBO3304 and related agents as potential treatments for obesity and other health conditions.”