Obesity Treatments Might Target a Protein for Cooling Brown Fat’s Burn

Brown fat, also known as brown adipose tissue (BAT), is a type of fat in our bodies that’s different from the white fat around our belly and thighs, and has a special job. Brown fat helps to convert the calories from the foods that we eat into heat. This can be helpful, especially when we’re exposed to cold temperatures, such as during during winter swimming, or cryotherapy. While scientists had long thought that only small animals such as mice and newborns had brown fat, more recent research has shown that adult humans also maintain brown fat throughout life. Because brown fat is so good at burning calories, scientists are trying to find ways to activate it safely using drugs that boost its heat-producing abilities.

Newly reported research has now demonstrated that brown fat has a previously unknown built-in mechanism that switches it off shortly after being activated. This mechanism limits its effectiveness as a potential treatment against obesity. Using advanced technology for predicting unknown proteins, the team discovered the protein, AC3-AT—a truncated version of adenylyl cyclase 3 (AC3)—which is responsible for this switching-off process. Studies in live mouse then showed that genetically depleting AC3-AT protected the animals from obesity.

Hande Topel, PhD, a senior postdoc at the University of Southern Denmark and the Novo Nordisk Center for Adipocyte Signaling (Adiposign), is first author of the team’s published paper in Nature Metabolism, and says the findings could point to new strategies for tackling obesity. “When we investigated mice that genetically didn’t have AC3-AT, we found that they were protected from becoming obese, partly because their bodies were simply better at burning off calories and were able to increase their metabolic rates through activating brown fat … Looking ahead, we think that finding ways to block AC3-AT could be a promising strategy for safely activating brown fat and tackling obesity and related health problems.”

Topel and colleagues, including senior authors and research leads Jan-Wilhelm Kornfeld, PhD, at the University of Southern Denmark/the Novo Nordisk Center for Adipocyte Signaling (Adiposign), and Dagmar Wachten, PhD, from the University Hospital Bonn and the University of Bonn, reported on their findings in a paper titled, “Cold-induced expression of truncated adenylyl cyclase 3 acts as rheostat to brown fat function.” In their report they noted, “Here, we describe a novel molecular rheostat, a truncated AC3 protein termed AC3-AT, that is selectively induced after cold and after beta-adrenergic stimulation and controls brown fat function.”

Most mammals carry two “morphologically and functionally distinct” types of fat cells (adipocytes), the authors wrote. “White adipocytes (WAs) consist of a single lipid droplet and predominantly ensure energy storage, whereas brown adipocytes (BAs) are multilocular and possess the ability to convert (diet-derived) macronutrients, like carbohydrates and lipids into heat in a molecular process termed non-shivering thermogenesis (NST).”

Interest in brown adipose tissue increased due to two key discoveries. The first was that active brown fat exists in adult humans as well as small animals such as rodents, and in human infants, the authors continued. Another key discovery was that, despite adults not having as much brown fat as newborns, it can still be activated, for instance by cold exposure. BAT activation then enhances the rate of metabolism of these individuals, which may help to stabilize weight loss in conditions where calorie intake is (too) high.

“Since the re-discovery of active and recruitable BAT in humans, enhancing brown fat activity has been recognized as an innovative therapeutic approach against obesity and obesity-related health decline,” the investigators further stated. Understanding BAT activity and, ultimately, increasing energy expenditure through BAT activation, could hold promise for promoting metabolic health, they suggested. However, while the transcriptional circuitry and hormonal cues driving thermogenic activation of BAT is well understood, “… we lack detailed understanding of how BAT activation is kept in balance to avoid negative consequences of prolonged energy dissipation.”

As part of their reported research the team fed two groups of mice a high-fat diet for 15 weeks, rendering the animals obese. They found that the group with genetically depleted murine AC3-AT (mAC3-AT) gained less weight than the control group and were metabolically healthier. The authors further wrote, “Our in vitro and in vivo data indicated that solely deleting expression of the cold-induced mAC3-AT protein isoform is sufficient to increase oxidative metabolism and thermogenic activation of BAs.”

“The mice that have no AC3-AT protein also accumulated less fat in their body and increased their lean mass when compared to the control mice”, said co-author, Ronja Kardinal, a PhD student at the University of Bonn in the lab of Dagmar Wachten at UKB. “As AC3-AT is found not only in mice but also in humans and other species, there are direct therapeutic implications for humans”. In their paper the authors concluded, “Here, we have delineated a novel, evolutionarily conserved molecular mechanism that functions as a rheostat for maintaining (and limiting) BAT function. This mechanism involves the expression of an N-terminally truncated AC3-AT protein isoform, which fine-tunes cAMP synthesis during periods of chronic CE [cold exposure] and, thereby, maintains BAT function during alterations of energy homeostasis.”

Intriguingly, the team’s study not only identified AC3-AT, which is a truncated, previously unknown form of the AC3 protein, it also identified other unknown protein/gene versions that respond to cold exposure, similar to AC3-AT. “However, further research is needed to elucidate the therapeutic impact of these alternative gene products and their regulatory mechanisms during BAT activation”, said Wachten, who is co-director of the Institute of Innate Immunity at the UKB and member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Areas (TRA) “Modeling” and “Life & Health” at the University of Bonn.

Kornfeld added, “Understanding these kinds of molecular mechanisms not only sheds light on the regulation of brown fat but also holds promise for unraveling similar mechanisms in other cellular pathways. This knowledge can be instrumental in advancing our understanding of various diseases and in the development of novel treatments.”