Brown Fat’s “Off Switch” Discovery Combats Obesity

Summary: Researchers have made significant discoveries about brown adipose tissue (BAT), which is known for its calorie-burning capabilities. Their study identifies a protein, AC3-AT, that acts as an “off switch” for BAT activation, limiting its effectiveness in combating obesity.

By potentially blocking this switch, the researchers believe they can enhance brown fat’s activity, offering a new avenue for treating obesity and related metabolic disorders. The findings, which also showed that mice without AC3-AT were protected from obesity and had increased metabolic rates, suggest promising strategies for human weight management.

Key Facts:

  1. Brown Fat Activation Limitation: The discovery of the AC3-AT protein explains why the calorie-burning effects of brown fat are typically short-lived, providing a target for prolonging its activation.
  2. Protective Effects in Mice: Mice lacking the AC3-AT protein demonstrated resistance to obesity, less fat accumulation, and higher metabolic rates, indicating the protein’s crucial role in energy balance.
  3. Implications for Human Obesity: Given that AC3-AT is also present in humans, these findings open up potential therapeutic applications to enhance brown fat activity and support weight loss in humans.

Source: University of Southern Denmark

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 that we are more familiar with.

Brown fat has a special job—it helps to burn calories from the foods that we eat into heat, which can be helpful, especially when we’re exposed to cold temperatures like during winter swimming or cryotherapy.

This shows an overweight person.
Intriguingly, this study not only identified AC3-AT, which is a shorter, previously unknown form of the AC3protein. Credit: Neuroscience News

For a long time, scientists thought that only small animals like mice and newborns had brown fat. But new research shows that a certain number of adults maintain their 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.

A new study from the research groups of Prof. Jan-Wilhelm Kornfeld from the University of Southern Denmark/the Novo Nordisk Center for Adipocyte Signaling (Adiposign) and Dagmar Wachten from the University Hospital Bonn and the University of Bonn (Germany) has found that brown fat has a previously unknown built-in mechanism that switches it off shortly after being activated.

This limits its effectiveness as treatment against obesity. According to first author of the study, Hande Topel, who is a Senior Postdoc at the University of Southern Denmark and the Novo Nordisk Center for Adipocyte Signaling (Adiposign), the team has now discovered a protein responsible for this switching-off process. It is called ‘AC3-AT’.

Blocking the “off switch” opens up a new strategy

“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”, Hande Topel says.

The research team found the switch-off protein using advanced technology predicting unknown proteins.

Hande Topel explains: “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”.

Two groups of mice were fed a high-fat diet for 15 weeks, which rendered them obese. The group that had their AC3-AT protein removed, gained less weight than the control group and were metabolically healthier.

“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”, says co-author, Ronja Kardinal, who is a PhD student at the University of Bonn in the lab of Dagmar Wachten at UKB, continuing: “As AC3-AT is found not only in mice but also in humans and other species, there are direct therapeutic implications for humans”.

Hope for strategies that support weight loss

Although the prevalence of brown fat decreases as humans age, and despite grown-ups not having as much brown fat as newborns, it can still be activated, for instance by cold exposure. When it gets activated, it enhances the rate of metabolism of these individuals, which again may help to stabilize weight loss in conditions where calorie intake is (too) high.

Intriguingly, this study not only identified AC3-AT, which is a shorter, previously unknown form of the AC3protein. The researchers 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”, says co-corresponding author Prof. Dagmar Wachten, 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) “Modelling” and “Life & Health” at the University of Bonn.

“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”, says co-corresponding author Prof. Jan-Wilhelm Kornfeld, University of Southern Denmark.

This study was conducted in the context of the DFG Collaborative Research Center Transregio-SFB 333 “Brown and Beige Fat – Organ Interactions, Signaling Pathways and Energy Balance (BATenergy)”, which is pursuing a better understanding of the different types of adipose tissue and their role in metabolic diseases and the Novo Nordisk Foundation Center for Adipocyte Signaling (Adiposign) at University of Southern Denmark that aims to understand fat cell dysfunction in model organisms and obese patients.

About this obesity and neuroscience research news

Author: Birgitte Svennevig
Source: University of Southern Denmark
Contact: Birgitte Svennevig – University of Southern Denmark
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function” by Jan-Wilhelm Kornfeld et al. Nature Metabolism


Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined.

Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5′ truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT).

Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances.

Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis.

Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.

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