Brown adipose tissue, also known as brown fat, plays a crucial role in regulating body temperature in mammals by generating heat through a process called non-shivering thermogenesis. This energy-intensive activity makes this tissue a promising target for therapeutic strategies aimed at combating obesity. Understanding how brown fat is activated could open new avenues for regulating energy expenditure and improving metabolic health.

A recent study conducted by researchers from the Research Center for Redox Processes in Biomedicine - RIDC Redoxoma showed that mitochondrial ATP-sensitive potassium channels (MitoK_ATP) are involved in both the development of brown fat cells and the activation of mitochondrial uncoupling in these cells, a process that dissipates energy in the form of heat.

“We discovered that for brown fat cells to produce heat efficiently, mitochondrial potassium channel needs to be inhibited”, explains Osvaldo Rodrigues Pereira Júnior, lead author of the article, published in the American Journal of Physiology-Cell Physiology. “This is unprecedented; it’s the first time this phenomenon has been reported, uncovering a previously unknown component of thermogenic activation.“

The study was conducted during Pereira Júnior’s master’s degree at the Energy Metabolism Laboratory of the Instituto de Química at Universidade de São Paulo (USP), under the supervision of Professor Alicia Kowaltowski. Additionally, it included an internship in the laboratory of Yu-Hua Tseng at Harvard Medical School in the United States. The researcher is currently a doctoral candidate at the Helmholtz Diabetes Center (HDC) in Munich, Germany.

Thermogenic activation depends on channel inhibition

The research showed that, in mice, cold exposure and adrenergic stimulation, that is, the action of hormones typically involved in the response to cold and stress, modulate the levels of the MitoK_ATP channel in brown adipose tissue.

To better understand the function of this channel, the researchers deleted the gene encoding an essential subunit of the channel in human preadipocytes, which are precursor cells of adipose tissue. This resulted in decreased oxygen consumption, reduced cell proliferation, and impaired differentiation of these precursors into mature adipocytes. In mouse cell lines, the absence of the same protein impaired cellular respiration in the precursor stage, but not in already differentiated cells.

The most surprising finding, however, came from mature adipocytes. By inhibiting the MitoK_ATP channel, the researchers saw an increase in oxygen consumption when the cells were stimulated, suggesting that channel shutdown is necessary for brown adipose tissue thermogenesis to reach its maximum efficiency.

This observation was confirmed in mitochondria isolated from mice treated with a compound that activates brown fat-specific adrenergic receptors. Under these conditions, MitoK_ATP inhibition also increased oxygen consumption.

According to Alicia Kowaltowski, the study presents two complementary pieces of evidence for the importance of MitoK_ATP channel inhibition in the activation of thermogenesis. “In addition to observing that cells with a closed channel generate more heat, we also saw that, in animals under a condition that stimulates heat production, the channels were more inhibited.“

She emphasizes that these two findings converge on the same conclusion: “At the same time that the tissue is being activated to generate heat, the channel closes. This indicates that there is a signaling process within the cell that leads to this ideal situation for heat generation. These are two different ways that demonstrate the importance of closing this channel to generate maximum heat.“

Brown fat, mitochondria, and potassium channels

Brown adipose tissue is abundant in newborns, as it helps the body cope with the cold shortly after birth. As babies grow, this tissue tends to atrophy and is present in much smaller quantities in adults. It is more common in women, thinner people, and those living in cold climates, suggesting that environmental temperature also influences its maintenance in the body.

“The main difference between white and brown fat is functional,” explains Pereira Jr. “Although both are fat deposits, white fat generally maintains its reserves and mobilizes them when needed for energy. Brown fat’s main function, on the other hand, is to produce heat to maintain body temperature when necessary. This heat is produced by mitochondria, which is why brown fat contains many more mitochondria than white fat.“

In brown fat, heat is generated through the action of uncoupling protein 1 (UCP1), which dissipates the mitochondrial proton gradient, releasing energy in the form of heat instead of ATP. To sustain this process, this tissue oxidizes glucose, fatty acids, and triglycerides.

According to Kowaltowski, it’s as if brown fat mitochondria are short-circuiting. “They perform the same chemical reactions that mitochondria normally do to transduce energy, except that, because of the uncoupling protein, instead of generating forms of energy that are useful for the cell, this energy is converted to heat.“

Potassium is the most abundant cation inside cells, and mitochondria are surrounded by an environment rich in this ion. Its transport into the organelle is essential for maintaining mitochondrial volume and structure. The inner mitochondrial membrane is permeable to potassium, which enters the matrix through ATP-sensitive channels (MitoK_ATP) or by passive diffusion, driven by the electrical potential generated during the organelle’s function.

Although the group is not developing immediate clinical applications, understanding the cellular mechanisms of thermogenesis may be the first step toward future interventions. I believe that understanding the biological mechanisms that generate more or less heat will help us better identify the differences and, eventually, allow us to manipulate these processes when needed,” Kowaltowski said.“

The article “Mitochondrial ATP-Sensitive K⁺ Channels (MitoK_ATP) Regulate Brown Adipocyte Differentiation and Metabolism,” by Osvaldo R. Pereira Jr., Julian D.C. Serna, Camille C. Caldeira da Silva, Henrique Camara, Sean D. Kodani, William T. Festuccia, Yu-Hua Tseng, and Alicia J. Kowaltowski, can be accessed here.