Potential New Obesity Target Found in Mitochondrial Protein Involved in Brown Fat Thermogenesis

Newly reported research in human tissue and in mice has uncovered a mechanism by which brown fat (brown adipose tissue; BAT) is converted into heat, and identified a control protein that may represent a therapeutic target for obesity. The researchers, led by Guadalupe Sabio, PhD, head of the Organ Crosstalk in Metabolic Diseases Group at the National Cancer Research Centre (CNIO), and Cintia Folgueira, PhD, at CNIO and the National Centre for Cardiovascular Research (CNIC), found that the mechanism is controlled by a mitochondrial protein, methylation-controlled J protein (MCJ). Their experiments showed that when MCJ is removed from obese mice the animals produce more heat and lose weight. The researchers also showed that they could reduce the weight of obese mice by transplanting the animals with fat lacking MCJ.

Reporting on their results in Nature Communications (“Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis”) the team stated, “These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.”

Obesity is a global health problem that affects 650 million people worldwide, and predisposes to the development of cardiometabolic diseases, the authors wrote. However, they pointed out, “Despite the societal impact of obesity, understanding the molecular mechanisms and multiple factors through which obesity leads to disease is still limited.”

Obesity is the result of either excessive food intake or inadequate total energy expenditure. Scientists now know that in addition to storing energy, body fat (adipose tissue; AT) plays a crucial role in the management of that energy by the body. “Current knowledge positions AT as a central rheostat in the regulation of systemic nutrient and energy homeostasis,” they stated. “In fact, AT is key to the control of whole-body metabolism and thus, modulating its function likely protects against obesity.”

Of two types of fat in the body, white adipose tissue (WAT) mostly stores energy, while brown adipose tissue—its cells have more mitochondria which gives them a brown hue—is responsible for heat generation, or thermogenesis, the process that maintains body temperature, and which is triggered by cold or other stimuli.

Several studies in the last decade have shown that activating brown fat protects against obesity and metabolic disease. “For some time,” explained Sabio, “it has been thought that obesity could be prevented by getting this fat to spend more energy by generating heat. So, the first thing is to understand how it works.”

“Discovering new mechanisms of heat production in brown fat is one of the most interesting targets in the study of obesity,” said Sabio. For a long time it was thought that brown fat used a single mechanism to generate heat, but today we know that this is not the case. There are several mechanisms involved. The newly reported research has uncovered one mechanism, which they found is controlled by the mitochondrial protein MCJ.

The researchers first identified what they described as reduced MCJ expression in human subcutaneous WAT (WATsc) during obesity, when AT thermogenesis is reduced. “… we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples,” they wrote. “In parallel, mice fed a high-fat diet (HFD) also displayed decreased MCJ expression in both WATsc and BAT.” In addition, cold exposure resulted in reduced MCJ levels in BAT. These collective findings, the team noted. “… point to a potential role of MCJ in regulating adipose tissue adaptation to obesity in both humans and mice,” they stated.

Their continued work then discovered that when the MCJ protein is removed from BAT in mice, these MCJ knockout (MCJ^KO) animals fed a high-fat diet (HFD) produced more heat and lost weight when compared with control (wild type; WT) animals, they wrote. “… when exposed to HFD, MCJ^KO mice showed outcomes distinct from WT control mice. MCJ^KO mice displayed less weight gain and fat mass accumulation with no discernible alterations in lean mass.” This was associated with increased energy expenditure, they further commented. “Here we found that mice lacking mitochondrial protein MCJ specifically in the BAT exhibited a significant increase in thermogenesis.”

Experiments also showed that it was enough to transplant into mice MCJ-deficient brown fat to reduce the animals’ weight. “BAT transplantation with MCJ^KO BAT led to a decrease in body weight gain and an increase in interscapular temperature,” the investigators stated.

The researchers observed that “… animals without MCJ in brown fat are protected against health problems caused by obesity, such as diabetes or increased blood lipids,” explained the two scientists. They believe that the MCJ protein could be a new therapeutic target to correct diseases associated with obesity. “Collectively, these results affirm that BAT-specific MCJ deficiency enhances BAT temperature and protects against diet-induced obesity,” they stated. “Overall, our work underscores MCJ as a promising candidate for the development of interventions aimed at harnessing the substantial thermogenic potential of BAT to combat obesity and its associated complications.”

CNIO researcher and lead author Beatriz Cicuéndez, PhD, further explained, “This protection is due to the activation of an essential signaling pathway to adapt to the stress caused by obesity. Known as the catabolic pathway, it causes an increase in the consumption of fats, sugars, and proteins to produce heat in brown fat. It is a mechanism that also happens in people with very active brown fat.” In their paper, the team concluded, “Our results in humans and mice suggest that the reduction of MCJ observed in patients with obesity appears to act as a compensatory mechanism to enhance BAT thermogenesis. This adaptation may serve as a protective strategy to counteract excessive weight gain.”

The researchers are now looking to develop a therapy to block this protein in obese patients. However, to do so they will first have to investigate whether the MCJ protein has vital functions in other tissues. At the same time, Sabio said, “We are trying to see if these changes in fat affect tumor growth or cachexia—loss of muscle and fat—which is also sometimes linked to cancer.”

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