Scientists Identify a New Molecular Dial Controlling Brown Fat Burning in Mice

Understanding the way the body burns fat is essential for making sense of metabolic systems involved in body-temperature control, weight management, energy levels and more. Researchers have now found a new molecular ‘dial’ that regulates fat burning in mice.

The research, headed by scientists at McGill University in Canada, examined brown fat, also known as brown adipose tissue. The body contains less brown fat than white fat: white fat mainly stores energy and is associated with weight and obesity, whereas brown fat chiefly burns calories to keep us warm.

Brown fat and the futile creatine cycle

Scientists recently established that brown fat can produce heat through two distinct routes. One is the long-recognised process involving the UCP1 protein, while the other is a more recently identified mechanism known as the futile creatine cycle.

Exactly what switches on the futile creatine cycle had remained uncertain. Pinpointing the molecular dial responsible could therefore have consequences for improving health in several areas.

"This is the first time we've identified how an alternative heat-producing pathway is activated, independent of the classic system," says biochemist Lawrence Kazak, from McGill University.

"That opens the door to understanding how multiple energy‑burning systems work together to keep the body warm at the just-right temperature."

How glycerol activates TNAP

The team made the discovery by closely studying brown fat in mice exposed to cold conditions, along with the chemicals that built up within it.

They then tested these chemicals against tissue-nonspecific alkaline phosphatase (TNAP), an enzyme already known to be important to the futile creatine cycle.

Their results showed that glycerol, the backbone of certain fat molecules, can activate TNAP. Detailed 3D mapping of the enzyme explained the mechanism: glycerol attaches to a particular cavity in TNAP, which the scientists named the ‘glycerol pocket’.

To confirm the result, the researchers investigated hypophosphatasia, a rare bone disorder associated with low TNAP levels. In this condition, bones fail to calcify properly and consequently become soft and weak.

They analysed genetic records from around 500,000 people in the UK Biobank database. Mutations affecting the glycerol pocket were associated with lower bone density and reduced TNAP activity, providing further support for TNAP's role as a vital molecular dial.

Potential implications for bone health, obesity and diabetes

"This finding," says McGill University cell biologist Marc McKee, "opens the door to a new kind of treatment, where increasing the activity of the TNAP enzyme through its glycerol pocket by natural or synthetic bioactive compounds could potentially boost the beneficial actions of the enzyme in patients, to help restore deficient bone mineralization to healthy levels."

It is still too soon to discuss treatments in detail, but establishing how this heat-generating brown-fat pathway is activated represents a significant advance towards being able to control it.

Hypophosphatasia is currently treated using enzyme replacement therapy, which involves three injections each week. The researchers hope their findings could ultimately support medicines that are simpler to administer, and drug candidates are already under assessment.

Although the link to bone health is more immediate, the findings may also matter for efforts to address obesity and diabetes, where energy expenditure plays an important part.

Earlier studies have connected the futile creatine cycle with obesity in mice. However, these rodents possess more brown fat relative to their body size than humans do.

Future work could investigate TNAP's role in these conditions. For now, the study provides fresh insight into an important energy-burning mechanism: two pathways that function alongside one another while remaining independent.

"Our work not only expands the conceptual framework of energy-dissipating pathways but also opens avenues for structure-guided design of TNAP activators, offering a targeted alternative to enzyme replacement therapy for skeletal disease," the researchers write in their published paper.

"The broader implications may extend well beyond adipose and bone."

The research was published in Nature.