TNAP Glycerol Pocket Links Brown Fat and Bone Health

Fat cells and bone cells perform two very different roles. One either stores or burns energy, while the other forms and maintains the skeleton.

For years, metabolism researchers and specialists in bone disease have largely operated in separate fields.

A new study, however, has revealed a biological mechanism that bridges this gap. The same enzyme is present in both systems and responds to an identical molecular trigger.

A second heat-producing pathway

The established system relies on a protein known as UCP1 to warm brown fat. In recent years, researchers found that brown fat could continue producing heat even when UCP1 was switched off.

This was puzzling, as it suggested another heat-generating mechanism must be at work. Scientists called it the futile creatine cycle, but were unable to establish what switched it on.

At McGill University (McGill), Professor Lawrence Kazak and his team at the Rosalind and Morris Goodman Cancer Institute have now identified that trigger.

The study follows earlier research which demonstrated the cycle’s role in conventional brown fat. That previous work had left open the question of how the pathway was activated.

Finding the molecular switch

As the body breaks down stored fat in cold conditions, it releases glycerol. The McGill researchers discovered that glycerol is more than a leftover product of metabolism.

Instead, it attaches to a previously unidentified region of an enzyme called TNAP.

This binding substantially increases the enzyme’s activity. The researchers called the site the glycerol pocket.

In collaboration with structural biologist Alba Guarné, Kazak’s team used X-ray crystallography to map the pocket’s structure atom by atom.

They showed that, when glycerol binds in place, TNAP accelerates the futile creatine cycle considerably.

“This is the first time we’ve identified how an alternative heat-producing pathway is activated, independent of the classic system,” said Kazak.

TNAP links fat and bone

The next finding was unexpected. TNAP is active not only in fat, but also in bone mineralisation.

This is the process that strengthens the skeleton by removing molecules that would otherwise prevent calcium from being deposited.

Before this study, there was no reason to believe these two roles depended on one molecular switch. The team demonstrated that they do, using the same laboratory methods to establish both functions.

The glycerol pocket needed for heat generation also seems to be vital in bone-forming cells.

Known as osteoblasts, these cells are essential for normal mineralisation. Disrupting the pocket impairs both functions.

Soft bones and disease

When TNAP functions poorly, bones fail to harden as they should. This is precisely what occurs in hypophosphatasia, a rare inherited condition.

It may lead to fractures, persistent pain, tooth loss and skeletal deformities. Founder mutations have increased its prevalence in some areas of Quebec and Manitoba.

Existing enzyme replacement therapy benefits certain patients. However, it involves repeated injections and does not correct the defect in the enzyme itself.

A medicine capable of increasing a patient’s own TNAP activity would offer an entirely different approach.

Human genetic evidence

Despite the structural and mouse-based results, a key question remained: does the pocket genuinely affect human bone health?

The researchers used UK Biobank data to identify people with naturally occurring genetic variants that encode the glycerol pocket. The results showed a clear pattern.

Carriers had lower enzyme activity in their blood as well as lower bone mineral density.

The connection between the pocket, enzyme activity and skeletal strength was therefore shown in living people, rather than only in cell cultures and mice.

New drugs on the horizon

Kazak’s team has already tested dozens of potential molecules that attach to the glycerol pocket.

Encouragingly, several of them can increase TNAP activity. Such a drug could raise the activity of a patient’s own enzyme and restore mineralisation without the need for repeated injections.

Whether this strategy might also influence heat production in brown fat remains a separate issue.

Brown fat is still an important focus of obesity research, and a clearly defined activation pocket gives doctors a tangible place to begin.

One switch, two systems

The researchers identified one molecular site that serves two entirely different functions. Glycerol – the ordinary by-product of fat breakdown – proved central to both.

This finding brings together distinct research areas that did not realise they shared a common mechanism.

For people with the disorder, the result is encouraging. A new generation of treatments may be able to enhance TNAP rather than replace it.

Several candidate compounds are already prepared for the next stage of testing.