Dr. Saltiel and his team recently directed their attention toward the enzyme TANK-binding kinase 1 (TBK1), which they identified as key when it comes to the body’s process of “deciding” how much fat to burn and how much to keep in store, especially over a period of fasting.
“There are two important observations that we have linked to slowing metabolism in obesity and fasting,” explains Dr. Saltiel.
Vicious metabolic cycles
Dr. Saltiel and team worked on the mouse model — using both obese and normal-weight animals — in order to study the role of TBK1 in metabolic processes. They noticed that the enzyme was implicated in two distinct processes, leading to the same result each time.
The first process is kick-started by obesity-related chronic stress, and it leads to inflammation as it activates a pro-inflammatory signaling pathway called NFKB.
NFKB enhances the expression of genes that “dictate” the production of enzymes thought to play a role in both inflammation and the accumulation of body fat, including the gene that encodes TBK1.
TBK1 then disactivates another enzyme, AMPK, which is largely responsible for regulating how much fat we convert into raw energy. This means that, instead of being burned, fat is able to accumulate and lead to excess weight.
The TBK1 enzyme is also implicated in the mechanism that is triggered by fasting. In fasting, the body’s energy levels go down. The enzyme AMPK perceives that, and to boost energy, it sends signals to fat cells to convert into energy.
However, when AMPK is activated, it also boosts the expression of the TBK1 gene, which, once again, leads to the TBK1 enzyme inhibiting the activity of AMPK. A vicious cycle thus ensues, preventing the body from burning the accumulated fat.
“This feedback loop blocks energy expenditure both through inflammation and fasting,” Dr. Saltiel explains. When the scientists noticed this mechanism, they looked for a way to modify it.
“Energy expenditure was restored when we deleted TBK1 from fat cells [in] mice,” he continues. “But something else occurred that surprised us — there was an increase in inflammation.”
How can we restore energy balance
A second process with TBK1 at its core leads to an equally vicious cycle. The team also noted that, even as the NFKB pathway triggers the production of TBK1, the enzyme ends up inhibiting the NFKB pathway.
TBK1 normally helps to reduce inflammation without extinguishing it, however. Instead, it keeps it at low levels — when TBK1 is inactivated, the inflammatory response is heightened without regulatory action of the enzyme.
When Dr. Saltiel and colleagues deleted the TBK1 gene in obese mice, this triggered weight loss as well as increased inflammation. To the contrary, when TBK1 was deleted in normal-weight mice, no metabolic change was observed, suggesting that cutting down on calories could also help to reduce inflammation.
“Inhibiting TBK1 has the potential to restore energy balance in states of obesity by enhancing the ability to burn some fat,” explains Dr. Saltiel.
While he notes that “[t]his is probably not the only pathway accounting for energy expenditure in fasting or obesity,” he adds, “[T]his information provides new insight into how we might develop drugs that inhibit TBK1 or other enzymes involved in metabolism.”
Still, the researchers note that taking special drugs won’t be enough for those who want to be fitter.
“I think you’ll probably still have to do both: reduce energy intake through diet and increase energy expenditure by blocking this compensatory reduction in burning calories,” stresses Dr. Saltiel.