Highlights

• TBK1 operates at the intersection of energy expenditure and inflammation
• TBK1 deficiency attenuates HFD-induced obesity but exaggerates inflammation
• TBK1 represses energy expenditure by phosphorylating and inhibiting AMPK
• TBK1 attenuates NF-κB activation and mediates the anti-inflammatory effect of AMPK

Do you ever wonder why fat body burns even fewer calories, or why dieting for weight loss always has bottlenecks? That’s because in both cases, our body tries to defend its own weight by regulating Energy expenditure. Until now, how this has happened has still been a mystery.

Dr. Alan Saltiel, director of the Diabetes and Metabolism Health Research Institute at the University of California, San Diego, said: “The human body stores energy efficiently by inhibiting Energy Consumption so that it can be used when needed later, which ensures you survive when hunger comes.”

In a new study, researchers from the University of California, San Diego, identified that TANK-binding kinase 1 (TBK1) plays a key role in controlling Energy Expenditure (or calorie burning) during obesity and fasting. The results of the relevant study were published in the February 8th, 2018 issue of Cell, entitled “TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue.”

Saltiel said, “The two important observations we have obtained are related to the metabolic slowing in obesity and fasting. We have found two new feedback loops that interweave this self-regulating energy expenditure system. Seen as a thermostat, it senses changes in temperature, turning off or turning on heat consumption.”

Fig1. Graphic Abstract

Using mouse models, these researchers observed the first feedback loop: Obesity induces chronic stress, which triggers inflammation by activating the NFκB pathway. This pathway induces expression of genes involved in inflammation and obesity (including TBK1). When TBK1 is activated, it shuts off one of the major regulators of energy expenditure, AMPK, thereby reducing the ability of cells to burn calories, resulting in fat storage. This is the mechanism by which obesity reduces energy expenditure.

The results confirm that the AMPK also senses changes in energy levels during fasting and increases the energy consumption by directing cells (especially fat cells) to burn fat as an energy source. However, when fasting activates AMPK, it activates TBK1, which ultimately inhibits the role of AMPK in burning fat.

Saltiel said, “This feedback loop stops energy consumption through inflammation and fasting. When we remove TBK1 from mouse adipocytes, energy consumption is restored. But other things that happened surprised us—inflammation increased.”

TBK1 participates in the second feedback loop: Although NFκB induces TBK1 expression, TBK1 turns over to inhibit NFκB. Activation of TBK1 usually reduces inflammation, but it cannot eliminate it completely, only causes it to drop to a lower level. In the absence of TBK1, inflammation increased.

Loss of TBK1 in obese mice leads to weight loss and increased inflammation, but this loss does not result in such changes in normal-weight mice. This feedback loop explains how limiting calories may reduce inflammation.

Saltiel said that “suppressing TBK1 has the potential to restore energy balance in obesity by increasing the ability to burn some fat. This is probably not the only way to explain the energy consumption in fasting or obesity, but this information provides new insights for us on the development of drugs that inhibit TBK1 or other enzymes involved in metabolism.”

One possible TBK1 inhibitor is called Amlexanox. Amlexanox is an anti-inflammatory and anti-allergic drug used to treat asthma. It was developed in Japan in the 1980s. In a paper published last year in Cell Metabolism, Saltiel and his team reported in a randomized, double-blind, placebo-controlled clinical trial of a small group of patients with type 2 diabetes who take Amlexanox for 12 weeks. There is a clinically significant drop in blood glucose.

In a previous study, Saltiel and colleagues reported that when TBK1 was induced in obese mice, it resulted in decreased energy expenditure or reduced calories burned. Giving Amlexanox to obese mice can cause them to lose weight while their susceptibility to insulin increases, thereby improving their conditions of diabetes and fatty liver disease.

The current new study reveals why Amlexanox may be effective.

Saltiel said, “If we adjust this approach, then we may speed up the metabolism again and thus increase energy consumption. I think it may also need to do two things: reduce energy intake through dieting, and at the same time by preventing the compensatory decline of calories burning, in which way increase energy consumption. We know that diet alone will not work for the reasons stated above.”

Reference

Peng Zhao, Kai in Wong, Xiaoli Sun et al. Enzyme Plays a Key Role in Calories Burned both During Obesity and Dieting. Cell, 8 February 2018, 172(4):731–743, doi:10.1016/j.cell.2018.01.007