Enzyme plays a key role in calories burned both during obesity and dieting

February 8, 2018, University of California - San Diego
Credit: CC0 Public Domain

Ever wonder why obese bodies burn less calories or why dieting often leads to a plateau in weight loss? In both cases the body is trying to defend its weight by regulating energy expenditure. Until now, how this happens has been a mystery.

"Human bodies are very efficient at storing energy by repressing energy expenditure to conserve it for later when you need it," said Alan Saltiel, PhD, director of the UC San Diego Institute for Diabetes and Metabolic Health. "This is nature's way of ensuring that you survive if a famine comes."

In a paper publishing in Cell on February 8, University of California San Diego School of Medicine researchers identify the enzyme TANK-binding kinase 1 (TBK1) as a key player in the control of energy expenditure—or calories burned—during both obesity and fasting.

"There are two important observations that we have linked to slowing metabolism in obesity and fasting," said Saltiel. "We've discovered two new feedback loops that are intertwined to self-regulate the system. Think of it like your home thermostat, which senses change in temperature to turn heat off and on."

Using mouse models, researchers observed the first loop: Chronic stress triggered by obesity causes inflammation through the activation of the pathway NFKB. This pathway induces genes associated with inflammation and obesity including TBK1. When TBK1 is activated, it shuts down AMPK, one of the master regulators of energy expenditure, thus reducing a cell's ability to burn calories, and resulting in fat storage. This is the mechanism by which obesity reduces energy expenditure.

As it turns out, the enzyme AMPK also senses changes in energy levels during fasting and increases expenditure by instructing cells—especially adipocytes (fat cells)—to burn fat as an energy source. But, when fasting activates AMPK it initiates TBK1, which ultimately inhibits AMPK's role in burning fat.

"This feedback loop blocks energy expenditure both through inflammation and fasting," said Saltiel. "Energy expenditure was restored when we deleted TBK1 from fat cells mice. But, something else occurred that surprised us—there was an increase in inflammation."

TBK1 is involved in a second feedback loop: While NKFB induces TBK1, TBK1 turns around and inhibits NFKB. The activation of TBK1 normally reduces inflammation, without completely eliminating it, causing it to be low grade. Without TBK1, inflammation increases.

Deletion of TBK1 in resulted in and increased inflammation, but in normal weight mice there was no change. This also explains how restricting calories might reduce .

"Inhibiting TBK1 has the potential to restore energy balance in states of obesity by enhancing the ability to burn some fat," said Saltiel. "This is probably not the only pathway accounting for energy expenditure in fasting or , but this information provides new insight into how we might develop drugs that inhibit TBK1 or other enzymes involved in metabolism."

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

In a previous study, Saltiel and colleagues reported that when TBK1 is induced in obese mice it caused a drop in energy expenditure or reduction in calories burned. Giving obese mice amlexanox caused them to lose weight, while their sensitivity to insulin increased, improving their diabetes and fatty liver disease.

The current paper reveals why amlexanox may have been effective.

"It may be that if we tweak this pathway we will rev up the metabolism again to improve energy expenditure," said Saltiel. "I think you'll probably still have to do both: reduce intake through diet and increase by blocking this compensatory reduction in burning calories. We know that diets alone don't work and this is why."

Explore further: Breaking the cycle of obesity, inflammation and disease

More information: Cell (2018). DOI: 10.1016/j.cell.2018.01.007 , http://www.cell.com/cell/fulltext/S0092-8674(18)30042-4

Related Stories

Breaking the cycle of obesity, inflammation and disease

December 19, 2013
Researchers at University of Michigan have illuminated an aspect of how the metabolic system breaks down in obesity. The findings provide additional evidence that a drug entering clinical trials at the university could reverse ...

Researchers uncover more clues to how drug reverses obesity, diabetes, fatty liver disease

January 12, 2015
Researchers at the University of Michigan have identified how a promising drug in clinical trials for the treatment of obesity and related metabolic disorders improves the metabolism of sugar by generating a new signal between ...

Old drug may point the way to new treatments for diabetes and obesity

February 10, 2013
Researchers at the University of Michigan's Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty ...

Repurposed asthma drug shows blood sugar improvement among some diabetics

July 5, 2017
After 12 weeks of taking an anti-asthma drug, a subset of patients with type 2 diabetes showed a clinically significant reduction in blood glucose during a randomized, double blind, placebo-controlled clinical trial, report ...

MEND researchers are ready for human trials of an obesity drug showing dramatic results in mice

June 28, 2013
As sometimes happens in science, a medication used for one thing turns out to be very good for something else.

'Thrifty phenotype' leads to less weight loss in obese

August 1, 2015
(HealthDay)—For obese individuals, energy expenditure during fasting and response to overfeeding predict weight loss in response to caloric restriction, according to a study published in the August issue of Diabetes.

Recommended for you

Receptor proteins that respond to nicotine may help fat cells burn energy

May 21, 2018
The same proteins that moderate nicotine dependence in the brain may be involved in regulating metabolism by acting directly on certain types of fat cells, new research from the University of Michigan Life Sciences Institute ...

Atomic-level study reveals why rare disorder causes sudden paralysis

May 21, 2018
A rare genetic disorder in which people are suddenly overcome with profound muscle weakness is caused by a hole in a membrane protein that allows sodium ions to leak across cell membranes, researchers at the University of ...

Hotter bodies fight infections and tumours better—researchers show how

May 21, 2018
The hotter our body temperature, the more our bodies speed up a key defence system that fights against tumours, wounds or infections, new research by a multidisciplinary team of mathematicians and biologists from the Universities ...

New era for blood transfusions through genome sequencing

May 18, 2018
Most people are familiar with A, B, AB and O blood types, but there are hundreds of additional blood group "antigens" on red blood cells—substances that can trigger the body's immune response—that differ from person to ...

Robots grow mini-organs from human stem cells

May 17, 2018
An automated system that uses robots has been designed to rapidly produce human mini-organs derived from stem cells. Researchers at the University of Washington School of Medicine in Seattle developed the new system.

Scientists uncover a new face of a famous protein, SWI2/SNF2 ATPase

May 17, 2018
A team of Texas A&M and Texas A&M AgriLife Research scientists now have a deeper understanding of a large switch/sucrose non-fermentable (SWI/SNF) protein complex that plays a pivotal role in plant and human gene expression ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.