TKB1 enzyme sabotaging weight loss.

Researchers discover key enzyme sabotaging our weight loss

Summary: A research team at UCSD discovered a key enzyme that plays a role in burning calories during both obesity and dieting and sabotages weight loss. Moreover, these scientists may have just found an existing drug that counteracts this enzyme. [This article first appeared on the website Author: Brady Hartman. ]

Ever wonder why dieting often leads to a plateau in weight loss? It happens because the body is trying to maintain a steady weight by regulating the expenditure of energy. How this happens has remained a mystery until now.

In a paper published on February 8 in the journal Cell, a team of researchers at the University of California San Diego (UCSD) School of Medicine led by Alan Saltiel, Ph.D. has identified a key enzyme that sabotages weight loss efforts during dieting. Dr. Saltiel is the director of  UCSD’s Institute for Diabetes and Metabolic Health, and says,

“We know that diets alone don’t work and this is why.”

TBK1 in Our Tank

The UCSD team identified the enzyme TANK-binding kinase 1 (TBK1) as a key player in the control of calories burned during both obesity and fasting. Moreover, the team shows how the TBK1 enzyme sabotages our weight loss efforts. As Dr. Alan Saltiel says

“Human bodies are very efficient at storing energy by repressing energy expenditure to conserve it for later when you need it,” adding “This is nature’s way of ensuring that you survive if a famine comes.”

Dr. Alan Saltiel is a leading cell biologist who has dedicated much of his professional career to understanding the link between obesity and type 2 diabetes and finding solutions to the twin problems. Dr. Saltiel specializes in researching the hormone insulin and how it relates to diabetes, obesity, and other metabolic disorders. Saltiel holds 18 patents and has developed drugs for diabetes and cancer. He has published more than 280 original papers and is ranked 18th among the most highly cited authors in biology and biochemistry over the most recent decade. As Dr. Saltiel says,

“There are two important observations that we have linked to slowing metabolism in obesity and fasting.” Adding, “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.”

Feedback Loops of Obesity

Using lab mice as models, the researchers in Saltiel’s lab observed the first loop that involves AMPK and NF-KB pathways. In this loop, chronic stress triggered by obesity causes inflammation by activating the nuclear factor kappa B (NF-KB) pathway. The NF-KB pathway stimulates genes associated with inflammation and obesity including TBK1. When TBK1 is activated, it shuts down the enzyme AMPK, reducing the cell’s ability to burn calories, and resulting in fat storage. In this way, obesity reduces energy expenditure.

AMPK is one of the master regulators of energy expenditure and also senses changes in energy levels during fasting and increases expenditure by instructing cells to burn fat as an energy source. However, when fasting activates AMPK, it initiates the TBK1 enzyme, which ultimately inhibits AMPK’s role in burning fat.

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

The TBK1 enzyme is also involved in a second feedback loop: When NK-FB induces TBK1, in turn, it inhibits NF-KB. Activating TBK1 normally reduces inflammation, without completely eliminating it, reducing it to a lower level. Without the TBK1 enzyme, inflammation increases.

TBK1 and Weight Loss

Deleting TBK1 in obese mice resulted in increased inflammation and weight loss, however, there was no change in normal-weight mice. This also explains how restricting calories through periods of sustained or intermittent fasting, might reduce inflammation.

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

The anti-inflammatory and anti-allergic drug amlexanox is a TBK1 inhibitor. Developed in Japan in the 1980s, amlexanox is used to treat asthma although it has been discontinued in the U.S.  In a paper published in the journal Cell Metabolism last year, Dr. Saltiel and colleagues reported a clinically significant reduction in blood sugar during a randomized, double-blind, clinical trial of a group of patients with type 2 diabetes who took amlexanox for 12 weeks.

In a previous study, Dr. Saltiel and his team reported that when the TBK1 enzyme is induced in obese mice, it caused a reduction in calories burned or a drop in energy expenditure. Giving obese mice amlexanox caused them to lose weight, while at the same time increasing their sensitivity to insulin, improving their diabetes and fatty liver disease.

The current study shows why amlexanox may be effective, says Dr. Saltiel, who adds,

“It may be that if we tweak this pathway we will rev up the metabolism again to improve energy expenditure,”  adding, “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.”

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Cover photo credit: Getty Images(iStock).

Yadira Galindo. “Enzyme plays a key role in calories burned both during obesity and dieting.” The University of California – San Diego via ScienceDaily. February 8, 2018. Link to the release in ScienceDaily.

Peng Zhao, Kai in Wong, Xiaoli Sun, Shannon M. Reilly, Maeran Uhm, Zhongji Liao, Yuliya Skorobogatko, Alan R. Saltiel. “TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue.” Cell (2018), Volume 172, Issue 4, 731 – 743.e12. DOI: 10.1016/j.cell.2018.01.007. Link to article in Cell.

Elif A. Oral, Shannon M. Reilly, Andrew V. Gomez, Rasimcan Meral, Laura Butz, Nevin Ajluni, Thomas L. Chenevert, Evgenia Korytnaya, Adam H. Neidert, Rita Hench, Diana Rus, Jeffrey F. Horowitz, BreAnne Poirier, Peng Zhao, Kim Lehmann, Mohit Jain, Ruth Yu, Christopher Liddle, Maryam Ahmadian, Michael Downes, Ronald M. Evans, Alan R. Saltiel. “Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.” Cell Metabolism, 2017; 26 (1): 157 DOI: 10.1016/j.cmet.2017.06.006. Link to article in Cell Metabolism.


Diagnosis, Treatment, and Advice:  This article is intended for educational and informational purposes only and is not a substitute for qualified, professional medical advice.  The information and opinions provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. Consult a qualified and licensed physician for the diagnosis and treatment of any and all medical conditions. Experimental therapies such as amlexanox for weight loss carry a much higher risk than FDA-approved ones. Dial 9-1-1, or an equivalent emergency hotline number, for all medical emergencies. As well, consult a licensed, qualified physician before changing your diet, supplement or exercise programs.
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