TBK1 inhibitors may deal with obesity
An enzyme called TBK1
is involved in the control of energy expenditure under different conditions, according to a study carried out by a team composed of researchers from the University of California–San Diego (UCSD) and the University of Michigan. According to Dr. Alan Saltiel, a cell biologist from UCSD who led the study, our bodies are good at storing energy by suppressing energy expenditure and this is very important for survival.
The Saltiel lab has been focused on the molecular events involved in the regulation of glucose uptake and storage. One aim of Dr. Saltiel's research is to understand the pathogenesis of obesity, diabetes, and other metabolic disorders and to use the knowledge to develop new drugs targeting defects in metabolic processes.
The enzyme TBK1 is activated by pro-inflammatory cytokines. It has essential roles in innate immunity. But its role in regulating metabolism is still unclear.
In previous work, Dr. Saltiel and colleagues found that amlexanox, an approved small-molecule drug used in the clinic to treat aphthous ulcers and asthma, also reverses obesity, diabetes and fatty liver in mice by inhibiting two genes — IKKE and TBK1 — that together act as a sort of brake on metabolism. Findings of the study were reported in a paper titled "An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice," which was published online in the journal Nature Medicine in 2013.
In the current study, Dr. Saltiel's team continued to study the role of TBK1 in energy metabolism. Mice fed a high-fat diet (HFD) exhibited elevated TBK1 expression in adipocytes (fat cells). Specifically inhibiting TBK1 in adipocytes reduced obesity induced by HFD by enhancing energy expenditure. TBK1 was found to directly inhibit AMPK to suppress respiration and promote energy storage.
This study, titled "TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue," appeared in the journal Cell on February 8, 2018. Other researchers participating in the study include Peng Zhao, Kai in Wong, Xiaoli Sun, Shannon M. Reilly, Maeran Uhm, Zhongji Liao, and Yuliya Skorobogatko.
AMPK is an enzyme that functions as a master metabolic regulator. It is expressed in various tissues and it is a sensor of energy status that maintains cellular energy homeostasis. In addition to its role in metabolism, AMPK has many other functions, such as regulation of mitochondrial biogenesis and disposal, autophagy, cell polarity, and cell growth and proliferation.
The researchers pointed out that inhibition of TBK1 represents a potential way to restore energy balance in the content of obesity by promoting the ability to burn some fat. More research is needed to evaluate the efficacy of TBK1 inhibitors like amlexanox in treating obesity and other metabolic disorders.
Amlexanox is a specific inhibitor of IKKε and TBK1. The beneficial effects of this drug in elevating energy expenditure, producing weight loss, improved insulin sensitivity, and decreasing steatosis have been demonstrated in animal experiments. Given that amlexanox is safely used in human patients, developing it as a therapeutic for obesity and related disorders could be a more time-consuming task than developing a totally new drug.