Can shutting down the IRF3 kinases be the magic pill to treat obesity?

amlexanoxCan amlexanox, a small molecule drug that has been approved for asthma, allergic rhinitis and aphthous ulcers be an effective treatment for obesity? Many are excited about this prospective presented in a recent article in Nature Medicine by Reilly et. al. as simply Googling “amlexanox” and “obesity” resulted in a plethora of news articles on this report.  Interestingly, the two highly related proteins allegedly inhibited by amlexanox that led to this result in mice are the IRF3-kinases, TBK1 (TANK-binding Kinase-1, T2K, NAK) and IKK-ε (IκB kinase-epsilon, IKK-i), whose major known functions are during pathogen infections: the activation of IRF-3 (interferon regulatory kinase-3), the major transcription factor regulating expression of interferon-β (IFNβ).

Inflammation is considered a key link between obesity and insulin resistance.  The canonical NF-ĸB signaling pathway has been shown to playing a major role in this linkage.  IKK-ε and TBK1 are two IKK-β-related kinases with an unclear role in NF-ĸB activation, and thus their role in obesity and insulin resistance was explored in this and a previous study by the same group (Chiang et. al).

In this study, the authors show that expression and kinase activity of IKK-ε and TBK1 were increased in mice fed a high-fat diet and in response to TNFα in an in vitro adipocyte inflammation model. In the previous study, IKK-ε deficient mice were partially resistant to development of obesity and insulin resistance when fed a high fat diet.  Thus, the authors sought to determine if inhibiting these kinases would have a therapeutic effect on obesity.  A screen for small molecule inhibitors to block IKK-ε and TBK1 identified amlexanox, a drug currently used to treat asthma, allergic rhinitis and aphthous ulcers.  Amlexanox treatment inhibited the in vitro kinase activity of both IKK-ε and TBK1 at a much lower concentration than it did the related canonical NF-ĸB pathway kinase IKK-β.

To determine the effect of in vivo inhibition of these kinases on obesity indexes, mice fed a high fat diet were treated with amlexanox.  Amlexanox-treated mice gained significantly less weight than non-treated mice, and treatment of mice with pre-established diet-induced obesity led to a significant, but reversible weight loss accompanied by a decrease in adipose tissue, without a lower food intake.  Additionally, ob/ob mice which are genetically disposed to overt obesity due to deficient leptin expression, also lost adipose tissue mass when treated with amlexanox.

Interestingly, compared with mice fed a normal diet, mice on a high fat diet have a decreased core body temperature. Amlexanox-treated mice had body temperatures raised to normal levels along with increased oxygen consumption, indicating that an increase in energy expenditure of these mice may contribute to their weight loss.  Other indexes of obesity and glucose intolerance also returned to normal levels following amlexanox treatments.

Despite the promising results achieved with this drug in decreasing obesity and insulin resistance, the mechanisms by which inhibition of these kinases lead to this effect remains unclear.  Thus, future studies need to clarify the effects of amlexanox on IKK-ε and TBK1 regulation of the NF-ĸB pathway and obesity-associated inflammation, as well as address effects on the IRF3-interferon pathway.  Finally, it will be important to determine if other molecules are targeted by this drug.

 

Further Reading:

An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice.  Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I, Downes M, Yu RT, Liddle C, Evans RM, Oh D, Li P, Olefsky JM, Saltiel AR. Nat Med. 2013 Mar;19(3):313-21.

The protein kinase IKKepsilon regulates energy balance in obese mice.  Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR. Cell. 2009 Sep 4;138(5):961-75.

Turning off the inflammatory, but not the metabolic, flames.  Calay ES, Hotamisligil GS. Nat Med. 2013 Mar 6;19(3):265-7.

Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription.  Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ, Elia AJ, Shillinglaw W, Mak TW, Cao Z, Yeh WC. EMBO J. 2000 Sep 15;19(18):4976-85.

Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood.  Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E, Sancho-Shimizu V, Pérez de Diego R, Abhyankar A, Israelsson E, Guo Y, Cardon A, Rozenberg F, Lebon P, Tardieu M, Heropolitanska-Pliszka E, Chaussabel D, White MA, Abel L, Zhang SY, Casanova JL. J Exp Med. 2012 Aug 27;209(9):1567-82.

TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2.  Delhase M, Kim SY, Lee H, Naiki-Ito A, Chen Y, Ahn ER, Murata K, Kim SJ, Lautsch N, Kobayashi KS, Shirai T, Karin M, Nakanishi M. Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):E177-86.

*Image courtesy of RXlist.com*

About Andrea

Andrea Miyahira is currently a post-doctoral fellow at the Beckman Research Institute of the City of Hope, in Duarte, CA. She received her Ph.D. from UCLA and her main research interest is in the field of cancer immunology.