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Have you ever wondered why obese bodies burn less calories or why dieting often leads to a plateau or stall in weight loss? In both cases the body is trying to defend its weight by regulating energy expenditure. The human body is very efficient at storing energy by decreasing energy expenditure to try and conserve it for later when you need it.
Amlexanox is an anti-inflammatory and anti-allergic compound which has traditionally be used to treat ulcers by reducing healing time and pain, but is also used for weight loss.
It has multiple mechanisms of action, including inhibiting inflammation by inhibiting the release of histamine (augments cAMP content in mast cells) and leukotrienes. It has been shown to selectively inhibit TBK1 (TANK-binding kinase 1) and IKK-3 (Inflammatory Kinase), which produces weight loss and improved insulin sensitivity.
We combine Amlexanox with Tetradecylthioacetic Acid, or TTA. It is known as a PPAR-alpha activator protecting the body from excess fats by clearing fats from the blood to be used by muscle or liver cells. It is a fatty acid that does not get used for fuel by the body, but instead helps to regulate how much fat the body stores by influencing genes that control the metabolism.
TTA can help individuals feel full more quickly while the fatty acid decreases overall hunger and burns fat. In addition to regulating fat metabolism, this fatty acid has LDL lowering, antioxidant, cardioprotective, anti-inflammatory and immunity-enhancing properties.
Loop 1: The first loop involves AMPK (adenosine monophosphate-activated protein kinase) and NF-KB (nuclear factor kappa B) pathways. In this loop, chronic stress triggered by obesity causes inflammation by activating the 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 thereby impeding the burning of calories and causing fat to be stored. This was all reversed when TBK1 was deleted from fat cells. Research also showed that this deletion caused an increase in inflammation.
Loop 2: Now TBK1 switches roles and inhibits the gene pathway that initially ramped up its production. 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.
Some of the benefits of Amlexanox can include:
One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are 'defending' their body weight. Amlexanox seems to tweak the metabolic response to excessive calorie storage and rev up the metabolism again to improve energy expenditure. This medication does not work for everyone, some people will respond, others will not.
Growing evidence points to an inflammatory link between obesity and type 2 diabetes. Obesity produces a state of low-grade inflammation, particularly in the liver and in adipose cells. Using next generation RNA-sequencing analysis, researchers have compared gene expression in fat cells. They have found that inhibition of IKK-3 and TBK1 improves glucose control in certain patients with type 2 diabetes. The inflammatory kinases IKK-3 and TBK1 are elevated in obesity; their inhibition in obese mice reduced weight, insulin resistance, fatty liver and inflammation.
Amlexanox (an inhibitor of IKK 3and TBK1) was studied in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease.
Treatment of patients with Amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, in a group drug responders (people who reacted positively) also exhibited improvements in insulin sensitivity and hepatic steatosis (fatty liver). This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at the beginning of the study. They also exhibited a unique pattern of gene expression changes in response to Amlexanox, consistent with increased energy expenditure. Together, this data suggests that dual-specificity inhibitors of IKK-3 and TBK1 may be effective therapies for metabolic disease in certain groups of patients.
Dosanjh A, Won CY. Amlexanox: A Novel Therapeutic for Atopic, Metabolic, and Inflammatory Disease. Yale J Biol Med. 2020 Dec 29;93(5):759-763. PMID: 33380937; PMCID: PMC7757066
Zhao P, Wong KI, Sun X, Reilly SM, Uhm M, Liao Z, Skorobogatko Y, Saltiel AR. TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell. 2018 Feb 8;172(4):731-743.e12. doi: 10.1016/j.cell.2018.01.007. PMID: 29425491; PMCID: PMC5808582.
