University of Michigan scientists have revealed the underlying mechanisms on how an asthma drug currently in clinical trials for the treatment of obesity and other related metabolic disorders increases sugar metabolism by generating a novel signal between fat and liver cells.

In a study (“A subcutaneous adipose tissue–liver signaling axis controls hepatic gluconeogenesis”) in Nature Communications, researchers from the laboratory of Alan Saltiel, Ph.D., the Mary Sue Coleman Director of the University of Michigan’s Life Sciences Institute, provided evidence for how amlexanox reversed the signs of obesity diabetes and fatty liver disease. Their findings suggest a possible new pathway for pharmacological intervention in treating metabolic diseases.

Amlexanox, which had been previously used in the treatment of asthma, had been shown by Dr. Saltiel’s group to improve diabetes and weight loss in obese mice. “We know that amlexanox works to reverse obesity and insulin resistance in part by resolving chronic inflammation and increasing energy expenditure, but that's not the whole story of the drug's effects,” said lead author of the current study, Shannon Reilly, Ph.D. “Understanding how the drug also enables crosstalk between fat cells and the liver in obese mice allows us to see more of the amlexanox picture, and also sheds light on communication between different tissues in the body.”

Dr. Reilly found that the crosstalk was facilitated by amlexanox’ effects on increasing the levels of the second messenger molecule (cAMP) in fat cells. This led to an increased rate by which the mice metabolized fat, in turn leading to weight loss. Concomitantly, amlexanox elicits the release of the interleukin-6 (IL-6) from the fat cells of the mice. IL-6 then travels to the liver and reduces the production of glucose in the diabetic mice.

One of the primary goals of Dr. Saltiel’s lab has been to reveal the pathways and interconnections associated with obesity, diabetes, and inflammation. Earlier findings suggest that obesity leads to chronic inflammation in the liver and adipose tissue, which Dr. Saltiel’s lab previously found was due to an increase in two protein kinases: IKK-ε and TBK1. In a study (“Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKK- ε and TBK1”) published in eLife in December 2013 the investigators observed that amlexanox reduced IKK- ε and TBK1 levels.

“In vivo inhibition of these kinases by treatment of obese mice with the drug amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a Beta-3 adrenergic agonist,” wrote the investigators in the eLife paper. “These studies suggest that by reducing production of cAMP in adipocytes, IKK-ε and TBK1 may contribute to the repression of energy during obesity.”








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