Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKε and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. 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 β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKε and TBK1 may contribute to the repression of energy expenditure during obesity.
Obesity is a complex metabolic disorder that is caused by increased food intake and decreased expenditure of energy. Obesity also increases the risk of developing type 2 diabetes, heart disease, stroke, arthritis, and certain cancers. There is considerable evidence to suggest that adipose tissue becomes less sensitive to catecholamines such as adrenaline in states of obesity, and that this reduced sensitivity in turn reduces energy expenditure. However, the details of this process are not fully understood.
It is well established that obesity generates a state of chronic, low-grade inflammation in liver and adipose tissue, accompanied by the secretion of signaling proteins that prevent fat cells from responding to insulin, which leads to type 2 diabetes. Activation of the NFκB pathway is thought to have a central role in causing this inflammation. Now Mowers et al. have investigated whether inflammation caused by activation of the NFκB pathway also has a role in producing catecholamine resistance in fat cells.
Obesity-dependent activation of the NFκB pathway increases the levels of a pair of enzymes, IKKε and TBK1. Mowers et al. found that elevated levels of these two enzymes reduced the ability of certain receptors (called β-adrenergic receptors) in the fat cells of obese mice to respond to catecholamines. High levels of the two enzymes also resulted in lower levels of a second messenger molecule called cAMP, which increases energy expenditure by elevating fat burning. However, treating the fat cells with drugs that interfere with the two enzymes restored sensitivity to catecholamine, allowing the fat cells to burn energy.
Mowers et al. also treated obese mice with amlexanox, a drug that inhibits these enzymes, and found that this treatment made the mice sensitive to a synthetic catecholamine that triggered the release of energy from fat. Mowers et al. suggest, therefore, that IKKε and TBK1 respond to inflammation in the body by reducing catecholamine signaling, thus preventing energy expenditure. Drugs targeting these enzymes may be useful for treating conditions like obesity or type 2 diabetes.