Abstract
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. DOI: http://dx.doi.org/10.7554/eLife.01119.001.
Highlights
There is currently a worldwide epidemic of obesity, which is manifesting itself as a leading risk factor in industrialized countries for the development of type 2 diabetes, dyslipidaemia, nonalcoholic fatty liver disease, cardiovascular disease and some cancers.[1]
Previous studies by Takeda investigators showed that the oral administration of amlexanox (1) in mice, rats, guinea pigs, and dogs generated in plasma a major mono-hydroxyl metabolite (2) from oxidation of the C-7 isopropyl substituent, and two minor metabolites 3 and 411,12 (Figure 1)
As part of a program toward making analogues of amlexanox,[14,15] we decided to synthesize a derivative 5 (Figure 1) in which deuterium is introduced into two sites of metabolism on the C-7 isopropyl function
Summary
There is currently a worldwide epidemic of obesity, which is manifesting itself as a leading risk factor in industrialized countries for the development of type 2 diabetes, dyslipidaemia, nonalcoholic fatty liver disease, cardiovascular disease and some cancers.[1]. Previous studies by Takeda investigators showed that the oral administration of amlexanox (1) in mice, rats, guinea pigs, and dogs generated in plasma a major mono-hydroxyl metabolite (2) from oxidation of the C-7 isopropyl substituent, and two minor metabolites 3 and 411,12 (Figure 1). As part of a program toward making analogues of amlexanox,[14,15] we decided to synthesize a derivative 5 (Figure 1) in which deuterium is introduced into two sites of metabolism on the C-7 isopropyl function. The deuterium kinetic isotope effect associated with placing deuterium at the site of metabolic derivatization slows metabolic activation and is expected to increase the lifetime of the active drug in vivo.[16] we provide data of the activity of 5 relative to amlexanox (1) in inhibiting TBK1 and its metabolic stability against mouse, rat and human microsomes
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