Combined use of IKK inhibitors with β-adrenergic receptor agonists for the treatment of obesity and metabolic disorders.
Studies conducted at the University of Michigan show that the induction of IKKε and TBK1 reduces sensitivity of adipocytes to β-adrenergic signaling and accounts for the decreased energy expenditure in obesity. Overexpression of IKKε and TBK1 represses β-adrenergic-dependent lypolytic signaling in adipose cells, and activation of NFκB signaling by TNFα treatment decreased the sensitivity of adipocytes to β-adrenergic stimulation in a manner dependent on the activity of IKKε and TBK1. The kinases reduce β-adrenergic stimulation by phosphorylating and activating PDE3B, the enzyme that catalyzes the breakdown and degradation of cAMP. Selective inhibitors for PDE3B blocked the inhibitory effect of IKKε and TBK1on cAMP levels and PKA signaling. In vivo, inhibition of of IKKε and TBK1 by treatment of obese mice with selective IKKε and TBK1 inhibitor, amlexanox, reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of β-adrenergic agonist. These results suggest that IKKε and TBK1 contribute to decreasing energy expenditure and lipolysis in obesity through PDE3B dependent reduction of cAMP levels and β-adrenergic signaling. This IKK mediated catecholamine resistance may be a major reason for reduced energy expenditure that hampers weight loss efforts by diet and pharmacotherapy. Thus, combined use of IKK inhibitors with β-adrenergic receptor agonists or with sympathetic nervous system activators may be a more effective strategy for the treatment of obesity.
Role of the inflammatory response and adrenergic signaling in the regulation of energy balance
The prevalence of obesity in the USA and worldwide continues to increase and has reached epidemic proportions. In the United States, more than one third of the adult population (35.7%) is obese. Obesity is a major economic burden with an estimated annual medical cost of $148 billion. Obesity is caused by increased energy intake and decreased energy expenditure leading to a huge increase in adipose tissue. The activation of the sympathetic nervous system and the resulting release of catecholamines (adrenaline, noradrenaline and dopamine) are important regulators of energy balance and lipolysis. Catecholamines mediate their actions by binding to lipolytic β-adrenoceptors and antilipolytic α2-adrenoceptors. Activation of β-adrenoceptors leads to an increase of cAMP which then activates protein kinase A (PKA). The activation of PKA signaling cascade culminates in the transcriptional program that increases energy expenditure. In fat cells, β1, β2, and β3-adrenergic receptors are known to stimulate cAMP production and lipolysis in vitro and in vivo. Obesity is characterized as a state of low-level inflammation where chronic macronutrient and lipid overload induces cellular stress that initiates and perpetuates immunoinflammatory signaling in adipocytes. A central mediator of inflammatory and stress response is the NFκB family of transcription factors. In the unstimulated state NFκB proteins are localized in the cytoplasm as homo- or heterodimers bound to IκB family proteins which prevents the complex from translocating to the nucleus. Upon stimulation of NFκB signaling, the IκB kinase (IKK) complex is activated, which then phosphorylates IκB proteins. Phosphorylated IκBs are recognized by the ubiquitin ligase machinery leading to their degradation by the proteasome. The freed NFκB dimers translocate to the nucleus, where they bind to specific sequences in the promoter or enhancer regions of target genes. Recent studies suggest that NFκB plays a role in the development of insulin resistance which, in part, is attributed to the role of IKKs. The IκB kinase (IKK) family has four members: IKKα, IKKβ, IKKε, and TANK binding kinase 1 (TBK1). IKKε and TBK1 are direct transcriptional targets of NF-κB and their expression is increased in mice subjected to high fat diet, which may further amplify inflammatory signals in adipose tissue. In addition, IKKε knockout mice have increased energy expenditure and are partially resistant to the deleterious effects of high fat feeding, including weight gain, insulin resistance and systemic inflammation. At present, treatment with lifestyle and pharmacotherapy interventions has resulted in limited efficacy in reversing the upward trend in this present-day health crisis.
- Therapy for obesity, type 2 diabetes and metabolic syndrome
- Repurposing of FDA approved drugs for the anti-obesity therapy
- New treatment strategy for obesity, type 2 diabetes and metabolic syndrome
- Therapy that targets both central and peripheral control of metabolism
- Drugs are already clinically approved and being repurposed for new indication