Abstract
ObjectiveThe inappropriate release of free fatty acids from obese adipose tissue stores has detrimental effects on metabolism, but key molecular mechanisms controlling FFA release from adipocytes remain undefined. Although obesity promotes systemic inflammation, we find activation of the inflammation-associated Mitogen Activated Protein kinase ERK occurs specifically in adipose tissues of obese mice, and provide evidence that adipocyte ERK activation may explain exaggerated adipose tissue lipolysis observed in obesity. Methods and ResultsWe provide genetic and pharmacological evidence that inhibition of the MEK/ERK pathway in human adipose tissue, mice, and flies all effectively limit adipocyte lipolysis. In complementary findings, we show that genetic and obesity-mediated activation of ERK enhances lipolysis, whereas adipose tissue specific knock-out of ERK2, the exclusive ERK1/2 protein in adipocytes, dramatically impairs lipolysis in explanted mouse adipose tissue. In addition, acute inhibition of MEK/ERK signaling also decreases lipolysis in adipose tissue and improves insulin sensitivity in obese mice. Mice with decreased rates of adipose tissue lipolysis in vivo caused by either MEK or ATGL pharmacological inhibition were unable to liberate sufficient White Adipose Tissue (WAT) energy stores to fuel thermogenesis from brown fat during a cold temperature challenge. To identify a molecular mechanism controlling these actions, we performed unbiased phosphoproteomic analysis of obese adipose tissue at different time points following acute pharmacological MEK/ERK inhibition. MEK/ERK inhibition decreased levels of adrenergic signaling and caused de-phosphorylation of the β3-adrenergic receptor (β3AR) on serine 247. To define the functional implications of this phosphorylation, we showed that CRISPR/Cas9 engineered cells expressing wild type β3AR exhibited β3AR phosphorylation by ERK2 and enhanced lipolysis, but this was not seen when serine 247 of β3AR was mutated to alanine. ConclusionTaken together, these data suggest that ERK activation in adipocytes and subsequent phosphorylation of the β3AR on S247 are critical regulatory steps in the enhanced adipocyte lipolysis of obesity.
Highlights
The effects of obesity contribute to decreased life expectancy
What drives the increased rate of basal lipolysis observed in obese adipose tissue? We observed that treating obese mice with an FDA-approved whole body MEK inhibitor dramatically improved insulin sensitivity and sought to better understand the causal mechanisms [5]
Mice treated with MEKi and ATGLi C57BL/6J mice were purchased from Jackson Laboratories (Jackson Labs, 000664) and fed with high-fat diet (HFD) for 8 weeks
Summary
The effects of obesity contribute to decreased life expectancy. The risks of cardio-metabolic diseases and cancer, among numerous other co-morbidities, are increased by obesity [1e3]. Mechanisms linking increased fat mass in obese individuals to the development of insulin resistance include augmented release of free fatty acids (FFA), certain hormones, and pro-inflammatory factors [4]. We observed that treating obese mice with an FDA-approved whole body MEK inhibitor dramatically improved insulin sensitivity and sought to better understand the causal mechanisms [5]. What drives the increased rate of basal lipolysis observed in obese adipose tissue? Through these studies, we investigate the relationship between obesity, increased ERK kinase activation, and stimulation of beta adrenergic-mediated lipolysis. The catalytic steps responsible for catecholaminemediated lipolysis involve the b-adrenergic activation of cAMP-
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