Highlights d Blocking PPARg S273 phosphorylation protects mice from insulin resistance in obesity d These mice do not show the side effects associated with TZD-based PPARg agonism d These mice have reduced expression of Gdf3 mainly in macrophages d Gdf3 is sufficient to cause impaired glucose homeostasis in vivo and in vitro

SignificanceBioactive lipids control a wide variety of physiologic processes. We have recently identified a branch of bioactive lipid signaling mediated by N-acyl amino acids (NAAs) and the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Here we generate and characterize mice globally deficient in PM20D1. These PM20D1-KO mice have bidirectional changes in NAA levels in blood and tissues and exhibit a variety of metabolic and nociceptive phenotypes. Our findings elucidate the endogenous physiologic functions for NAA signaling in vivo and suggest PM20D1 inhibitors might be useful for the treatment of pain.

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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.