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  • br Acknowledgements The authors would like to

    2024-06-11


    Acknowledgements The authors would like to thank Dr. Bradford B. Lowell for providing us with β-less and WT breeding pairs. Funding sources: This work was supported by NIH Grant DK028082 (to E.M.F) and by an Institutional Research Training Grant NRSA 5T32DK751627 (to N.D.).
    Introduction 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 [1], [2], [3]. 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]. However, a key unanswered question remains. 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]. Through these studies, we investigate the relationship between obesity, increased ERK kinase activation, and stimulation of beta adrenergic-mediated lipolysis. Circulating FFA levels are predominantly derived from stored triglycerides that are actively broken down through enzymatic lipolysis in WAT. Signals that promote lipolysis include catecholamines and natriuretic peptides. The catalytic steps responsible for catecholamine-mediated lipolysis involve the β-adrenergic activation of cAMP-dependent protein kinase (PKA), and its downstream phosphorylation targets: hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and perilipin [6], [7]. Multiple lines of evidence demonstrate that obesity increases rates of basal, unstimulated lipolysis—an effect that can be reversed by weight loss surgery or thiazolidinedione treatment [8], [9], [10]. FFA released from hypertrophied obese adipose tissue have systemic effects on whole body metabolism [11]. Elevated circulating FFA promote ectopic lipid deposition in peripheral tissues, decrease t-type calcium channel uptake and oxidation, increase insulin resistance, and lead to lipotoxicity induced impairment of insulin secretion from β-cells [11]. Given the strong link between obesity, lipolysis, and metabolic dysfunction, the pharmacological inhibition of lipolysis is a promising target to combat lipotoxicity [12]. Importantly, anti-lipolytic agents that lower FFA levels have potent antidiabetic effects [10], [13], [14]. Thus, identification and pharmacological inhibition of the signals driving basal lipolysis holds great therapeutic promise to counter the health burden of obesity-related disease. The mitogen-activated protein kinase kinase/extracellular signal–regulated kinase (MEK/ERK) signaling pathway is an evolutionarily conserved signaling module that is involved in a wide variety of cellular processes including proliferation, inflammation, and metabolism [15], [16], [17]. Humans and mice express two similar ERK isoforms, ERK1 and ERK2. In mice, the in vivo effects of ERK1 and ERK2 are more nuanced owing to their 83% amino acid identity and biochemical redundancy [18], [19]. Although they are encoded by distinct genes [20], relative levels of ERK1 and ERK2 vary considerably from one tissue to another [21]. As a model organism with a powerful genetic toolkit and similar physiological regulation to mammals, Drosophila expresses a single ERK ortholog, encoded by Rolled (rl) [22]. Previous studies have indicated a conserved MEK/ERK signaling pathway and its impact on organ development and stress responses [23]. The metabolic roles of ERK in adipocyte proliferation, differentiation, and insulin action have been well studied [24]. However, the pattern of ERK dysregulation in different tissues involved in metabolic regulation and how these contribute to energy overload-associated metabolic dysfunction remains controversial. Here we show that obesity increases ERK kinase activity levels in adipose tissue and fat body from mice and Drosophila, respectively. We find that mouse primary adipocytes selectively express ERK2 but have undetectable levels of ERK1. Adipocyte-specific ERK2 knock-out mice (ERK2AKO) and fat body-specific ERK knockdown flies exhibit decreased rates of lipolysis. We find that in vivo inhibition of the MEK/ERK pathway alters lipolysis in adipose tissue, by decreasing β3AR phosphorylation at serine 247 and subsequent downstream phosphorylation events that control release of FFA. Mice with ERK inactivation or inhibition also fail to appropriately activate thermogenesis and defend body temperature upon cold challenge due to lack of substrate availability. We conclude that ERK plays a critical role in regulating lipolysis from obese adipose tissue through its direct phosphorylation of β3AR, and these are likely contributing mechanisms to insulin resistance and type 2 diabetes.