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2010). (Fisher and Maratos-Flier 2016; BonDurant and Potthoff 2018; Kliewer and Mangelsdorf 2019). Thus, gene expression is increased by the nuclear hormone receptor PPAR in response to starvation CAY10603 or consumption of a ketogenic diet (Badman et al. 2007; Inagaki et al. 2007), by the transcription factor ChREBP in response to simple sugars (Fisher et al. 2017; Iroz et al. 2017), by the transcription factor ATF2 in response to cold exposure (Hondares et al. 2011), and by the integrated stress response pathway mediated by eIF2/ATF4 and IRE1/XBP1 in response to ER stress, amino CAY10603 acid starvation, and mitochondrial dysfunction (Salminen et al. 2017). The liver is the major source of the endocrine FGF21 that circulates in the blood and regulates energy expenditure, glucose/lipid metabolism, and insulin sensitivity (Markan et al. 2014; Vernia et al. 2016a), but muscle can act also as an endocrine source of FGF21 in response to mitochondrial myopathy (Tyynismaa et al. 2010). Interestingly, pancreatic acinar cells secrete exocrine FGF21 that functions to maintain acinar cell proteostasis (Coate Corin et al. 2017). In contrast, adipocyte FGF21 functions primarily in an autocrine/paracrine manner in response to feeding/fasting cycles (Dutchak et al. 2012) and cold exposure (Chartoumpekis et al. 2011; Hondares et al. 2011; Fisher et al. 2012). These autocrine actions of FGF21 may be mediated, in part, by increased expression of the coactivator PGC1 and the expression of thermogenic genes (Fisher et al. 2012), increased PPAR activity and insulin sensitization (Dutchak et al. 2012), and increased expression of adipokines (Holland et al. 2013; Lin et al. 2013; Huang et al. 2017). The absence of an endocrine function for adipocyte FGF21 may reflect expression levels and the very short half-life of FGF21 in the blood (Fisher and Maratos-Flier 2016; BonDurant and Potthoff 2018; Kliewer and Mangelsdorf 2019). The responsiveness of FGF21 to nutritional stress (BonDurant and Potthoff 2018) is shared by the cJun NH2-terminal kinase (JNK) signaling pathway (Sabio and Davis 2010). Indeed, JNK acts to suppress PPAR-induced hepatic gene expression and promotes systemic insulin resistance by reducing the amount of FGF21 circulating in the blood (Vernia et al. 2014, 2016a). The observed insulin resistance is characterized by decreased endocrine signaling by FGF21 and reduced sympathetic tone, fatty acid -oxidation, energy expenditure, hyperglycemia, and hyperlipidemia (Owen et al. 2014; Douris et al. 2015). This role of hepatic JNK to regulate endocrine expression of hepatic FGF21 raises questions concerning the potential function of JNK-regulated FGF21 expression by adipocytes. We report that autocrine signaling by adipocyte FGF21 triggers a feed-forward regulatory loop that promotes endocrine FGF21 signaling by the liver. This mechanism represents a novel signaling paradigm CAY10603 that connects autocrine and endocrine signaling modes of the same hormone in different tissues. Results JNK in adipose tissue promotes systemic diet-induced insulin resistance We established mice with deficiency of JNK1 plus JNK2 in adipocytes (and gene ablation in inguinal fat (IngF), epididymal fat (EpiF), retroperitoneal fat (RetF), brown adipose tissue (BAT), and isolated adipocyte fraction (ADF), but not in liver, muscle, or the adipose tissue stromal vascular fraction (SVF) (Supplemental Fig. S1A). Immunoblot analysis demonstrated that JNK expression was decreased in the adipocyte fraction, but not in the stromal vascular fraction, of epididymal adipose tissue of JNK-deficient (ADKO) mice compared with Control (ADWT) mice (Supplemental Fig. S1B). These studies demonstrate an adipocyte-selective defect in JNK expression in ADKO mice. The mice were CAY10603 fed a chow diet (ND) or a high fat diet (HFD) for 16 wk. No difference altogether body mass between your ADWT mice and ADKO mice was recognized (Fig..