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  • br Material and methods br Results

    2024-04-01


    Material and methods
    Results
    Discussion This study explores the hypothesis that ASK1, via transcriptional upregulation by E2F1, molecularly defines AT that supports a dys-metabolic obese phenotype in humans. We demonstrate associations between increased visceral-AT ASK1 expression and multiple parameters of metabolically-unhealthy obesity, even beyond BMI and patients' sub-phenotyping by fat distribution pattern. Associations of ASK1 with markers of dys-glycemia, dyslipidemia, and systemic inflammation were attenuated by adjusting for E2F1 expression, suggesting that E2F1 and ASK1 share a common mechanistic pathway. At the molecular level, in human-AT, E2F1's occupancy of the ASK1 promoter increases with BMI, more so in visceral than in subcutaneous fat, and two adipocyte cellular models of E2F1 knockdown/knockout demonstrate decreased ASK1 expression and attenuated downstream signaling. Furthermore, an E2F1 binding sequence in the human ASK1 promoter was identified, and elevated E2F1 was shown to contribute to increased ASK1 expression by both a direct transcriptional mechanism and by a JNK-mediated feed-forward loop. These render E2F1 over-expressing cells hyper-sensitive to ASK1 upregulation by inflammatory stimuli. Finally, the functional impact of ASK1 is demonstrated by adipocyte-specific ASK1-KO cells, which exhibit an improved adipokine secretory profile (secreting less leptin and more adiponectin, both basally and in response to an inflammatory stimulus). Obese sub-phenotypes, particularly based on body-fat distribution patterns (‘apples’ vs ‘pears’), were noticed decades ago [43]. Yet, with its growing prevalence, obesity requires a better characterization of obesity sub-phenotypes for a more stratified/personalized management of the disease. Differences in ATs' zcl to chronic caloric surplus can serve as an effective means of patient stratification. For example, adipocyte size, indicating the reliance of AT expansion on hypertrophy, has been shown as a potentially clinically-useful tool to stratify obesity-related type 2 diabetes risk [44], [45], [46]. Other histopathological features of a dysfunctional AT include altered cellular composition of the tissue, in particular macrophage infiltration and lipid accumulation (foam cells) [36], [38], [47], [48], and AT fibrosis [49], [50]. Yet, a molecular definition of AT signatures that defines metabolically-unhealthy obese sub-phenotype(s) has not been systematically attempted. In oncology, molecular typing of tumors largely relies on the identification of different tumors' genetic perturbations, increasingly used to guide patients' management [51]. Genetic polymorphisms related to obesity sub-phenotypes and/or responses to therapy are just beginning to be unraveled [52]. Nevertheless, molecular pathways that mediate AT stresses could constitute promising leads for molecular-based obesity sub-phenotyping and personalized treatment. Along this line, MAP kinases, and in particular the stress-activated MAP kinases [53], are promising candidates. Indeed, different members of this family of kinases, including p38MAP kinase, JNK, and upstream kinases such as the MAP3K's Tpl-2 and ASK1, and even MAP4K's, have been shown to regulate AT/adipocyte biology and to be activated in obesity [14], [15], [16], [17], [18], [54]. MAP kinases are frequently shown to be regulated by rapid phosphorylation-dephosphorylation [55], and, indeed, phosphorylation-based activation of a MAP kinase pathway consisting of ASK1–MKK4,3/6–JNK/p38MAP kinase has been demonstrated in obese humans' visceral-AT [18], [19]. Yet, we previously proposed that a significant level of regulation may be attributed to the expression level of these MAP kinases, reflecting a more chronic adaptation of AT in obesity [18]. Moreover, the association between ASK1 mRNA levels in visceral-AT and insulin resistance, which remained significant even after adjusting for BMI, supported the notion that ASK1 expression levels may define obese sub-phenotypes, i.e. that higher levels of visceral ASK1 may molecularly define obese persons with a more dys-metabolic “type” of obesity [18].