Abstract
The characteristics of human resistin (RETN) are unclear and controversial despite intensive adipose-focused research. Its transcriptional and functional similarity with the murine myeloid-specific and CCAAT/enhancer binding protein epsilon (Cebpe)-dependent gene, resistin-like gamma (Retnlg), is unexplored. We examined the human CEBPE-regulatory pathway by unbiased reference and custom gene expression assays. Real-time RT-PCR analysis demonstrated lack of both the transcriptional factor CEBPE and RETN expression in adipose and muscle cells. In contrast, primary myelocytic samples revealed a concerted CEBPE-RETN transcription that was significantly elevated in inflammatory synoviocytes relative to intact peripheral blood mononuclear cells (PBMC). Mouse Cebpe and Retnlg were predictably expressed in macrophages, whereas Retn was abundant in adipocytes. Quite the opposite, a low and inconsistent RETN transcription was seen in some human white adipose tissue (WAT) biopsies without any relationship to body mass index, insulin sensitivity, or fat depot. However, in these cases, RETN was co-detected with CEBPE and the leukocyte-specific marker, EMR1, indicating the presence of inflammatory cells and their possible resistin-mediated effect on adipocytes. Indeed, addition of human resistin to WAT in culture induced, like in PBMC, the inflammatory cytokines IL6, IL8 and TNF. Importantly, the expression of the adipose-specific markers CEBPA, FABP4 and SLC2A4 was unchanged, while the expected inhibitory effect was seen with TNF. Both cytokines increased the mRNA level of CCL2 and MMP3, which may further promote inflammation in WAT. Thus, the myeloid-restricted nature of CEBPE precludes the expression of RETN in human adipocytes which, however, are targeted by this innate immune-derived proinflammatory cytokine.
Highlights
Obesity is clearly associated with the development of insulin resistance, diabetes and other metabolic and cardiovascular disorders in man
Human cells were tested for CCAAT/enhancer binding protein epsilon (CEBPE) and RETN as well as EMR1, a leukocytespecific receptor which indicates the presence of white blood cells in a sample
The transcription level of CEBPE was readily detectable and RETN was expressed in freshly prepared peripheral blood mononuclear cells (PBMC) and synoviocytes as well as in differentiated macrophages, albeit at a lower level
Summary
Obesity is clearly associated with the development of insulin resistance, diabetes and other metabolic and cardiovascular disorders in man. An important mechanistic link between these debilitating diseases and an increased fat mass is thought to be the anomalous production by adipose cells of a group of diverse effector molecules, collectively named adipocytokines. This hormonal or endocrine hypothesis was primarily explored in mouse, human genome and physiology significantly diverge from the rodent settings. Mouse resistin was described as a novel obesity-mediated adipocytokine that impairs glucose homeostasis by affecting both insulin-stimulated glucose uptake in adipose tissue and hepatic glucose production during fasting. The human homolog appears as an adipose-specific and obesity-regulated antagonist of insulin action or, blood/immune cells and not adipocytes are source of resistin
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