Abstract
Coiled-coil domain-containing 80 (CCDC80) is an adipocyte-secreted protein that modulates glucose homeostasis in response to diet-induced obesity in mice. The objective of this study was to analyze the link between human CCDC80 and obesity. CCDC80 protein expression was assessed in paired visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from 10 patients (body mass index range 22.4–38.8 kg/m2). Circulating CCDC80 levels were quantified in serum samples from two independent cross-sectional cohorts comprising 33 lean and 15 obese (cohort 1) and 32 morbidly obese (cohort 2) male patients. Insulin sensitivity, insulin secretion and blood neutrophil count were quantified in serum samples from both cohorts. Additionally, circulating free insulin-like growth factor (IGF)-1 levels and oral glucose tolerance tests were assessed in cohort 1, whereas C-reactive protein levels and degree of atherosclerosis and hepatic steatosis were studied in cohort 2. In lean patients, total CCDC80 protein content assessed by immunoblotting was lower in VAT than in SAT. In obese patients, CCDC80 was increased in VAT (P < 0.05) but equivalent in SAT compared with lean counterparts. In cohort 1, serum CCDC80 correlated negatively with the acute insulin response to glucose and IGF-1 levels and positively with blood neutrophil count independent of BMI, but not with insulin sensitivity. In cohort 2, serum CCDC80 was positively linked to the inflammatory biomarker C-reactive protein (r = 0.46; P = 0.009), atherosclerosis (carotid intima-media thickness, r = 0.62; P < 0.001) and hepatic steatosis (analysis of variance P = 0.025). Overall, these results suggest for the first time that CCDC80 may be a component of the obesity-altered secretome in VAT and could act as an adipokine whose circulant levels are linked to glucose tolerance derangements and related to inflammation-associated chronic complications.
Highlights
Adipokines are bioactive polypeptides secreted by adipocytes and adipose tissue immune cells [1]
coiled-coil domain-containing 80 (CCDC80) was detected as a major immunoreactive species of approximately 108 kDa (Figure 1A), which is consistent with the molecular weight of the predicted human CCDC80 encoded protein and confirmed by in vitro transcription-translation [10]
Our finding of upregulated CCDC80 expression in the visceral adipose tissue (VAT) of obese patients indicates that it may be a component of the obesity-altered secretome in this depot
Summary
Adipokines are bioactive polypeptides secreted by adipocytes and adipose tissue immune cells [1]. The gene coiled-coil domain-containing 80 (CCDC80) was initially identified by differential display as upregulated in brown adipose tissue of bombesin receptor subtype-3–deficient mice [6], a model of mild late-onset obesity. CCDC80 downregulation was detected in white adipose tissue (WAT) in other obese mouse models, including ob/ob, KKAy and diet-induced obesity [7]. CCDC80 is widely expressed in normal tissues, and in preadipocytes and adipocytes of both primary cultured human cells [7] and mouse 3T3L1 cells [7,8], while it is transiently downregulated during differentiation [7,8]. CCDC80 expression is repressed by insulin, tumor necrosis factor-a, H2O2 and hypoxia [7], and by dexamethasone and 3-isobutyl-1-methylxanthine (IBMX) in confluent preadipocytes [8]. CCDC80 has been shown to play a dual role in adipogenesis in vitro through mechanisms
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