Abstract
Urocortin3 (UCN3) regulates metabolic functions and is involved in cellular stress response. Although UCN3 is expressed in human adipose tissue, the association of UCN3 with obesity and diabetes remains unclear. This study investigated the effects of Type 2 diabetes (T2D) and increased body weight on the circulatory and subcutaneous adipose tissue (SAT) levels of UCN3 and assessed UCN3 modulation by a regular physical exercise. Normal-weight (n = 37) and overweight adults with and without T2D (n = 98 and n = 107, respectively) were enrolled in the study. A subset of the overweight subjects (n = 39 for each group) underwent a supervised 3-month exercise program combining both moderate intensity aerobic exercise and resistance training with treadmill. UCN3 levels in SAT were measured by immunofluorescence and RT-PCR. Circulatory UCN3 in plasma was assessed by ELISA and was correlated with various clinical and metabolic markers. Our data revealed that plasma UCN3 levels decreased in overweight subjects without T2D compared with normal-weight controls [median; 11.99 (0.78–86.07) and 6.27 (0.64–77.04), respectively; p < 0.001], whereas plasma UCN3 levels increased with concomitant T2D [median; 9.03 (0.77–104.92) p < 0.001]. UCN3 plasma levels were independently associated with glycemic index; fasting plasma glucose and hemoglobin A1c (r = 0.16 and r = 0.20, p < 0.05, respectively) and were significantly different between both overweight, with and without T2D, and normal-weight individuals (OR = 2.11 [1.84–4.11, 95% CI] and OR = 2.12 [1.59–3.10, 95% CI], p < 0.01, respectively). Conversely, the UCN3 patterns observed in SAT were opposite to those in circulation; UCN3 levels were significantly increased with body weight and decreased with T2D. After a 3-month supervised exercise protocol, UCN3 expression showed a significant reduction in SAT of both overweight groups (2.3 and 1.6-fold change; p < 0.01, respectively). In conclusion, UCN levels are differentially dysregulated in obesity in a tissue-dependent manner and can be mitigated by regular moderate physical exercise.
Highlights
Chronic metabolic stress and low-grade inflammation are key factors in obesity, insulin resistance and Type 2 diabetes (T2D) and involve the impairment of mechanisms in both central and peripheral tissues [1]
We previously reported the impact of exercise on various markers and showed that it was more prominent in people without T2D, where adiposity markers [body mass index (BMI), waist circumference, and percent body fat (PBF)] were significantly decreased, along with ameliorated cardiorespiratory markers (HR and VO2max) [25, 28]
The main findings of this study are: [1] plasma UCN3 levels decreased with BMI; [2] UCN3 plasma levels were independently associated with glycemic index (FPG, Hemoglobin A1c (HbA1c)) and were significantly different between overweight individuals with and without T2D; [3] the UCN3 expression in subcutaneous adipose tissue (SAT) was increased with BMI and blunted with T2D; and [4] a 3-month supervised exercise protocol showed a significant reduction of UCN3 expression in both overweight group SAT
Summary
Chronic metabolic stress and low-grade inflammation are key factors in obesity, insulin resistance and Type 2 diabetes (T2D) and involve the impairment of mechanisms in both central and peripheral tissues [1]. Corticotropin-releasing factor (CRF) neuropeptides are involved in such mechanisms [2]. CRF peptides were initially discovered in the brain but are expressed in peripheral metabolic tissues, including skeletal muscle and the pancreas [7, 8]. The CRF system is not yet fully understood, its modulation has been proposed as treatment for human metabolic disorders [5]. The genetic manipulations of the CRF family in mouse models has demonstrated distinct metabolic phenotypes, suggesting different but crucial endogenous roles for each of these peptides and their receptors in metabolic pathways [9]
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