Urocortin 3 Levels Are Impaired in Overweight Humans With and Without Type 2 Diabetes and Modulated by Exercise

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.

Soluble Epoxide Hydrolase 2 Expression Is Elevated in Obese Humans and Decreased by Physical Activity

“…Obese subjects were enrolled in a supervised exercise program at the Medical Fitness Center (MFC) of the DDI, as previously reported [43]. Before the first exercise session, each subject underwent the "CPET" cardiopulmonary exercise test (COSMED, Quark, Italy), which uses an ergometer to measure the maximum heart rate (max HR) and maximum oxygen consumption (VO 2 max ) during use of an electromagnetically-braked cycle.…”

“…Western Blot analysis was performed using PBMCs from lean and obese subjects (at least n = 9 for each group), differentiated 3T3-L1 cells, and 3T3-L1 preadipocytes as previously reported [43] (3 independent experiments). Briefly, whole cell extracts were prepared in RIPA buffer, and protein concentration was determined using the Bradford method using β-globulin as a standard.…”

Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes

“…Interestingly, UCN3 and CRHR2 are proposed as potential anti-obesity targets owing to their co-location with quantitative trait loci for obesity on chromosome 10p15.1 16 . Recently, we reported that the plasma UCN3 levels decrease with increased body weight in human subjects without T2D; however, such levels increase with concomitant T2D 12 . Conversely, the UCN3 levels in the same subjects in the subcutaneous adipose tissue (SAT) increase with body weight and decrease with T2D 12 .…”

“…UCN3 and CRHR2 are highly expressed in pancreatic β cells, where UCN3 modulates insulin secretion through the regulation of somatostatin secretion 4 . Moreover, they are co-expressed in the adipose tissue and adipocytes 12 , suggesting local activity in this tissue. UCN3 is involved in energy homeostasis 13 , 14 , and mice with global UCN3 overexpression exhibit resistance to metabolic impairment that is related to a high-fat diet 2 .…”

“…The local overexpression of UCN3 in the muscle improves local glucose homeostasis 2 . Furthermore, impaired UCN3 expression is reported in various metabolic syndromes, such as type 2 diabetes (T2D), obesity, polycystic ovary syndrome (PCOS), and sleep apnea 4 , 12 , 15 . Interestingly, UCN3 and CRHR2 are proposed as potential anti-obesity targets owing to their co-location with quantitative trait loci for obesity on chromosome 10p15.1 16 .…”