Abstract
Cardiotrophin-1 (CT-1) is a gp130 cytokine that was previously characterized for its effects on cardiomyocytes and identified as a marker of heart failure. More recent studies reported elevated circulating levels of CT-1 in humans with obesity and metabolic syndrome (MetS). However, a subsequent rodent study implicated CT-1 as a potential therapeutic target for obesity and MetS. Adipose tissue (AT) is broadly acknowledged as an endocrine organ and is a substantial source of CT-1. However, no study has examined the expression of adipose-derived CT-1 in humans. We present the first analysis of CT-1 mRNA expression in subcutaneous AT and its association with clinical variables in 22 women with obesity and 15 men who were 40% overfed for 8-weeks. We observed that CT-1 expression was higher in the subcutaneous abdominal (scABD) than the femoral (scFEM) depot. Importantly, we reveal that scFEM but not scABD, CT-1 expression was negatively associated with visceral adiposity and intrahepatic lipid, while positively correlated with insulin sensitivity in obese women. Also, men with higher CT-1 levels at baseline had less of a decline in insulin sensitivity in response to overfeeding. Our data provide new knowledge on the regulation of adipose-derived CT-1 in obesity and during weight gain in response to overfeeding in humans and suggest that CT-1 may play a protective role in obesity and related disorders.
Highlights
In recent years, gp130 receptor ligands, including ciliary neurotrophic factor (CNTF) and interleukin (IL)-6, have been shown to modulate energy balance and investigated as potential therapeutic targets for obesity and insulin resistance [1]
Elevated circulating CT-1 levels have been observed in humans with obesity [7,8], metabolic syndrome (MetS) [8] and type 2 diabetes (T2DM) [9], suggesting that CT-1 may play a pathophysiological role in obesity-related complications
We examined the mRNA expression of CT-1 in subcutaneous Adipose tissue (AT) and its association with clinical variables in a population of 22 healthy women with obesity (30 ± 6 years of age; 32.4 ± 2.5 kg/m2 ), as well as a cohort of 15 lean men who were overfed by 40% more than their baseline energy requirements for 8-weeks (25 ± 4 years of age; body mass index (BMI) 24.7 ± 2.1 kg/m2 )
Summary
Gp130 receptor ligands, including ciliary neurotrophic factor (CNTF) and interleukin (IL)-6, have been shown to modulate energy balance and investigated as potential therapeutic targets for obesity and insulin resistance [1]. Elevated levels of CT-1 were subsequently recognized as a marker of cardiovascular disease risk and heart failure [4,5,6,7]. More recent studies support an additional role for CT-1 in the pathogenesis of metabolic disease. Elevated circulating CT-1 levels have been observed in humans with obesity [7,8], metabolic syndrome (MetS) [8] and type 2 diabetes (T2DM) [9], suggesting that CT-1 may play a pathophysiological role in obesity-related complications. CT-1 levels in overweight and obese individuals compared to normal-weight [9,10,11]. A compelling rodent study from Moreno-Aliaga et al revealed CT-1 to be an important and beneficial regulator of glucose and lipid metabolism with potential applications for the treatment of obesity and MetS [12]. The findings regarding the functions of CT-1 in human obesity and metabolism are inconsistent
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