Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

Abstract

Objectives: The orexigenic hormone ghrelin circulates mainly in two forms, acylated and desacyl ghrelin. We evaluated the impact of obesity and obesity-associated type 2 diabetes (T2D) on ghrelin forms and the potential role of acylated and desacyl ghrelin in the control of adipogenesis in humans. Methods: Plasma concentrations of the different ghrelin forms were measured in 80 subjects. The expression of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) was analyzed in omental adipose tissue using western blot and immunohistochemistry, and the effect of acylated ghrelin and desacyl ghrelin (0.1-1000 pmol l À1 ) on adipogenesis was determined in vitro in omental adipocytes. Results: Circulating concentrations of acylated ghrelin were increased, whereas desacyl ghrelin levels were decreased, in obesity and obesity-associated T2D. Body mass index, waist circumference, insulin and HOMA (homeostasis model assessment) index were positively correlated with acylated ghrelin levels. Obese individuals showed a lower protein expression of GHS-R in omental adipose tissue. In differentiating omental adipocytes, incubation with both acylated and desacyl ghrelin significantly increased PPARg (peroxisome proliferator-activated receptor g) and SREBP1 (sterol-regulatory element binding protein-1) mRNA levels, as well as several fat storage-related proteins, including acetyl-CoA carboxylase, fatty acid synthase, lipoprotein lipase and perilipin. Consequently, both the ghrelin forms stimulated intracytoplasmatic lipid accumulation. Conclusions: Both acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Given the lipogenic effect of acylated ghrelin on visceral adipocytes, the herein-reported elevation of its circulating concentrations in obese individuals may play a role in excessive fat accumulation in obesity.

Ghrelin in obesity and endocrine diseases

“…Ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans (Tong et al, 2010) thus ghrelin leads to increase in blood glucose levels and impairs glucose tolerance . Ghrelin has been shown to significantly increase sterol-regulatory element binding protein-1 (SREBP1) mRNA levels, as well as several fat storage-related proteins, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS) and lipoprotein lipase (LPL) leading to stimulation of intracytoplasmic lipid accumulation (Rodriguez et al, 2009). Ghrelin reduces the use of fat as a metabolic fuel and promotes an increase in adipose tissue and body weight (Tschop et al, 2000).…”

Increased Levels of Calprotectin in Obesity Are Related to Macrophage Content: Impact on Inflammation and Effect of Weight Loss

“…Human stromovascular fraction cells (SVFCs) were isolated from omental adipose tissue from obese normoglycemic subjects as previously described (26 …”

The ghrelin O-acyltransferase–ghrelin system reduces TNF-α-induced apoptosis and autophagy in human visceral adipocytes

“…On the one hand, ghrelin increases food intake by activating hypothalamic neuropeptide Y/agouti-related peptide neurons, which produce GHS-R type 1a, via the modulation of fatty acid metabolism [7]. On the other hand, adipose tissue is also an important target for the adipogenic actions of ghrelin in rodents and humans [8,9]. Thus ghrelin (GHRL) gene expression increases during adipogenesis with preproghrelin knockdown reducing insulin-mediated adipogenesis in 3T3-L1 adipocytes [9].…”

“…Thus ghrelin (GHRL) gene expression increases during adipogenesis with preproghrelin knockdown reducing insulin-mediated adipogenesis in 3T3-L1 adipocytes [9]. Moreover, acylated and desacyl ghrelin directly stimulate the production of several fat storage-related proteins, including acetyl-CoA carboxylase, fatty acid synthase, lipoprotein lipase and perilipin, in human visceral adipocytes, thereby stimulating intracytoplasmic lipid accumulation [8,10].…”