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

Abstract

Aims/hypothesis Proinflammatory and proapoptotic cytokines such as TNF-α are upregulated in human obesity. We evaluated the association between ghrelin isoforms (acylated and desacyl ghrelin) and TNF-α in obesity and obesity-associated type 2 diabetes, as well as the potential role of ghrelin in the control of apoptosis and autophagy in human adipocytes. Methods Plasma concentrations of the ghrelin isoforms and TNF-α were measured in 194 participants. Ghrelin and ghrelin O-acyltransferase (GOAT) levels were analysed by western-blot, immunohistochemistry and real-time PCR in 53 biopsies of human omental adipose tissue. We also determined the effect of acylated and desacyl ghrelin (10 to 1,000 pmol/l) on TNF-α-induced apoptosis and autophagy-related molecules in omental adipocytes. Results Circulating concentrations of acylated ghrelin and TNF-α were increased, whereas desacyl ghrelin levels were decreased in obesity-associated type 2 diabetes. Ghrelin and GOAT were produced in omental and subcutaneous adipose tissue. Visceral adipose tissue from obese patients with type 2 diabetes showed higher levels of GOAT, increased adipocyte apoptosis and increased expression of the autophagyrelated genes ATG5, BECN1 and ATG7. In differentiating Diabetologia (2012) human omental adipocytes, incubation with acylated and desacyl ghrelin reduced TNF-α-induced activation of caspase-8 and caspase-3, and cell death. In addition, acylated ghrelin reduced the basal expression of the autophagyrelated genes ATG5 and ATG7, while desacyl ghrelin inhibited the TNF-α-induced increase of ATG5, BECN1 and ATG7 expression. Conclusions/interpretation Apoptosis and autophagy are upregulated in human visceral adipose tissue of patients with type 2 diabetes. Acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in human visceral adipocytes.

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

“…Human adipose tissue is very dynamic, with 10% of adipocytes being renewed each year after cell death (300). However, the generation of hypoxic areas together with the proinflammatory milieu of the adipose tissue in obesity is associated with an increase in adipocyte cell death that is further aggravated by insulin resistance (48,268). Two forms of programmed cell death, apoptosis and autophagy, are increased in the adipose tissue of obese subjects (48,106,167,268).…”

“…However, the generation of hypoxic areas together with the proinflammatory milieu of the adipose tissue in obesity is associated with an increase in adipocyte cell death that is further aggravated by insulin resistance (48,268). Two forms of programmed cell death, apoptosis and autophagy, are increased in the adipose tissue of obese subjects (48,106,167,268). Apoptosis, or type I cell death, is characterized by morphological and biochemical hallmarks, including cell shrinkage, chromatin condensation (pyknosis), membrane blebbing, nuclear DNA fragmentation (karyorrhexis), and apoptotic body formation (48,89,94).…”

“…TNF␣ is overexpressed in adipose tissue of obese individuals and constitutes a well-known regulator of apoptosis in white and brown adipocytes (134,221,223). Upon binding to TNFR1, TNF␣ triggers caspase-8 cleavage and activation, which further activates caspase-3, leading to adipocyte cell death (268). Other death receptor ligands, such as FAS-L or TRAIL, are also associated with adiposity and are related to adipocyte apoptosis (4,90,156).…”

“…Obesity is associated with the activation of both the extrinsic and intrinsic pathways of adipocyte apoptosis (4,48,268). Interestingly, transgenic mice lacking the Bid gene, a key proapoptotic molecule that serves as a link between these two apoptotic pathways, exhibit reduced caspase activation, adipocyte apoptosis, and adipose tissue macrophage recruitment and are protected against the development of systemic insulin resistance and hepatic steatosis (4).…”

Ghrelin Gene Products in Acute and Chronic Inflammation

“…Among the wide range of common biological functions, acylated and unacylated ghrelin exert a protective activity on several cell lines including cardiac and endothelial cells, pancreatic b cells, islets, and islet microendothelial cells, cortical neurons, vascular smooth muscle cells, and visceral adipocytes (Baldanzi et al 2002;Chung et al 2008;Favaro et al 2012;Granata et al 2007;Hwang et al 2009;Rodríguez et al 2012;Zhan et al 2008). Both peptides promote the differentiation of skeletal myoblasts, preadipocytes, and embryonic stem cells toward cardiomyocytes (Filigheddu et al 2007;Gao et al 2012Gao et al , 2013Giovambattista et al 2008;Miegueu et al 2011).…”