Trans-10,cis-12 CLA increases adipocyte lipolysis and alters lipid droplet-associated proteins: role of mTOR and ERK signaling

Abstract

Lipid droplet-associated proteins play an important role in adipocyte triglyceride (TG) metabolism. Here, we show that trans -10, cis -12 conjugated linoleic acid (CLA), but not cis -9, trans -11 CLA, increased lipolysis and altered human adipocyte lipid droplet morphology. Before this change in morphology, there was a rapid trans -10, cis -12 CLA-induced increase in the accumulation of perilipin A in the cytosol, followed by the disappearance of perilipin A protein. In contrast, protein levels of adipose differentiation-related protein (ADRP) were increased in cultures treated with trans -10, cis -12 CLA. Immunostaining revealed that ADRP localized to the surface of small lipid droplets, displacing perilipin. Intriguingly, trans -10, cis -12 CLA increased ADRP protein expression to a much greater extent than ADRP mRNA without affecting stability, suggesting translational control of ADRP. To this end, we found that trans -10, cis -12 CLA increased activation of the mammalian target of rapamycin/p70 S6 ribosomal protein kinase/S6 ribosomal protein (mTOR/p70S6K/ S6) pathway. Collectively, these data demonstrate that the trans -10, cis -12 CLA-mediated reduction of human adipocyte TG content is associated with the differential localization and expression of lipid droplet-associated proteins. This process involves both the translational control of ADRP through the activation of mTOR/p70S6K/S6 signaling and transcriptional control of perilipin A. Conjugated linoleic acid (CLA) refers to a group of dienoic derivatives of linoleic acid. The two primary isomers of CLA found in ruminant meats and milk products and commercial preparations are cis -9, trans -11 CLA and trans -10, cis -12 CLA. CLA isomers have potential anticancer (1, 2) and antiobesity properties (reviewed in 3, 4). Concerning the isomer specificity of CLA and obesity, numerous animal studies have demonstrated that trans -10, cis -12 CLA prevents the development of adiposity (5-9). Similarly, we have shown that trans -10, cis -12 CLA, but not cis-9, trans -11 CLA, inhibits the differentiation of human preadipocytes into adipocytes and reduces the triglyceride (TG) content of mature or newly differentiated human adipocytes (10-12). However, the molecular mechanism(s) and physiological consequences of CLA supplementation are unclear, especially in humans.Recently, we reported that trans -10, cis -12 CLA treatment of cultures of human stromal vascular (SV) cells containing newly differentiated adipocytes caused delipidation by activating mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling (12). This relatively rapid activation of MEK/ERK signaling by trans -10, cis -12 CLA was followed by a decrease in the mRNA levels of peroxisome proliferator-activated receptor ␥ and many of its downstream adipogenic target genes, including perilipin, glucose transporter 4, adipocyte-specific fatty acid binding protein, lipoprotein lipase, and adiponectin. These CLA-mediated alterations were accompanied by decreased gluco...

Dietary conjugated linoleic acid and leucine improve pork intramuscular fat and meat quality

“…This mechanism is independent of changes in C/EBPα mRNA abundance and may involve COUP-TF (Brandebourg and Hu, 2005). Trans-10, cis-12 CLA promotes adipocyte delipidation, which may result from ERK-dependent alterations in perilipin and ADRP gene expression, protein activation, and localization (Chung et al, 2005). In contrast the cis-9, trans-11 isomer of CLA fails to inhibit the proliferation and differentiation of pig preadipocytes, and it may even stimulate the differentiation of these cells (Ding et al, 2000;McNeel and Mersmann, 2003).…”

Leptin and mTOR: Partners in metabolism and inflammation

“…Similarly, mTOR-dependent translational control of ADRP expression has also been observed in adipocytes stimulated with conjugated linoleic acid. 67 Further implications for the influence of leptin on lipid-laden foam cell formation come from observations that vascular smooth muscle cells treated with an adipocyte differentiation medium accumulate lipids and express both leptin and leptin receptor ObRb. 68 Leptin's induction of neutral lipid accumulation is in agreement with work showing that leptin increases cholesterol ester storage in a mouse macrophage cell line.…”

Effect of Conjugated Linoleic Acid on Testosterone Levels In Vitro and In Vivo After an Acute Bout of Resistance Exercise

“…The effect of CLA supplementation on body fat mass reduction has been investigated (5), and in in vitro studies, the lipolytic effect of CLA on adipocytes seems to be mediated by an increase in the levels of a protein named perilipin A (6). The proteins of the perilipin family are found not only on the outer surface of lipid storage droplets of adipocytes (linked to the hormone-sensitive lipase) but also in steroidogenic cells, such as Leydig cells in testicles, associated to the cholesteryl esterase (22).…”