Antiobesity mechanisms of action of conjugated linoleic acid

Abstract

Conjugated linoleic acid (CLA), a family of fatty acids found in beef, dairy foods and dietary supplements, reduces adiposity in several animal models of obesity and some human studies. However, the isomer-specific antiobesity mechanisms of action of CLA are unclear, and its use in humans is controversial. This review will summarize in vivo and in vitro findings from the literature regarding potential mechanisms by which CLA reduces adiposity, including its impact on (a) energy metabolism, (b) adipogenesis, (c) inflammation, (d) lipid metabolism and (e) apoptosis.

Figure 1

10,12 CLA antagonizes the expression and activity of PPARγ and C/EBPα, master regulators of adipocyte differentiaiton and maintenance. We propose that 10,12 CLA impairs preadipocyte differentiation and maintenance of mature adipocytes by 1) decreasing the expression of PPARγ and C/EBPα, and 2) activating inflammatory proteins like NFκB and MAPKs that antagonize PPARγ activity, thereby reducing the expression of PPARγ target genes.

Figure 2

10,12 CLA may antagonize PPARγ activity by 1) decreasing PPARγ gene expression, 2) enhancing PPARγ degradation via phosphorylation, ubiquination, and proteosome degradation, or 3) increasing NFκB activation which impairs PPARγ DNA binding and subsequent induction of adipogenic and lipogenic gene expression.

Figure 3

10,12 CLA activation of inflammatory proteins and induction of inflammatory genes interfers with PPARγ transcriptional activation of target genes such as lipoprotein lipase (LPL), adiponectin (AMP1), glucose transporter 4 (GLUT4), and adipocyte-specific fatty acid binding protein (aP2).

Figure 4

10,12 CLA-mediated insulin resistance is linked to 1) antagonism of PPARγ-induced GLUT4 and adiponectin (AMP1) expression, and 2) induction of inflammatory proteins and genes that decrease IRS-1-P (tyr) abundance, thereby reducing GLUT4 translocation to the plasma membrane.

Figure 5

10,12 CLA increases lipolysis acutely and decreases lipogenesis chronically by decreasing phosphodiesterase (PDE) and acetyl-CoA carboxylase (ACC) activities, respectively, key proteins regulated by insulin.

Figure 6

10,12 CLA increases apopototic cell death of (pre)adipocytes by increasing ER stress. 10,12 activates upstream signals that induce cell stress including ER stress and the ISR. These stress responses increase the levels of intracellular calcium, ROS, and proteins that together induce apoptosis.

Figure 7

Working model by which 10,12 CLA causes insulin resistance and delipidation in adipocytes. We propose that 10,12 CLA induces upstream signals that cause 1) an ISR that increases apoptosis, FFA release, and inflammatory gene expression, 2) NFκB and ERK activation that antogonizes PPARγ activity, and 3) increased UCP and lipolysis, further enhancing FFA levels. Together, these CLA-mediated signals cause adipocyte insulin resistance and delipidation.