GLUT4 Expression in Adipocytes Regulates De Novo Lipogenesis and Levels of a Novel Class of Lipids With Antidiabetic and Anti-inflammatory Effects

Abstract

Adipose tissue (AT) regulates systemic insulin sensitivity through multiple mechanisms, and alterations in de novo lipogenesis appear to contribute. Mice overexpressing GLUT4 in adipocytes (AG4OX) have elevated AT lipogenesis and enhanced glucose tolerance despite being obese and having elevated circulating fatty acids. Lipidomic analysis of AT identified a structurally unique class of lipids, branched fatty acid esters of hydroxy-fatty acids (FAHFAs), which were elevated in AT and serum of AG4OX mice. Palmitic acid esters of hydroxy-stearic acids (PAHSAs) are among the most upregulated FAHFA families in AG4OX mice. Eight PAHSA isomers are present in mouse and human tissues. PAHSA levels are reduced in insulin resistant people, and levels correlate highly with insulin sensitivity. PAHSAs have beneficial metabolic effects. Treatment of obese mice with PAHSAs lowers glycemia and improves glucose tolerance while stimulating glucagon-like peptide 1 and insulin secretion. PAHSAs also reduce inflammatory cytokine production from immune cells and ameliorate adipose inflammation in obesity. PAHSA isomer concentrations are altered in physiological and pathophysiological conditions in a tissue- and isomer-specific manner. The mechanisms most likely involve changes in PAHSA biosynthesis, degradation, and secretion. The discovery of PAHSAs reveals the existence of previously unknown endogenous lipids and biochemical pathways involved in metabolism and inflammation, two fundamental physiological processes.

Figure 1

Structure of FAHFAs. A: FAHFAs are branched fatty acid esters of hydroxy-fatty acids. B: There are at least 16 different FAHFA family members in mouse serum, and these lipids arise from many possible combinations of common fatty acids and hydroxy–fatty acids. C: There are a number of different FAHFA isomers within each family. For example, 5- and 9-PAHSA combine palmitate as the fatty acyl group with a hydroxy–stearic acid backbone. But they differ in the position of the ester bond, which is 5 carbons away from the carboxylic acid group in 5-PAHSA and 9 carbons away in 9-PAHSA. Adapted with permission from Yore et al. (27).

Figure 2

Proposed role of fatty acid receptors in the actions of FAHFAs in metabolic regulation. GPR120 and GPR40 regulate several physiologic processes. Activation of these receptors increases GLP-1 secretion from intestinal enteroendocrine cells and insulin secretion from pancreatic β-cells, stimulates glucose uptake and GLUT4 translocation to the plasma membrane in adipocytes, and inhibits inflammation (40,44,45). FAHFAs are synthesized in multiple tissues in vivo. They activate GPR120, which mediates the effect of FAHFAs to augment insulin-stimulated glucose transport and GLUT4 translocation in adipocytes. GPR120 may be involved in the effects of FAHFAs to stimulate GLP-1 secretion by enteroendocrine cells and possibly insulin secretion by pancreatic islets indirectly through effects on δ-cells. FAHFAs also inhibit dendritic cell activation in vitro and AT proinflammatory cytokine production in vivo. The receptors mediating the anti-inflammatory effects are not yet known.

Figure 3

Regulation of glucose homeostasis by FAHFAs. FAHFAs exert a number of effects that result in improved glucose homeostasis. They activate GPR120 and other G-protein–coupled receptors, which mediate at least some of their local and systemic effects. FAHFAs have insulin-sensitizing effects, as evidenced by the fact that they augment insulin-stimulated glucose uptake in adipocytes by increasing GLUT4 translocation. FAHFAs are also anti-inflammatory. They reduce dendritic cell activation in vitro and AT inflammation in vivo including decreasing the production of proinflammatory cytokines by macrophages. FAHFAs also stimulate insulin secretion both directly and indirectly. They enhance insulin secretion indirectly by inducing GLP-1 secretion from enteroendocrine cells. FAHFAs also stimulate insulin secretion directly in human pancreatic islets. Together, the effects on insulin sensitivity, insulin secretion, and immune function improve systemic glucose homeostasis. Reprinted with permission from Yore et al. (27).