Lipid metabolism: Treasure hunt in fat

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The adipose tissue-derived hormone palmitoleate enhances insulin signaling in muscle cell lines by inducing insulin-stimulated AKT phosphorylation, and suppresses inflammatory alterations in adipose tissue.

Deregulation of lipid metabolism in individual tissues causes metabolic diseases, such as diabetes, fatty liver disease and atherosclerosis. How do alterations in tissue-specific lipid metabolism affect whole-body homeostasis? Now, Cao et al. show that palmitoleate is an adipose tissue-derived hormone that regulates systemic metabolic homeostasis.


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Lipid chaperone proteins, such as fatty acid binding proteins (FABPs), modulate lipid composition and dictate the distribution of lipids inside cells. To understand how local lipid alterations in the adipose tissue are linked to whole-body metabolic outcomes, the authors used mice that lack adipose tissue FABPs; these mutants are altered in the systemic metabolic balance and are protected against metabolic diseases.

High-resolution lipidomics analyses on wild-type and FABP-deficient animals that were kept on either a regular or a high-fat diet (HFD) showed that, unlike other tissues, the lipid composition of mutant adipose tissue was similar to that of insulin-sensitive control animals, despite the diet used. These results suggest that adipose tissue lipid composition and metabolism remained refractory to dietary influence and might cause improved metabolic responses in the FABP-deficient animals.

The detailed examination of the lipid profiles of the adipose tissue and plasma of FABP mutants highlighted an enrichment of the fatty acid palmitoleate, which is the main product of de novo lipogenesis, a process that converts glucose to fatty acids. In agreement with this, adipose tissue of FABP-deficient mice had elevated expression of enzymes involved in de novo lipogenesis.

Is palmitoleate a hormonal signal that is produced by the adipose tissue and that affects the metabolic activity of distant organs, such as liver and muscle? Treatment of liver cell lines with palmitoleate repressed stearoyl-CoA desaturase-1 (SCD1), and this was used as a read-out of increased liver metabolic activity. A HFD induced the expression of SCD1 in the liver of wild-type but not FABP-deficient mice. In vitro and in vivo reporter assays linked FABP-regulated lipid signals and palmitoleate to the suppression of liver Scd1. Moreover, forced expression of SCD1 in FABP-mutant mice resulted in elevated hepatic triglyceride levels that are similar to control animals on HFD, which suggests that high circulating levels of palmitoleate in FABP-deficient mice regulate liver metabolism by repressing SCD1. Indeed, palmitoleate infusions in wild-type mice decreased Scd1 and fatty acid synthase (Fas) expression in the liver of the treated animals.

Palmitoleate also enhanced insulin signalling in muscle cell lines by inducing insulin-stimulated AKT/protein kinase B phosphorylation, and suppressed inflammatory alterations in adipose tissue. Finally, using hyperinsulinaemic euglycemic clamp assays to quantify insulin resistance, Cao et al. showed that infusions of palmitoleate enhanced insulin signalling and improved glucose metabolism in vivo.

These findings reveal that adipose tissue communicates with distant organs by producing palmitoleate, a 'lipokine' that regulates systemic metabolic homeostasis.

Francesca Cesari

References

Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008) | Article | PubMed |