Research ArticleMetabolism

Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism

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Sci. Signal.  15 Dec 2015:
Vol. 8, Issue 407, pp. ra127
DOI: 10.1126/scisignal.aab3357

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Fighting fat with FTO

Individuals with a common variant of the FTO gene, which encodes an enzyme that modifies mRNAs, are more likely to become obese both as children and as adults. Wang et al. found that mice lacking FTO in adipocytes became more obese on a high-fat diet than did control mice. The deficiency of FTO in adipocytes resulted in increased extracellular lipolysis, which provided more fatty acids for uptake by adipose tissue, and in decreased intracellular lipolysis, which favored the storage of fatty acids in adipose tissue. Without FTO, adipose tissue produced less Angptl4, an adipokine that stimulates intracellular lipolysis. Thus, FTO in adipocytes affects body weight by regulating the translation of Angptl4 in adipose tissue.

Abstract

A common variant of the FTO (fat mass– and obesity-associated) gene is a risk factor for obesity. We found that mice with an adipocyte-specific deletion of FTO gained more weight than control mice on a high-fat diet. Analysis of mice lacking FTO in adipocytes fed a normal diet or adipocytes from these mice revealed alterations in triglyceride metabolism that would be expected to favor increased fatty acid storage by adipose tissue. Mice lacking FTO in adipocytes showed increased serum triglyceride breakdown and clearance, which was associated with lower serum triglyceride concentrations. In addition, lipolysis in response to β-adrenergic stimulation was decreased in adipocytes and ex vivo adipose explants from the mutant mice. FTO is a nucleic acid demethylase that removes N6-methyladenosine (m6A) from mRNAs. We found that FTO bound to Angptl4, which encodes an adipokine that stimulates intracellular lipolysis in adipocytes. Unexpectedly, the adipose tissue of fasted or fed mice lacking FTO in adipocytes had greater Angptl4 mRNA abundance. However, after high-fat feeding, the mutant mice had less Angptl4 protein and more m6A-modified Angptl4 than control mice, suggesting that lack of FTO prevented the translation of Angptl4. Injection of Angptl4-encoding adenovirus into mice lacking FTO in adipocytes restored serum triglyceride concentrations and lipolysis to values similar to those in control mice and abolished excessive weight gain from a high-fat diet. These results reveal that FTO regulates fatty acid mobilization in adipocytes and thus body weight in part through posttranscriptional regulation of Angptl4.

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