Editors' ChoiceInsulin Signaling

Driving expression of leptin

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Science Signaling  23 Apr 2019:
Vol. 12, Issue 578, eaax7601
DOI: 10.1126/scisignal.aax7601

The transcriptional regulator Egr1 mediates the insulin-dependent production of leptin by adipocytes.

The hormone leptin, which is produced mainly by adipocytes, is increased in concentration in the circulation shortly after nutrient intake but is reduced after food deprivation. Leptin targets receptors in the hypothalamus to inhibit hunger and regulate energy balance, among other functions. Mohtar et al. investigated the molecular mechanism responsible for driving the expression of ob, the gene that encodes leptin. The authors found that treatment of 3T3-L1 adipocytes with insulin resulted in an increase in the amounts of the transcription factor Egr1 (early growth response protein 1), which preceded the production of ob mRNA. In mice, intraperitoneal injection of insulin increased the abundance of Egr1 protein and ob mRNA in epididymal fat pads and increased the circulating concentration of leptin. Reporter assays and chromatin immunoprecipitation experiments showed that Egr1 bound to the ob promoter in an insulin-dependent manner. The lipid droplet protein FSP27, which is a corepressor of Egr1, blocked the activity of Egr1 on the ob promoter. Knockdown of Egr1 in adipocytes blocked insulin-dependent increases in ob mRNA abundance, which was rescued by adenoviral-mediated expression of Egr1. The mTORC1 inhibitor PP242 blocked the insulin-dependent increase in Egr1 protein abundance and thus prevented leptin production. Lastly, deletion of the 5′ untranslated region of the gene encoding Egr1 removed the requirement for insulin to drive Egr1 protein production and resulted in increased activity of an ob promoter–containing reporter. Together, these data suggest that Egr1 is required for the ability of insulin to stimulate leptin production.

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