Two proteins, YAP and TAZ, attach to a specific DNA region far upstream of the leptin gene in both mice and humans, and this attachment is required for the gene to produce more leptin, even when fat...
Mechanism
Synthesis from 1 study
When fat cells shrink, proteins called YAP and TAZ move into the nucleus and stick to a specific DNA switch 28,000 bases away from the leptin gene, forcing it to stay turned on — even when there’s almost no fat left. This has been shown in mice during fasting, refeeding, and high-fat diets, and the...
Most probable mechanism
When fat cells lose their stored fat, proteins called YAP and TAZ move into the nucleus and latch onto a specific DNA switch located 28,000 bases away from the leptin gene. This switch, which is the same in mice and humans, turns on the leptin gene even when there’s very little fat left, causing the body to keep producing leptin. This happens because YAP and TAZ team up with another protein called TEAD to force the gene to stay active, and this process has been seen during fasting, refeeding, and high-fat diets — all without needing more fat tissue. The same mechanism explains why leptin levels stay high even when fat mass drops dramatically, as shown in studies where the switch was deleted or blocked, and leptin production stopped.
Reduced activity of LATS1 and LATS2 kinases in adipocytes allows YAP and TAZ to escape phosphorylation and accumulate in the nucleus, as observed during adipocyte delipidation, refeeding, and high-fat diet conditions (10.1038/s42255-024-01045-4).
Nuclear YAP and TAZ form complexes with TEAD transcription factors and directly bind to a conserved enhancer region located 28 kb upstream of the mouse leptin gene transcription start site and 24 kb upstream of the human leptin gene, as confirmed by ChIP-seq and ChIP-qPCR (10.1038/s42255-024-01045-4).
The YAP/TAZ-TEAD complex bound to this enhancer recruits transcriptional machinery to activate leptin gene expression, demonstrated by luciferase reporter assays showing enhancer activation only with functional TEAD-binding YAP/TAZ and abolished by CRISPR deletion of the TEAD site (10.1038/s42255-024-01045-4).
This enhancer-driven leptin transcription occurs independently of adipose tissue mass, as evidenced by 15-fold increases in serum leptin and Lep mRNA in mice with near-complete fat loss due to YAP/TAZ activation, and blunted leptin induction in YAP/TAZ knockout mice during refeeding or high-fat diet (10.1038/s42255-024-01045-4).
Evidence from Studies
Supporting (1)
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Hippo–YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass
Contradicting (0)
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