In mice, activating two specific proteins (YAP/TAZ) only in fat cells leads to higher energy use and increased breakdown of fats in the liver, which stops fat from building up in the wrong places and...
Mechanism
Synthesis from 1 study
When YAP and TAZ are turned on in fat cells, they make the body produce more leptin even when fat is gone, and that leptin tells the liver to burn fat instead of storing it, keeping blood sugar normal and preventing fatty liver (10.1038/s42255-024-01045-4). This happens even though the fat tissue...
Most probable mechanism
When YAP and TAZ are activated in fat cells, they turn on the leptin gene even when the fat cells shrink and lose their fat, causing a big rise in leptin levels in the blood. This high leptin tells the liver to burn more fat for energy instead of storing it, which prevents fat from building up in the liver and keeps blood sugar stable, even though the body has almost no fat left. This is shown in mice where turning on YAP/TAZ in fat cells increases leptin (10.1038/s42255-024-01045-4), boosts fat burning in the liver (10.1038/s42255-024-01045-4), and stops high blood sugar and fatty liver even when fat tissue is nearly gone (10.1038/s42255-024-01045-4).
Deletion of LATS1 and LATS2 in adipocytes prevents phosphorylation of YAP and TAZ, allowing their nuclear translocation where they bind TEAD transcription factors to repress PPARG-driven adipogenic gene expression and induce adipocyte dedifferentiation into progenitor-like cells (10.1038/s42255-024-01045-4).
Nuclear YAP/TAZ-TEAD complexes directly bind a conserved enhancer located 28 kb upstream of the leptin gene transcription start site, activating Lep transcription and increasing serum leptin levels independently of adipose tissue mass (10.1038/s42255-024-01045-4).
Elevated leptin signaling increases whole-body energy expenditure and shifts substrate utilization toward fatty acid oxidation, as evidenced by reduced respiratory exchange ratio and increased oxygen consumption without changes in physical activity (10.1038/s42255-024-01045-4).
Fatty acids are preferentially oxidized in the liver, not in muscle or adipose tissue, as shown by increased 13C-palmitate turnover and 13C-citrate enrichment specifically in the liver, driven by upregulation of Ppargc1a (Pgc1a) (10.1038/s42255-024-01045-4).
Increased hepatic fatty acid oxidation prevents ectopic lipid accumulation and glucose intolerance, as demonstrated by rescue of liver steatosis and hyperglycemia in leptin-deficient mice via exogenous leptin administration, despite persistent adipose tissue loss (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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