In mice with a specific genetic change that causes fat loss, the absence of the hormone leptin leads to high blood sugar, high insulin levels, and fat accumulation in the liver, even when energy use...
Mechanism
Synthesis from 1 study
When fat cells lose their fat due to YAP/TAZ activation, they make way more leptin, which tells the liver to burn fat instead of storing it, keeping blood sugar and insulin normal — even when there’s almost no fat left (10.1038/s42255-024-01045-4). If leptin is missing, the liver gets fatty and...
Most probable mechanism
When fat cells lose their fat due to YAP/TAZ activation, they don't stop making leptin — instead, they make way more of it, which tells the liver to burn fat instead of storing it, and keeps blood sugar and insulin levels normal, even when there's almost no fat left in the body (10.1038/s42255-024-01045-4). If leptin is missing, the liver starts storing fat, blood sugar spikes, and insulin goes wild, but giving back leptin fixes all of that without bringing back the fat (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 (10.1038/s42255-024-01045-4).
Nuclear YAP/TAZ-TEAD complexes bind a conserved enhancer 28 kb upstream of the leptin gene, directly activating its transcription and increasing leptin mRNA and serum protein levels despite severe adipose tissue loss (10.1038/s42255-024-01045-4).
Elevated leptin signaling increases whole-body energy expenditure and shifts substrate utilization toward fatty acid oxidation, primarily in the liver, as shown by reduced respiratory exchange ratio and increased hepatic Ppargc1a expression and 13C-palmitate oxidation (10.1038/s42255-024-01045-4).
Increased hepatic fatty acid oxidation prevents ectopic lipid accumulation, while leptin-mediated suppression of hepatic glucose production and enhanced insulin sensitivity prevent hyperglycemia and hyperinsulinemia (10.1038/s42255-024-01045-4).
In the absence of leptin (iAKO ob/ob mice), the protective effects of YAP/TAZ activation are lost, resulting in severe fatty liver, hyperglycemia, and hyperinsulinemia, which are fully reversed by exogenous leptin administration without restoring adipose tissue (10.1038/s42255-024-01045-4).
Evidence from Studies
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Hippo–YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass
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