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Hippo-YAP/TAZ signaling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

ABSTRACT: Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that transcriptional coregulators YAP and TAZ mediate the crosstalk between fat mass and leptin levels to maintain metabolic homeostasis. Activating YAP/TAZ in adipocytes by Lats1 and Lats2 deletion results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells. Surprisingly, Lats1/2 knockout mice did not exhibit lipodystrophy-related metabolic dysfunction, attributed to a paradoxical increase in circulating leptin levels. Mechanistically, YAP/TAZ-TEAD signaling upregulates leptin expression by directly binding an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is linked to, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ plays an essential role in coordinating adipose storage capacity and systemic energy balance through dual control of adipocyte plasticity and leptin gene transcription.

ORGANISM(S): Mus musculus

PROVIDER: GSE261825 | GEO | 2024/03/21

REPOSITORIES: GEO

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Hippo-YAP/TAZ signaling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

Project description:Adipose tissue contributes to systemic energy homeostasis by serving as an energy reservoir and endocrine organ. Coordinated regulation of these functions is essential for metabolic health, but the mechanisms that underlie cross-talk between them have been unknown. Here we show that the transcriptional coregulators YAP and TAZ of the Hippo signaling pathway in adipose tissue control systemic energy balance. Mechanistically, we identify a YAP/TAZ-TEAD axis that upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene.

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Project description:Hippo-YAP/TAZ signaling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

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Hippo-YAP/TAZ signaling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

Project description:Hippo-YAP/TAZ signaling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass

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The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis

Project description:Fibrosis disrupts adipose tissue (AT) homeostasis in response to chronic caloric excess, exacerbating metabolic dysfunction. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGFbeta signaling to orchestrate a functional adipocyte-to-myofibroblast transition in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4+ progenitor cells and convert to DPP4- myofibroblasts upon TGFbeta stimulation. Macrophages recruited by CCL2 served as a major cell source of TGFbeta. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target.

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Phenotypic characterization of Adig null mice suggests roles for adipogenin in the regulation of fat mass accrual and leptin secretion

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The obesity-linked human lncRNA AATBC regulates adipocyte plasticity by stimulating mitochondrial dynamics and respiration [1]

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