Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7-Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.