**Background:** Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide without effective treatment. Acute alcoholic hepatitis, often linked to binge drinking, has high mortality. Alcohol consumption dysregulates lipid metabolism, increases adipose tissue lipolysis, and induces liver steatosis and adipose tissue atrophy, suggesting critical liver-adipose crosstalk. Mechanistic target of rapamycin (mTOR) regulates lipid metabolism, cell proliferation, and autophagy, but its tissue-specific role in binge drinking-induced organ damage was unclear.
**Methods:** The authors generated liver-specific and adipocyte-specific knockout mice for Rptor (mTORC1 component) and Mtor (catalytic core of mTOR) using Cre-lox technology. Rptor floxed and Mtor floxed mice were crossed with albumin Cre (liver-specific) or adiponectin Cre (adipocyte-specific) mice. Double knockout mice (liver and adipocyte) were also generated. Male mice aged 8–10 weeks were treated with 7 g/kg ethanol or maltose by oral gavage for 6 hours. Outcomes included hepatic triglyceride and cholesterol levels, serum ALT, histology (H&E, F4/80, CD68 staining), adipose tissue mass, adipocyte size distribution, and serum adipokine/cytokine profiling using a Proteome Profiler Mouse Adipokine Array Kit. Hepatic FGF21 protein was measured by immunoblot.
**Key Results:** Acute alcohol exposure induced hepatic steatosis and elevated serum ALT in all genotypes. Liver-specific deletion of Mtor or Rptor did not alter steatosis or liver injury compared to wild-type. However, adipocyte-specific deletion of Mtor or Rptor significantly exacerbated alcohol-induced liver injury, with further increased serum ALT and hepatic triglyceride levels. Adipocyte Mtor or Rptor knockout mice developed hepatomegaly and adipose tissue atrophy at baseline: Mtor AKO and LAKO mice had approximately 20–25% decreased eWAT, 40–50% decreased iWAT, and 50–60% decreased iBAT mass. Rptor AKO and LAKO mice had approximately 50% decreased eWAT, 40–60% decreased iWAT, and 40–50% decreased iBAT mass. Adipocyte Rptor deletion, but not Mtor deletion, also altered adipocyte size distribution with increased heterogeneity. Serum adipokine analysis showed that adipocyte Mtor or Rptor knockout mice had increased basal adiponectin, decreased basal FGF21, and decreased fetuin A. Alcohol gavage increased circulating FGF21 in wild-type mice but not in adipocyte knockout mice. Pro-inflammatory cytokines IL-6, TNFα, and MCP-1 were elevated in adipocyte Mtor knockout mice, while anti-inflammatory IL-10 was decreased. Hepatic FGF21 levels were lower in Mtor AKO control mice and further decreased by alcohol. CD68-positive macrophages increased in all genotypes after alcohol, but Rptor AKO and LAKO mice already had higher basal CD68 counts.
**Clinical Implications:** This study identifies adipocyte mTOR signaling, particularly mTORC1, as a critical regulator of liver-adipose crosstalk in acute alcohol-induced liver injury. The finding that adipocyte-specific, but not liver-specific, mTOR deletion worsens ALD suggests that adipose tissue dysfunction—rather than hepatic mTOR activity—drives alcohol-related liver damage in this acute model. The altered adipokine profile (decreased FGF21, increased adiponectin, decreased fetuin A) in adipocyte mTOR knockout mice may represent maladaptive responses that exacerbate liver injury. Targeting adipose mTOR signaling or adipocyte lipolysis could represent a novel therapeutic approach for ALD. Limitations include the use of only male mice and the acute (6-hour) model, which may not reflect chronic alcohol exposure. Future studies should investigate gender differences and the differential mTOR response to acute versus chronic alcohol.