Hepatic SCD1 overexpression limits high‑fat diet hyperphagia and liver lipid storage via PPARα and ketone signaling in zebrafish
The authors used liver‑specific scd1 overexpression in zebrafish to test whether hepatic SCD1 can modulate feeding and hepatic lipid accumulation during chronic high‑fat feeding. Overexpression reduced food intake, lowered hepatic lipid deposition, and altered neuropeptide expression, effects that depended partly on hepatic PPARα activation and increased ketone body production.
Study and findings
In a series of experiments, the investigators generated zebrafish lines that overexpressed scd1 specifically in the liver. When these fish were fed a high‑fat diet (HFD) for several weeks, hepatic scd1 overexpression markedly attenuated the diet‑induced rise in liver triglyceride content compared with non‑transgenic controls. Concurrently, both larval and adult transgenic fish displayed a substantial reduction in daily food intake. Gene‑expression analysis revealed lower levels of the orexigenic neuropeptide agouti‑related peptide (agrp) and higher levels of anorexigenic markers cart and gonadotropin‑releasing hormone 2 in the brain. Mechanistic probing showed that hepatic scd1 overexpression increased hepatic concentrations of the fatty‑acid ethanolamides palmitoylethanolamide and oleoylethanolamide, promoted nuclear translocation of PPARα, and up‑regulated transcripts involved in fatty‑acid oxidation and ketogenesis, including hmgcs2. Accordingly, β‑hydroxybutyrate and acetoacetate were elevated in both liver and brain, while brain AMPKα phosphorylation was reduced. In a PPARα‑deficient background, the lipid‑lowering effect of scd1 overexpression was blunted and the suppression of orexigenic signaling was partially restored, indicating that hepatic PPARα mediates a significant portion of the observed phenotype.
Clinical interpretation
These data identify hepatic SCD1 as a node that can influence whole‑body energy balance in a vertebrate model. By enhancing hepatic PPARα activity and ketone body production, liver‑derived signals appear to reach the brain and modify appetite‑regulating circuits. Although the work is limited to zebrafish, the pathways implicated—PPARα‑driven fatty‑acid oxidation, ketogenesis, and fatty‑acid ethanolamide signaling—are conserved in mammals. If similar liver‑to‑brain communication operates in humans, hepatic SCD1 activity could represent a target for modulating hyperphagia and hepatic steatosis associated with high‑fat diets. However, translation to clinical practice would require confirmation that hepatic SCD1 can be safely up‑regulated in humans and that the downstream neuroendocrine effects are comparable.
Limitations and open questions
The study is confined to a non‑mammalian species; zebrafish metabolism and neurocircuitry differ from those of humans, limiting direct extrapolation. The experiments relied on genetic overexpression rather than pharmacologic modulation, so the feasibility of therapeutic activation of hepatic SCD1 remains uncertain. Moreover, the contribution of peripheral (non‑hepatic) SCD1 to appetite control was not addressed, and the relative importance of ketone bodies versus fatty‑acid ethanolamides in brain signaling was not dissected. Future work should test whether hepatic SCD1 activation produces comparable effects in mammalian models, clarify the dose‑response relationship, and determine safety profiles before considering clinical relevance.
Source
Jia K et al. Hepatic stearoyl‑CoA desaturase 1 suppresses diet‑induced hyperphagia and hepatic lipid accumulation through PPARα activation and ketone body signaling. J Biol Chem. 2026;301(45):113515.