Hepatic stearoyl-CoA desaturase 1 suppresses diet-induced hyperphagia and hepatic lipid accumulation through PPARα activation and ketone body signaling.

Abstract

Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in fatty acid desaturation with a well-established role in lipid metabolism, but its function in appetite regulation remains insufficiently understood. Here, we investigated whether hepatic SCD1 regulates high-fat diet (HFD)-induced lipid accumulation and feeding behavior through liver-to-brain metabolic signaling. Long-term HFD feeding suppressed hepatic scd1 expression in black seabream and zebrafish despite progressive hepatic lipid accumulation. Using liver-specific scd1-overexpressing zebrafish and peroxisome proliferator-activated receptor α (PPARα)-deficient scd1-overexpressing zebrafish, we found that hepatic scd1 overexpression attenuated HFD-induced lipid deposition and markedly suppressed food intake in both larval and adult zebrafish. These effects were accompanied by reduced agouti-related peptide (agrp) expression and increased cocaine- and amphetamine-regulated transcript (cart) and gonadotropin-releasing hormone 2 (gnrh2) expression. Mechanistically, hepatic scd1 overexpression increased palmitoylethanolamide and oleoylethanolamide levels, enhanced hepatic PPARα nuclear translocation, and activated hepatic fatty acid oxidation and ketogenesis programs. Genetic ablation of PPARα weakened the lipid-lowering effect of scd1 overexpression and partially restored orexigenic signaling. Moreover, hepatic scd1 overexpression increased hepatic 3-hydroxy-3-methylglutaryl-CoA synthase 2 (hmgcs2) mRNA expression and elevated β-hydroxybutyrate and acetoacetate levels in both the liver and brain, accompanied by reduced brain AMPKα phosphorylation. Together, these findings identify hepatic SCD1 as a metabolic regulator that suppresses HFD-induced hyperphagia and lipid accumulation, involving lipid-derived PPARα signaling and ketone body-mediated brain energy sensing.