Dietary cysteine and methionine promote peroxisome elevation and fat loss by induction of CG33474 expression in Drosophila adipose tissue

Abstract The high-protein diet (HPD) has emerged as a potent dietary approach to curb obesity. Peroxisome, a highly malleable organelle, adapts to nutritional changes to maintain homeostasis by remodeling its structure, composition, and quantity. However, the impact of HPD on peroxisomes and the underlying mechanism remains elusive. Using Drosophila melanogaster as a model system, we discovered that HPD specifically increases peroxisome levels within the adipose tissues. This HPD-induced peroxisome elevation is attributed to cysteine and methionine by triggering the expression of CG33474 , a fly homolog of mammalian PEX11G . Both the overexpression of Drosophila CG33474 and human PEX11G result in increased peroxisome size. In addition, cysteine and methionine diets both reduce lipid contents, a process that depends on the presence of CG33474 . Furthermore, CG33474 stimulates the breakdown of neutral lipids in a cell-autonomous manner. Moreover, the expression of CG33474 triggered by cysteine and methionine requires TOR signaling. Finally, we found that CG33474 promotes inter-organelle contacts between peroxisomes and lipid droplets (LDs), which might be a potential mechanism for CG33474 -induced fat loss. In summary, our findings demonstrate that CG33474/PEX11G may serve as an essential molecular bridge linking HPD to peroxisome dynamics and lipid metabolism. Graphical abstract HPD, with cysteine and methionine serving as key amino acids, specifically elevates peroxisome levels in the adipose tissues of Drosophila by inducing CG33474 expression. CG33474 / PEX11G performs two essential biological roles in an evolutionarily conserved manner: firstly, overexpression of CG33474 / PEX11G leads to increased peroxisome size; secondly, CG33474 / PEX11G promotes the breakdown of LDs in a cell-autonomous manner (by strengthening peroxisome-LD interaction). Furthermore, TOR signaling is required for cysteine- and methionine-induced CG33474 / PEX11G expression.