TSPO deficiency uncovers a novel role for porphyrins in adipocyte lipid metabolism

The translocator protein (TSPO) is a mitochondrial outer membrane protein enriched in lipid-metabolic tissues, including white adipose tissue (WAT), but its physiological role in adipocytes remains poorly defined. Building on prior work that demonstrated a role for TSPO in mitochondrial fatty acid oxidation, we investigated whether TSPO contributes to adipocyte lipid homeostasis under metabolic stress. We employed a combination of in vivo and in vitro approaches using global Tspo knockout (Tspo-/-) mice, primary adipocyte cultures, and pharmacological TSPO-binding drugs to examine TSPO function. Our findings show that Tspo-/- mice exhibited increased gonadal and inguinal WAT mass and adipocyte hypertrophy following high-fat diet feeding in both sexes, with a modest late body weight increase in females, but no differences in feed intake. These changes were accompanied by suppression of key lipolytic genes, reduced circulating NEFA and glycerol levels, and altered expression of fatty acid oxidation genes. Lipidomic profiling showed no genotype-dependent changes, indicating impaired mobilization rather than altered lipid composition. In vitro, primary adipocytes derived from inguinal WAT of Tspo-/- mice exhibited enhanced lipid accumulation during differentiation and reduced expression of lipolytic genes. TSPO-binding drugs phenocopied this response in TSPO-expressing cells. Mechanistically, we identify protoporphyrin IX (PPIX), an endogenous TSPO ligand, as a suppressor of adipogenic and lipolytic programs. PPIX levels increase during adipogenesis, and its accrual inhibits both lipid accumulation and lipolytic programs. Our findings identify TSPO as a regulator of adipocyte lipid metabolism through a previously unrecognized TSPO-PPIX axis that influences lipid mobilization. This mechanism provides new insight into TSPO's role in adipose metabolic adaptation.