Dimethylmalonate suppresses white adipocyte differentiation and ameliorates diet-induced obesity.

Obesity is driven by pathological expansion of white adipose tissue (WAT), reflecting both adipocyte hypertrophy and the differentiation of preadipocytes into mature white adipocytes. Arresting adipogenic differentiation is therefore a logical anti-obesity strategy. Because adipogenesis relies on extensive metabolic rewiring, blocking it by targeting mitochondrial enzymes-without collapsing cellular bioenergetics-remains an attractive but unresolved objective. Here, we investigated dimethylmalonate (DMM), a membrane-permeable diester that undergoes intracellular cleavage to yield malonate, a classic competitive inhibitor of succinate dehydrogenase (SDH). During the induced differentiation of 3T3-L1 preadipocytes, DMM treatment concentration-dependently restrained intracellular lipid accumulation. Furthermore, it markedly blunted the differentiation-induced induction of Pparg, which encodes the master transcriptional regulator of the white adipocyte lineage. Importantly, this occurred without bioenergetic collapse: viability remained near 90% at 10 mM, oxygen consumption was sustained and modestly increased, and intracellular ATP content rose. Concurrently, elevated cellular succinate confirmed robust on-target SDH inhibition. In a murine model of high-fat diet (HFD)-induced obesity, daily oral administration of DMM at 600 mg/kg, but not at 200 mg/kg, attenuated body weight gain and reduced both subcutaneous and visceral WAT mass. These morphological improvements were accompanied by improved glucose tolerance and insulin sensitivity, with no significant alteration in daily food intake or in the mass of the liver, heart, and skeletal muscle. Collectively, our findings demonstrate that DMM suppresses white adipocyte differentiation and ameliorates diet-induced obesity while sustaining mitochondrial respiration and ATP content, highlighting targeted SDH modulation as a viable anti-obesity therapeutic strategy.