Loss of subcutaneous fat is a hallmark of ageing usually starting in the face. Attempts to ameliorate cosmetically the appearance of subcutaneous fat loss have been of limited success as they fail to rebuild the missing subcutaneous tissue. Ageing-driven loss of subcutaneous fat results from (i) the reduced capacity of pre-adipocytes to differentiate into adipocytes and (ii) the fact that adipocytes of the elderly secrete increased amounts of TNFα, that in turn enhances lipolysis, inhibits pre-adipocyte differentiation and induces dedifferentiation of adipocytes. The neolignan dihydrodehydrodiisoeugenol (DDE) caused a 30% increase in lipid accumulation in murine 3T3-L1 cells. This effect was accompanied by an induction of the differentiation-associated transcription factors peroxisome proliferator-activated receptorγ (PPARγ2), CAAT/enhancer-binding protein α (C/EBPα), fatty acid binding protein 4 and adiponectin, and a loss of the pre-adipocyte marker Pref1. In addition, DDE diminished both basal and TNFα-induced lipolysis. Similar results were obtained in human subcutaneous (hsc) pre-adipocytes cultured in an age-adapted hormone mix with reduced levels of insulin and dexamethasone. In this system, DDE significantly increased lipid accumulation by 71% and 94% and was associated with an induction of PPARγ2 and adiponectin mRNA expression. DDE also reduced basal lipolysis in mature hsc adipocytes. DDE acted as a partial PPARγ agonist because (i) DDE displaced PPARγ ligand from the human PPAR ligand-binding site, (ii) DDE-induced lipid accumulation and (iii) DDE-induced adiponectin secretion could be overcome by the addition of PPARγ antagonists. Taken together, these studies identify DDE as a compound well suited to prevent and reverse loss of subcutaneous fat.