AIMS/HYPOTHESIS: Diabetic cardiomyopathy is characterized by interstitial fibrosis, and cardiomyocyte hypertrophy and apoptosis. Also known as CCN2, Connective tissue growth factor (CTGF) is implicated in the fibrosis however whether it contributes to cardiomyocytes changes and adverse effects of high glucose and lipids on these cells, remains unknown. METHODS: Hearts from STZ induced diabetic rats had elevated CTGF and changes of pathological myocardial hypertrophy, fibrosis and cardiomyocyte apoptosis. Rat H9c2 cardiomyocytes were then treated with recombinant human (rh)CTGF, high glucose or the saturated free fatty acid, palmitate. RESULTS: Each reagent induced cell hypertrophy, as indicated by the ratio of total protein /cell number, cell size and gene expression of cardiac hypertrophy marker genes ANP and -skeletal actin. Each treatment also caused apoptosis, measured by increased caspase3/7 activity, apoptotic cells by TUNEL assay and lower viable cell number. Further studies showed CTGF mRNA was rapidly induced by high glucose and palmitate, in H9c2 cells and in mouse neonatal cardiomyocyte primary cultures. SiRNA against CTGF blocked the high glucose and palmitate induction of hypertrophy and apoptosis. In addition, these CTGF effects were through the TrkA receptor with tyrosine kinase activity, which has previously been implicated in CTGF signalling: TrkA was phosphorylated by CTGF and a specific TrkA blocker abrogated CTGF-induced effects on hypertrophy and apoptosis. CONCLUSIONS/INTERPRETATION: For the first time in any system, fatty acid is newly identified as a regulator of CTGF, and this work implicates autocrine CTGF as a mediator of adverse effects of high glucose and fatty acids in cardiomyocytes.