High fat diet induced insulin resistance correlates with dyslipidaemia and ectopic fat deposits in skeletal muscle and liver. The effects ofSutherlandia frutescens, an antidiabetic medicinal plant, on lipid metabolism were evaluated in an insulin resistant (IR) rat model and in 3 T3-preadipocytes. Wistar rats received normal diet (ND) or high fat diet (HFD). After the onset of IR in the HFD group, the rats were subdivided into two subgroups, which either continued with HFD or were treated with 50 mgS. frutescens/kg BW/day and HFD (HFD + SF). After 4 weeks, the HFD + SF rats had a significantly lower body weight than the HFD rats (p< 0.05). Blood plasma analysis showed a decrease in insulin, free fatty acids and triglycerides. Related changes in lipid parameters were observed in the liver, skeletal muscle and adipose tissue. To investigate the effects ofS. frutescenson adipose tissue, 3 T3-L1 cells were used as a model. Treatment withS. frutescensled to a decrease in triglyceride accumulation, whilst glucose consumption and lactate production were increased (p< 0.05). These results indicate thatS. frutescensdirectly affects mitochondrial activity and lipid biosynthesis in adipose tissue and provide a mechanism by whichS. frutescenscan restore insulin sensitivity by modulating fatty acid biosynthesis. Copyright © 2012 John Wiley & Sons, Ltd.