The Influence of a High Fat Diet and Metformin Treatment on the Activity of Respiratory Chain Complexes

High fat diet (HFD) is one cause of obesity and type 2 Diabetes and Diabetes is associated with mitochondrial dysfunction. Metformin the most common drug to treat T2D reduces blood glucose levels and improves insulin sensitivity and has recently been linked to beneficial effects in cardiac surgery. Metformin has been suggested to act on complex I of the respiratory chain of mitochondria. Our aim was to analyze how high fat diet and metformin treatment influence the activities of the mitochondrial complexes of the respiratory chain.

Male SD-rats were fed normal chow or a high fat diet. Animals were treated with or without Metformin. At 23 weeks of age mitochondria of heart and skeletal muscle were isolated. We analyzed individual complex activities of the respiratory chain in both, interfibrillar (IFM) and subsarcolemmal mitochondria (SSM).

HFD led to increased body weight and reduced glucose tolerance. Metformin treatment improved glucose tolerance. HFD led to an increase in complex I, III, IV and combined complex I and III activity in both heart and skeletal muscle (complex I, heart IFM NC versus HFD: 28,4 ± 7,59 versus 153 ± 54,5)but did not affect complex II. With HFD, Metformin treatment led to a reduction in complex I, III and in the combination of I and III activities in all tissues (complex I + III skeletal muscle IFM HFD versus HFD-MET: 626 ± 156 versus 143 ± 71,9). Influence of Metformin was strongest in skeletal muscle IFM. Metformin had fewer effects on skeletal muscle SSM or cardiac mitochondria. With normal chow Metformin reduced activity of complex I, III and combined complex I and III respiratory chain complexes (muscle SSM, complex I, NC vs NC-MET: 373 ± 30,1 versus 244 ± 41,5). Contrary to expectations we found no reduction of complex activities with HFD. Metformin treatment slightly decreased activities of complex I in heart and skeletal muscle with HFD. However, metformin treatment in healthy animals impaired complex activities significantly. Thus, Metformin may be detrimental without proper pathological stimulus such as HFD or diabetes. These findings should be considered if general use of metformin in cardiac surgery is discussed.