Sex differences in adipose tissue lipolysis and pathological cardiac hypertrophy

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Augmented adipose tissue lipolysis, elevation of circulating free fatty acids (FFA), and changes in FA composition occurs in hyperadrenergic situations such as exercise, and during the development of cardiac hypertrophy and chronic heart failure. In contrary, during the progression from pathological cardiac hypertrophy to end-stage heart failure, the rate of cardiac fatty acid oxidation is reduced indicating a mismatch between circulating substrate and local cardiac metabolism. The relevance of increased FFAs and changes in FAcomposition for the pathogenesis and progression of cardiac hypertrophy is mostly unknown. Female mice are protected against pathological hypertrophy/ heart failure. In parallel, females exhibit enhanced adrenergic lipolysis. Sex-differences in adrenergic adipose tissue lipolysis associated with sexual dimorphisms in cardiac energy substrate metabolism may contribute to the diminished hypertrophic responses in female mice to pathological stimuli. Based on our results from the first funding period, we aim to characterize the role of augmented adrenergic adipose tissue lipolysis in the progression of pathological cardiac hypertrophy by studying sex-differences in lipolysis and pathological myocardial hypertrophy. For this, female/ male adipose-specific ATGL (adipose triglyceride lipase)-deficient mice (aP2 Cre –ATGL-flox) and wild-type littermates will be challenged with transverse aortic constriction (TAC) to induce cardiac hypertrophy and subsequent heart failure. Mice will be followed by cardiac and metabolic phenotyping. To further delineate the molecular mechanisms of sex-specifc differences in cardiac FA metabolism, we will analyze key molecules of fatty acid uptake/ oxidation and cardiac responses to selected FAs.