Cardiac metabolism is highly adaptive in response to changes in substrate 
availability, as occur during fasting. This metabolic flexibility is essential 
to the maintenance of contractile function and is under the control of a group 
of select transcriptional regulators, notably the nuclear receptor family of 
factors member PPARα. However, the diversity of physiologic and pathologic 
states through which the heart must sustain function suggests the possible 
existence of additional transcriptional regulators that play a role in matching 
cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is 
required for the normal cardiac response to fasting. Specifically, we find that 
cardiac function is impaired upon fasting in systemic and cardiac specific 
Klf15-null mice. Further, cardiac specific Klf15-null mice display a 
fasting-dependent accumulation of long chain acylcarnitine species along with a 
decrease in expression of the carnitine translocase Slc25a20. Treatment with a 
diet high in short chain fatty acids relieves the KLF15-dependent long chain 
acylcarnitine accumulation and impaired cardiac function in response to fasting. 
Our observations establish KLF15 as a critical mediator of the cardiac adaptive 
response to fasting through its regulation of myocardial lipid utilization.