Brain pathology is tightly coupled to altered energy regulation. Under many pathophysiological conditions energy homeostasis, such as with altered glucose regulation, is frequently deranged and the metabolic consequences are often irreversible and deleterious. I have investigated the neuroprotective effects of ketosis and have published that ketone bodies are alternate energy substrates to brain and are signaling molecules that promote preservation of brain cells during recovery from ischemia, which we purport is through the downstream actions of hypoxia inducible factor-1 (HIF1α). My research continues to focus on the use of alternate energy substrates to glucose, such as ketone bodies or ketone analogues in brain. I have developed animal models (dog, rat and mouse) of diet induced ketosis and have resolved the long time question on brain’s utilization of ketone bodies during chronic ketosis. The use of mass spectrometry and stable isotopomer analysis has enabled me to measure the contributions and partitioning of glucose and ketones towards oxidative metabolism in vivo. I and my colleagues have shown that brain can utilize 40% of energy requirements, as ketones (suppressing of glucose), under an short term adapted state of ketosis. Stable isotopomer analysis revealed that ketone bodies partition towards GABA synthesis following short term feeding of a ketogenic diet to mice or rats. I continue to investigate the role of HIFs in neuroprotection following reperfusion injury which we purport is also through the regulation of CNS inflammatory responses.