Abstract
During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability.KeywordsKetogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis
Highlights
Metabolic conditions causing ketosis Ketosis is caused by the preferential breakdown of fats for energy production, resulting in ketone body formation in the absence of sufficient carbohydrate availability leading to low systemic insulin levels.Reasons for ketosis include the following:(a) Energy production preferentially from body fat reserves because of insufficient energy supply from dietary sources including digestible carbohydrates less than 5–10% of daily required energy
In recent reviews, we have described the role of elevated endogenous insulin levels in the development of obesity and arteriosclerosis [1, 2]
A normal blood glucose level is maintained by hepatic gluconeogenesis
Summary
Metabolic conditions causing ketosis Ketosis is caused by the preferential breakdown of fats for energy production, resulting in ketone body formation in the absence of sufficient carbohydrate (sugars or starches, glycogen) availability leading to low systemic insulin levels.Reasons for ketosis include the following:(a) Energy production preferentially from body fat reserves because of insufficient energy supply from dietary sources including digestible carbohydrates less than 5–10% of daily required energy (voluntary or during famine). The use of acetoacetate and βOHB is proportionate to systemic levels so that there is increased consumption of ketone bodies during ketosis free fatty acids remain the major substrate for ATP production [6].
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