What enzyme is down-regulated during prolonged fasting in favor of gluconeogenesis (glucose production) and fat utilization?

From the Guidelines

During prolonged fasting, pyruvate dehydrogenase (PDH) is the key enzyme that becomes down-regulated in favor of gluconeogenesis and fat utilization. As fasting becomes prolonged for more than several hours, glycogen stores become depleted, and the low levels of circulating insulin allow increased fatty acid release from adipocytes, as noted in a study on management of diabetes during Ramadan 1. The down-regulation of PDH is crucial because it normally catalyzes the conversion of pyruvate to acetyl-CoA, which enters the citric acid cycle for energy production when carbohydrates are abundant. However, during extended fasting, the body needs to preserve glucose for tissues that absolutely require it (like the brain) and shift toward using fat as the primary fuel source. Some key points to consider include:

• The inhibition of PDH prevents pyruvate from entering the citric acid cycle, instead redirecting it toward gluconeogenesis in the liver.
• Hormonal changes during fasting, particularly increased glucagon and decreased insulin levels, promote the breakdown of stored fats into fatty acids, which become the predominant energy substrate for most tissues, as seen in the context of managing diabetes during Ramadan 1.
• This metabolic adaptation is crucial for maintaining blood glucose levels and ensuring survival during periods of food scarcity. The shift towards fat utilization and gluconeogenesis is a vital adaptation mechanism during prolonged fasting, highlighting the importance of PDH down-regulation in this context.

From the Research

Enzyme Downregulation during Prolonged Fasting

• The enzyme that is downregulated during prolonged fasting in favor of gluconeogenesis and fat utilization is Pyruvate Dehydrogenase (PDH) 2.
• PDH is a crucial enzyme that converts pyruvate into acetyl-CoA, which is then used in the citric acid cycle to produce energy.
• During fasting, the activity of PDH is decreased, allowing pyruvate to be conserved for gluconeogenesis, a metabolic pathway that generates glucose from non-carbohydrate sources 2.
• The downregulation of PDH is largely responsible for the inactivation of the pyruvate dehydrogenase complex (PDC) in the fasted state, which helps maintain blood glucose levels by conserving pyruvate and other three-carbon compounds for gluconeogenesis 2.

Regulation of Pyruvate Dehydrogenase

• The activity of PDH is regulated by pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs) 2.
• PDK4 is a key regulator of PDH activity, and its upregulation is responsible for the inactivation of PDC in the fasted state 2.
• The regulation of PDH activity is also influenced by other factors, including the availability of pyruvate, the energy status of the cell, and the presence of allosteric effectors 3.

Metabolic Changes during Fasting

• During prolonged fasting, the body undergoes a metabolic shift from glucose to fat and ketone utilization 4, 5, 6.
• This shift is characterized by an increase in gluconeogenesis, fatty acid oxidation, and ketone body production, and a decrease in glycolysis and lipogenesis 5, 6.
• The downregulation of PDH activity is an important adaptation that allows the body to conserve glucose and maintain blood glucose levels during fasting 2.