9 Fasting, Postprandial States Integration

Course pack for Metabolic Integration session focusing on fasting/starvation and post-prandial processes

For this session it is important that you review and understand previously learned material including:

• Glycolysis and gluconeogenesis
• Glycogen synthesis and glycogen degradation
• Fatty acid synthesis (lipogenesis) and fatty acid degradation (lipolysis)
• Ketone production

Feed/Fast metabolism is best thought of as a cycle. You may transition between fed and fasted carbohydrate and lipid metabolism several times a day depending on your meal schedule.

After a meal (post-absorptive) the body relies on glucose for baseline metabolic function in most tissues (including liver, adipose tissue). All tissues that can store fuel (glycogen or triglycerides (TG)) replenish depleted supplies and increase fuel stores. Lipid particles deliver TG and cholesterol to all tissues for repair and cell division. Cells are generally more anabolic and making or replacing proteins as cells take advantage of the abundant amino acids in plasma. Excess glucose enters the pentose phosphate pathway for boosting NADPH levels for subsequent anabolic processes. This time of plenty lasts from 2-6 hours depending on the meal. The liver takes up chylomicron remnants with TG and cholesterol and then secretes synthesized TG and cholesterol as VLDL so that cells can continue to use these molecules as needed for as long as possible after a meal.

As the absorbed nutrients from the last meal are fully metabolized the transition to the fasting state begins, marked by a switch from glucose metabolism to fat metabolism for many cells (hormonal signals include decreasing insulin and increasing glucagon secretion from the pancreas). However, some cells (eg. neurons, red blood cells) remain dependent on glucose metabolism and would consume enough glucose over time to cause hypoglycemia (low blood sugar) without a new source of glucose (eg. while waiting for the next meal and the gut to deliver more glucose). That source of glucose is the liver and the kidneys which make glucose to prevent hypoglycemia during fasting. Glycogen synthesis is inhibited and glycogenolysis is activated as the liver begins to release glucose to prevent serum glucose from decreasing too much (you should understand how insulin/glucagon regulate this process). Glycolysis slows down and hepatic gluconeogenesis increases (you should understand how insulin/glucagon regulate this process) as TG breakdown in adipose tissue begins to deliver glycerol to the liver (understand how insulin/epinephrine regulate this process). The TG level in the blood decreases (primarily in VLDL and chylomicrons) and the FFA (bound to albumin) levels increase, and FA become the primary metabolic fuel for many tissues. Tissues (that can) switch to using beta oxidation of FA for ATP synthesis instead of glucose (brain, RBCs are important cells that cannot use FA for fuel). Muscle starts to break down and release amino acids to go to the liver as a key source of gluconeogenesis. Gluconeogenesis requires the liver to release Acetyl CoA produced from beta oxidation into the blood as ketones. This occurs because the hepatocyte TCA cycle can not operate while gluconeogenesis from amino acids is active (why is that not true for glycerol?). The ketones are rapidly taken up and metabolized for energy by a variety of tissues so that serum ketone levels in fasting remain below the detection threshold. Some ketones are filtered into the urine and can be measured during fasting (many physicians only associate ketones with hyperglycemia and diabetic ketoacidosis. Not you. You now understand that the liver making ketones is a normal part of the response to everyday fasting that allows the liver to release enough glucose to prevent hypoglycemia).

It is important for you to understand several metabolic adaptations that occur as fasting becomes more prolonged and progresses to starvation.

1. The rate of skeletal muscle catabolism (breakdown) decreases. The mechanism controlling this remains controversial, but is likely mediated by signals from the brain. Skeletal muscle preservation is critical to surviving starvation. Organ failure and death from starvation occur at a critical skeletal muscle mass, usually well before white adipose tissue is fully depleted.
2. Decreased skeletal muscle catabolism decreases hepatic gluconeogenesis which decreases hepatic glucose release into the blood. This would be expected to cause hypoglycemia, but this rarely occur because …
3. At about this time (roughly 48-72 hours of fasting) the brain and especially neurons have up-regulated their enzymatic machinery to be able to transport ketones across the blood brain barrier and metabolize ketones into acetyl CoA to be used for ATP production. This saves a large amount of serum glucose from being metabolized and can be used by other tissues.
4. The brain also implements a coordinated endocrine and neuronal effort to decrease energy expenditure. This includes decreasing thyroid signaling, shutting off the reproductive axis and decreasing adaptive immune function all of which decrease resting energy expenditure. Activity energy expenditure (the metabolic cost of low power muscle movements) also becomes more efficient. These adaptations save energy and prevent the body from using too much stored fuel (both glucose and TG) too rapidly. These changes are, at least partially, mediated by a rapid and profound decrease in the adipocyte hormone leptin and coordinated by various nuclei in the hypothalamus.

Enzyme activity and hormones that increase with fasting are inhibited by feeding and vice versa. The reciprocal regulation and coordination of these processes is very careful and efficient. It is important for you to understand the coordinated changes in carbohydrate and lipid metabolism, hormonal signals and enzymatic pathways that change as the fasting state transforms to the fed state following a meal.