During the fasting state, adipocytes undergo lipolysis, breaking down triglycerides into free fatty acids (FFAs) and glycerol. At the same time, there is a release of amino acids (AAs) through general net proteolysis. Glycerol and certain amino acids involved in gluconeogenesis are then released and transported to the liver. In the liver, these substances are used for gluconeogenesis, the process of producing glucose. This integration of catabolic pathways in adipocytes and skeletal myocytes with anabolic gluconeogenesis in hepatocytes is necessary for gluconeogenesis to occur. Glycogenolysis, the breakdown of glycogen, is eventually replaced by gluconeogenesis, which can continue as long as precursors flow into the liver.

Another process called glucose sparing helps maintain adequate levels of circulating glucose during fasting. Glucose sparing involves the shift in fuel utilization from glucose to non-gluconeogenic fuels, particularly in skeletal muscle, which has the highest demand for glucose. The uptake of glucose by skeletal muscle and adipocytes decreases significantly during fasting due to the presence of the GLUT4 transporter isoform inside the cells. Therefore, alternative fuels need to be supplied to these cells. Free fatty acids (FFAs) and ketone bodies (KBs) are considered non-gluconeogenic fuels, as they cannot be used for gluconeogenesis by the liver. FFAs are released from stored triglycerides in adipocytes, while KBs are produced by hepatocytes using acetyl CoA derived from FFAs and certain amino acids that become abundant during fasting. Glucose sparing relies on the catabolic metabolism of adipocytes, leading to the breakdown of stored triglycerides and release of FFAs. These FFAs are then taken up by hepatocytes, which utilize them to produce acetyl CoA. Protein degradation also occurs, providing additional substrates for ketogenesis. In hepatocytes, high levels of intramitochondrial acetyl CoA not only serve as a carbon source for ATP synthesis but also inhibit the conversion of pyruvate to acetyl CoA, promote the conversion of pyruvate to oxaloacetate for gluconeogenesis, and stimulate the synthesis of KBs. After several days of fasting, the central nervous system (CNS) can utilize KBs for energy, thereby further preserving glucose for erythrocytes. Many other cell types with mitochondria, particularly skeletal muscle, can use KBs and FFAs for ATP production.

Glucagon and catecholamines are the hormones that drive various metabolic processes during the fasting phase, including glycogenolysis, gluconeogenesis, lipogenesis, hepatic ketogenesis, and very-low-density lipoprotein (VLDL) production by the liver. When blood glucose levels are low, insulin levels decrease, removing the inhibitory effect of insulin on the secretion of glucagon. As a result, the ratio of circulating glucagon to insulin increases. Glucagon primarily acts on hepatocytes, directly stimulating glycogenolysis, gluconeogenesis, FFA oxidation, and ketogenesis.
39.3B ). TGs within adipocytes undergo lipolysis to FFAs and glycerol, and there is a general net proteolysis with the release of AAs during the fasting state. The glycerol and gluconeogenic AAs are released from cells and circulate to the liver, where they are subsequently used for gluconeogenesis. Thus gluconeogenesis requires an integration of catabolic pathways in adipocytes and skeletal myocytes with anabolic gluconeogenesis in hepatocytes. Gluconeogenesis eventually supplants glycogenolysis and can continue as long as precursors flow into the liver.
Glucose sparing represents the other general process that contributes to maintenance of adequate circulating glucose levels during the fasting phase. Glucose sparing means the switching of fuel utilization from glucose to a nongluconeogenic fuel in most cell types, but especially in skeletal muscle, which represents the potentially largest single consumer of glucose. First, the uptake of glucose by skeletal muscle and adipocytes is greatly reduced because the GLUT4 transporter isoform exists in an intracellular
CHAPTER 39 Hormonal Regulation of Energy Metabolism
Fig. 39.3B) during the fasting phase.
Thus alternative fuels need to be delivered to skeletal muscle and adipocytes.
The nongluconeogenic fuels (i.e., cannot be used for gluconeogenesis by the liver) are FFAs and KBs. FFAs are
Fig. 39.3B are also released after packaging of intrahepatic TGs into cussed later). KBs are produced by hepatocytes from acetyl
CoA, which in turn originates from FFAs and ketogenic
AAs, both of which become abundant during the fasting phase. Thus glucose sparing depends on catabolic adipocyte metabolism, which results in lipolysis of stored TGs and release of FFAs. FFAs are imported by hepatocytes, which use FFAs to produce acetyl CoA. Protein degradation in available for ketogenesis. High levels of intramitochondrial acetyl CoA in the hepatocyte not only provides ample carbons for ATP synthesis but serves to: (1) inhibit conver sion of pyruvate to acetyl CoA, (2) promote conversion of pyruvate to oxaloacetate for gluconeogenesis, and (3) promote synthesis of KBs (see
Fig. 39.3B ). After several days of fasting, the CNS can start using KBs for energy, thereby further sparing glucose for erythrocytes. Many other cell types with mitochondria use KBs along with FFAs for ATP production, especially skeletal muscle.
The hormones that drive glycogenolysis, gluconeogen esis, lipogenesis, and hepatic ketogenesis as well as VLDL production by the liver during the fasting phase are glucagon and catecholamines. In the presence of low glucose, insulin levels fall, and that removes the inhibition by insulin of the secretion of another pancreatic hormone, glucagon. Thus diminished blood glucose causes a rise in the circulating glucagon-to-insulin ratio. Hepatocytes are the primary target organ of glucagon, which directly drives glyco genolysis, gluconeogenesis, FFA oxidation, and ketogenesis by the hepatocyte (
Fig. 39.5B).