Bioc 460 - Dr. Miesfeld Fall 2008 1 of 14 pages Figure 1. Lecture 39 - Metabolic Integration: Physiology Key Concepts - Metabolic profiles of major organs - Metabolic homeostasis and signaling - Metabolic adaptations to starvation KEY QUESTION IN METABOLIC INTEGRATION: How do the pancreas, liver, skeletal muscle, and adipose tissues control serum glucose levels? Metabolic profiles of major organs We have focused primarily on cellular biochemistry up to this point, now we turn our attention to physiological biochemistry which involves metabolic integration throughout the organism. We will use humans as our organism of choice for this discussion, but of course metabolic integration is critical for all multi-cellular organisms, and even for single cell organisms such as yeast and bacteria which colonize environmental niches and depend on cell-cell communication. The metabolic map in figure 1 has been streamlined to better illustrate how the three major sources of metabolic fuel in our diets; carbohydrates, lipids (fats) and protein, contribute directly to ATP production. This version of the metabolic map emphasizes five energy conversion processes that we have discussed in some detail; 1) carbohydrate metabolism (glycolysis and gluconeogenesis), 2) lipid metabolism (fatty acid oxidation and synthesis), 3) amino acid metabolism (oxidation and synthesis), 4) the citrate cycle, and 5) oxidative phosphorylation. Note that liver cells can perform all of the synthesis and degradation reactions shown in figure 1, however, most other cell types are primarily limited to catabolizing glucose and fatty acids to generate ATP through mitochondrial oxidative phosphorylation reactions. The term energy balance relates energy input in the whole organism to energy expenditure. Positive and negative energy balance is determined by the energy content of the metabolic fuels ingested, compared to the amount of energy expended through endergonic chemical reactions, physical exertion, and thermogenic processes. In the simplest case, energy balance is achieved when energy input measured in kilocalories, also referred to as "food" Calories Body shape is importantBioc 460 - Dr. Miesfeld Fall 2008 2 of 14 pages Figure 2. (1 Calorie = 1 kilocalorie = 4.184 kilojoules), equals energy expenditure on a daily basis. Note that the relative proportions of carbohydrate, fat, and protein in our diets needs to be optimized to prevent metabolic disorders that can occur even under conditions of Caloric energy balance. For example, obtaining too many daily Calories from saturated fats can lead to cardiovascular disease, whereas, excessive amounts of protein can cause nitrogen toxicity due to NH4+ overload. The utilization of various metabolic fuels by different organs in the human body is controlled at the cellular level as a function of nutrient availability. Some of these biochemical processes are developmentally determined (cell-specific expression of required enzymes), while others are controlled more acutely by hormonal signaling through receptor proteins. Two of these hormones are insulin and glucagon which we have discussed numerous times throughout the course. Another important signaling pathway we introduce here is one that controls inter-organ metabolic flux through a subfamily of nuclear receptors known as the peroxisome proliferator-activated receptors (PPARs). The PPARs are a family of transcription factors (PPARγ, PPARα, PPARδ) that regulate gene expression in response to activation by fatty acid-derived ligands. PPARs are targets for a new class of pharmaceutical drugs used to treat metabolic disorders, including type 2 diabetes. Figure 2 shows the location and function of the primary tissues and organs in the human body that play a direct role in metabolic flux. In addition to the liver, muscle (skeletal and heart), adipose, brain and kidney which are described below, several other organs play an important supporting role in metabolic integration. One of these is the pancreas which secretes insulin and glucagon in response to changes in serum glucose levels and also produces a variety of proteasesBioc 460 - Dr. Miesfeld Fall 2008 3 of 14 pages Figure 3. that degrade dietary proteins in the small intestine (trypsin, chymotrypsin, elastase). Also shown in figure 2 is the small intestine which is an critical component of the gastrointestinal tract because it serves as the major site of dietary nutrient absorption. The large intestine or colon, absorbs water and electrolytes and also secretes a neuropeptide called PYY3-36 that controls eating behavior. The stomach prepares food for the small intestine by initiating the digestive process through protein hydrolysis at a low pH in the presence of the protease pepsin. Moreover, the stomach secretes a neuropeptide called ghrelin that sends hunger signals to the brain. Let's look a little more closely at the key metabolic organs in humans. LIVER The liver serves as the central processing facility and metabolic hub of the body by determining what dietary nutrients and metabolic fuels are distributed to the peripheral (non-liver) tissues. The liver also functions as a physiological glucose regulator that helps remove excess glucose from blood when carbohydrate levels are high, and releases glucose from stored glycogen, or as a product of gluconeogenesis, when serum glucose levels are low. Serum glucose regulation by the liver is controlled primarily through the insulin and glucagon signaling pathways which modulate metabolic flux through glycolysis, gluconeogenesis, and glycogen metabolism. With the exception of dietary triacylglycerols that are transported from the small intestine to peripheral tissues by chylomicrons that enter the lymphatic system, most nutrients absorbed in the small intestine are delivered directly to the liver via the portal vein. This anatomy explains why the liver plays such a key role in coordinating the distribution of dietary nutrients as it is the first organ to inventory the contents of your last meal. A large proportion of the dietary monosaccharides delivered by the portal vein are retained by the liver in the form of glucose-6-phosphate following phosphorylation of glucose by the enzymes hexokinase or glucokinase. As shown in figure 3, glucose-6-phosphate has several fates depending on the metabolic needs of the liver and the peripheral tissues. Most of the glucose-6-phosphate is used to
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