Metabolic Integration 1: Metabolic profiles of major organs, signaling and homeostasis, adaptations to starvation

1. Metabolic Integration 1:Metabolic profiles of major organs, signaling and homeostasis, adaptations to starvation Bioc 460 Spring 2008 - Lecture 40 (Miesfeld) Insulin hormone is a key regulator of glucose homeostasis and is produced by pancreatic  cells Eicosapentaenoic acid (EPA) is an omega-3 fatty acid that stimulates PPAR activity Visceral fat (apple shape) is associated with a higher risk of cardiovascular disease than subcutaneous fat (pear shape)

2. Key Concepts in Metabolic Integration • Metabolic homeostasis is a physiological state in which metabolite levels are maintained by regulatory systems acting on multiple tissues in the organism. The hormones insulin and glucagon maintain glucose homeostasis in blood. • The liver is the central processing facility and metabolic hub in the human body. Its main functions are to manage nutrient levels that enter the liver through the portal vein, and to detoxify harmful substances in the circulatory system. Glucose-6P is a key metabolite in the liver that has many different fates. • Adipose tissue is not only a energy storage depot, but it is also an endocrine organ that plays a major role in controlling fatty acid homeostasis. The recently discovered PPAR regulatory proteins control many aspects of lipid metabolism. • The two major metabolic adaptations to starvation are an increase in gluconeogenesis to supply glucose to the brain and red blood cells, and a switch to dependency on fatty acids as the major energy source for most tissues.

3. Metabolic Profiles of Major Organs The three major sources of metabolic fuel in our diets are carbohydrates, lipids (fats) and protein which contribute directly to ATP production. The five major energy conversion processes responsible for fuel utilization are: 1) carbohydrate metabolism 2) lipid metabolism 3) amino acid metabolism 4) the citrate cycle 5) oxidative phosphorylation.

4. Metabolic Profiles of Major Organs

5. What biochemical mechanisms determine G6P flux through these pathways? Metabolic functions of the liver Glucose-6P has several fates depending on the metabolic needs of the liver and other tissues. Most of the glucose-6P is used to either synthesize liver glycogen, or it is dephosphorylated and released into the blood to be used by other tissues. Two other fates of glucose-6P are the pentose phosphate pathway for NADPH generation, and conversion to precursors for lipid synthesis.

6. Metabolic functions of skeletal muscle During the resting state, skeletal muscle primarily uses fatty acids released from adipose tissue as a source of energy. The fatty acids are oxidized to generate acetyl-CoA which is then used by the citrate cycle to produce reducing power (NADH and FADH2) for oxidative phosphorylation. However, when muscle contraction is required for a very short burst of activity, the exercising muscles make use of the intracellular ATP pool.

7. Metabolic functions of skeletal muscle If a more sustained level of muscle activity is needed, such as a short sprint across the tennis court to return a serve (3-8 seconds), then the ATP pool is replenished with ATP made by a phosphoryl transfer reaction using phosphocreatine. The creatine kinase reaction is readily reversible and catalyzes the resynthesis of phosphocreatine when cellular ATP levels return to normal during muscle recovery.

8. Metabolic functions of adipose tissue Adipose tissue was once thought of as a simple fat depot in the body that stores and releases fatty acids from adipocytes (fat cells) in response to metabolic needs. It is now known to be an active player in metabolic integration serving as an endocrine organ that secretes peptide hormones called adipokines (adipocyte hormones). Adipokines are key regulators of metabolism and control important immunological, neurological and developmental functions in the body. There are two major types of fat. One is subcutaneous fat that is located just below the skin surface, most noticeable in the thighs, buttocks, arms and face. The other is visceral fat which lies deep within the abdominal cavity and is responsible for the size of your waistline.

9. Metabolic functions of adipose tissue One way to predict if someone has too much body fat is to determine their body mass index (BMI) using a ratio of their weight and height. Body Mass Index (BMI) = weight (kg)/[height (m)]2 It is generally accepted that a BMI value of less than 18.5 is considered underweight, 18.5-25 is within the normal weight range, 25-30 is overweight, and greater than 30 is obese. Find your approximate BMI on this chart using your height and weight (no math required).

10. Metabolic functions of adipose tissue BMI values do not provide information about the relative amounts of visceral fat and subcutaneous fat stores. Because adipokines produced in visceral fat contribute to the development of obesity-related diseases, one of the best ways to predict an individual's disease risk is to use both their BMI value and the circumference of a their waist in relationship to the size of their hips. By determining a person's waist to hip ratio (WHR), it is possible to obtain an approximate measurement of the relative amounts of visceral and subcutaneous fat stored on their body. A high WHR value corresponds to an "apple-shaped" body (more visceral fat in the waist than subcutaneous fat on the hips), whereas, a low WHR value leads to a "pear-shaped" body.

11. An explanation for CVD risks in people with a high WHR is that increased amounts of visceral fat alters the expression of certain adipocyte hormones such as leptin, tumor necrosis factor  (TNF-), and adiponectin. Body Mass Index (BMI) = weight (kg)/[height (m)]2

12. Metabolic functions of adipose tissue Adipose tissue is responsible for regulating the triacylglycerol cycle which is an inter-organ process that continuously circulates fatty acids and triacylglycerols between adipose tissue and liver. There are two parts to the triacylglycerol cycle, 1) the systemic component that recycles fatty acids released from adipose tissue, and 2) the intracellular component that recycles fatty acids that enter adipocytes following triacylglycerol hydrolysis. What might be the metabolic logic of maintaining circulating fatty acids even though 75% of it is returned to the adipose tissue and stored?

13. Metabolic functions of the brain The brain is the control center of our bodies, consisting of 100 billion nerve cells (neurons) that transmit electrical information along the neuronal axon using action potentials that are driven by changes in charge distribution across the plasma membrane. Left brain is the time to go to work center, the right brain is the time to party center. Blood glucose is distributed to neurons through microcapillaries.

14. Metabolic functions of the brain About 20% of the oxygen consumed by the body is used for oxidative phosphorylation in the brain. The brain requires as much as 120 grams of glucose each day which accounts for 60% of the glucose used by our bodies under normal conditions. The brain, unlike most other organs, is exclusively dependent on glucose under normal conditions to provide chemical energy for ATP production. Fatty acids cannot cross the blood-brain barrier because they are bound to carrier proteins, however, the energy-rich ketone bodies acetoacetate and D--hydroxybutyrate are able to enter the brain. High rates of glucose metabolism is indicative of neuronal activity

15. A liver-centric view of human metabolism The liver is the control center of this metabolic network and plays a crucial role in regulating metabolite flux between tissues and organs. One of the primary roles of the liver is to export glucose and triacylglycerols to the peripheral tissues for use as metabolic fuel. What are the two metabolic fuels exported by the liver?

16. Metabolic homeostasis and signaling Metabolic homeostasis describes steady-state conditions in the body and can apply to a wide variety of physiological parameters. These include glucose, lipid, and amino acid levels in the blood, electrolyte concentrations, blood pressure and pulse rate. During times of physical activity, psychological stress, or feeding, biochemical processes are altered to counteract the effects of these environmental stimuli in an attempt to return the body to metabolic homeostasis. Regulation of metabolic homeostasis requires both neuronal signaling from the brain and the release of small molecules into the blood that function as ligands for receptor-mediated cell signaling pathways.

17. Insulin and Glucagon Signaling Two of the most important global metabolic regulators in humans are the peptide hormones insulin and glucagon, both of which are secreted by the pancreas. Insulin and glucagon are synthesized as prohormones in a region of the pancreas called the islets of Langerhans. The  cells, which make up the majority of cells in this region of the pancreas, are responsible for insulin secretion, whereas, the  cells secrete glucagon. A third cell type, the  cells, produce somatostatin which is paracrine hormone that functions locally to control the secretion of insulin, glucagon, and digestive proteases.

18. Insulin and Glucagon Signaling ??? Glucagon circulates through the body,why “no effect” in muscle and brain tissue? ???

19. Peroxisome-proliferator activated receptors (PPAR) are recently discovered metabolic regulators First discovered in the early 1990s, the PPAR, PPAR and PPARnuclear receptor proteins are now known to be key players in controlling metabolic homeostasis in humans. However, unlike the insulin and glucagon receptors that rapidly activate intracellular phosphorylation signaling cascades in response to high affinity endocrine hormones, the PPARs function as transcription factors that regulate gene expression in response to the binding of low affinity fatty-acid derived nutrients such as polyunsaturated fatty acids and eicosanoids. This property of PPARs makes them ideal metabolic sensors of lipid homeostasis and results in long term control of pathway flux by directly altering the steady-state levels of key proteins.

20. PPARs are lipid-activated transcription factors

21. PPARs are pharmaceutical targets for diabetes One of the most important functions of PPAR is to control adipocyte differentiation and lipid synthesis in adipose tissue, but it also regulates insulin-sensitivity in all three tissues, as well as, lipid synthesis in liver cells. PPAR is the therapeutic target of thiazolidinediones (TZDs) which improve insulin-sensitivity in type 2 diabetics by activating PPARg target genes involved in lipid synthesis. The PPARs represent an attractive class of protein targets for the development of pharmaceutical drugs for treating human metabolic disease because they control lipid homeostasis in liver and adipose tissue, as well as, regulate glucose metabolism and thermogenesis in skeletal muscle. Diabetics who are treated with TZDs see a drop in blood glucose levels which is good, but they also gain weight. What explains this side effect?

22. PPARs are pharmaceutical targets for diabetes Gemfibrozil is a PPAR-selective fibrate currently in use to treat high cholesterol in patients, and rosiglitazone is a TZD compound that binds with high affinity to PPAR and is used to treat type 2 diabetes. The PPAR-selective agonist GW501516 has been evaluated in human clinical trials for the treatment of atherosclerosis and obesity by altering flux through lipid metabolic pathways.

23. PPARs are pharmaceutical targets for diabetes The ligand binding domain of human PPAR can accommodate the -3 polyunsaturated fatty acid eicosapentaenoate (all cis 20:5 5,8,11,14,17) in either the tail-up or tail-down orientation, indicating that the hydrophobic pocket is shaped like the letter "Y."

24. PPARs are pharmaceutical targets for diabetes The size of the ligand pocked in PPARs was confirmed by the PPAR protein structure shown below where it can be seen that the synthetic PPAR/PPAR agonist GW2433 is able to completely fill the binding ligand-binding pocket.

25. Metabolic Adaptations to Starvation Metabolic adaptation to food shortages has been preserved over evolutionary time to ensure survival during famine. The human body adapts to these near starvation conditions by altering the flux of metabolites between various tissues in order to extend life. The primary metabolic challenge is to provide enough glucose for the brain to maintain normal neuronal cell functions. Although fatty acids released from adipose tissue are plentiful in the blood, the brain cannot use fatty acids for metabolic fuel because they cannot cross the blood-brain barrier. Red blood cells (erythrocytes) are also dependent on serum glucose as a sole source of energy to generate ATP. Mature erythrocytes lack mitochondria and are not able to utilize fatty acids for energy because fatty acid oxidation takes place in the mitochondrial matrix.

26. In order to make up for the loss of liver glycogen after the first 24 hours, the body's metabolism changes in two important ways. flux through the gluconeogenic pathway in the liver and kidneys is increased to generate glucose for the brain and erythrocytes. switch most of the energy needs to using fatty acids as the primary metabolic fuel. This spares whatever glucose is available for the brain and erythrocytes.

27. Metabolic Adaptations to Starvation An average size man of 70 kg contains enough metabolic fuel to live ~98 days without food assuming a minimum energy expenditure of 1700 Calories per day (166,000/1700 = 97.6). The bulk of stored metabolic fuel is in the form of triacylglycerols in adipose tissue which is sufficient to prolong life for 3 months. Protein is the second most abundant stored fuel (14 days worth of energy) which is spared for as long as possible to permit mobility.

28. The four major adaptations are: • Increased triacylglycerol hydrolysis in adipose tissue. • Increased gluconeogenesis in liver and kidney cells. • Increased ketogenesis in liver cells. • Protein degradation in skeletal muscle tissue.