1、Energy-Related Hormones Dianzheng Zhang, Ph.D. Objectives:1. To understand what the energy-related hormones are and their roles in the normal functioning human body.2. To learn the specific actions of representative hormones.3. To appreciate the higher-order interactions between hormones which resul

2、t in the complexities of functions.NOTE: Hormones, Part 1 was given in SPOM.Outline:Some hormones act in metabolism and affect energy levels:A. Insulina peptide hormone B. Glucagona peptide hormone C. Epinephrinean amine hormone D. Hormones affecting appetite (for example, leptin), SecretagoguesRefe

3、rences:Voet & Voet, Biochemistry, 3rd Ed., Chap. 27, Energy Metabolism: Integration and Organ Specialization.Champe & Harvey, Biochemistry, 3rd Ed., Chapter 23Marks Basic Medical Biochemistry, Ed. 1. Chap.43, 44, 45.Harpers Illustrated Biochemistry, 26th Ed., Chap. 42, 43.1. Metabolic intera

4、ctions among the major fuel-metabolizing Fig 1. Metabolic interactions between different organsBrain: the most fastidious and voracious organ: need consistentglucose supply; adapted to ketone bodies if necessaryHeart: less fastidious than brain: can use fatty acids, ketone bodies andlactate for ener

5、gy suppliesMuscle: relative flexible in terms of fuel usage: Fatty acids are the major fuel source at resting, and glucose from glycogen storage is used at earlier stage of exertion, then turn to fatty acids as dominant fuelsLiver: most flexible, and plays major role in keeping stable blood glucose

6、levelIntestine: the organ responsible for the digestion and absorption of nutrients for the needs of different organismsBlood: the super highway for transportation and balance of the nutrients2. Pancreas plays pivotal roles in regulation of energy metabolisms Exocrine: Synthesizing and secreting dig

7、estive enzymes (95-98% of pancreatic mass)TrypsinogenChymotrypsinogenPancreatic lipaseAmylaseEndocrine: formed by the Islets of Langerhans (2-5% of the pancreatic mass)Insulin (beta cells)Glucagon (alpha cells)Gastrin and somatostatin (delta cells)Pancreatic polypeptide (F cells)Fig. 2. Blood supply

8、 to and cell distribution of the Islets of Langerhans. Alpha cells secrete glucagon and are located at the periphery of the islet. Beta cells secrete insulin, and are found in the core.Delta cells produce gastrin and somatostatin. F cells secrete pancreatic polypeptide, that inhibits somatostatin. (

9、Kierszenbaum, Histology and Cell Biology, 2002, Fig. 19.6, p. 521)A. Insulin1. Synthesis and secretionPeptide hormones are synthesized like any other secretory proteins which are secreted from the cell. The synthesis of insulin in the pancreatic beta cells is a typical example. Mature insulin consis

10、ts of two disulfide-bonded polypeptides: A-chain with 21 amino acids and B-chain with 30 amino acids. Proinsutin is the precursor of insulin, which also contains the connecting peptide, is shown in Figure1. Fig. 3. Structure of human proinsulin Greenspan & Gardner, Basic & Clin. Endocrin., f

11、ig. 18-3 Proinsulin is derived from preproinsulin, a single peptide with a 24 amino acid signal sequence at the N-terminus, which is responsible for directing the newly synthesized peptide to the granular endoplasmic reticulum (ER). The signal peptide is removed by signal peptidase in the ER to form

12、 proinsulin. Proinsulin is transported to the Golgi, where the connecting peptide (also known C-peptide) is cleaved off and the mature insulin is packed, together with the C-peptide, in the secretary granules ready for secretion. Equal number of the C-peptide and mature insulin is packed and release

13、d into the blood stream. The serum C-peptide levels can be used to assess the pancreatic beta cell function. Because of its importance in regulation of metabolism, insulin is a well-conserved peptide hormone during the evolution. Therefore, both porcine and bovine insulins have, and continuously, be

14、en used in treatment of human diabetics with little immunological concerns. The synthesis, maturation and secretion processes of insulin are summarized in Figure 4. Fig. 4. Synthesis and secretion of a peptide hormoneGreenspan & Gardner, Basic & Clin. Endocrin., fig. 18-22. Regulation of ins

15、ulin synthesis and secretion, Fig 5. GluT2 senses the blood glucose levels and enhance glucose transportation to pancreatic -cells Subsequent Increased glucose catabolism and ATP synthesis Close K+ channel and open Ca+ channel Ca+ influx Results in Insulin secretion and synthesis (regulated mainly o

16、n the transcriptional levels) Fig. 5 Regulation of insulin secretion3. Ways of insulin signaling pathwaysProtein hormones dont pass through the cell membrane. Instead, they must act through a receptor on the surface of the target cells, effecting changes in the cell through second messengers and sig

17、nal transduction pathways.The insulin receptor is a heavily glycosylated tetramer consisting of two subunits (a and b) in the typical configuration of a2b2. The a subunit is entirely extra-cellular and binds insulin. The b subunit is equipped with enzymatic activitytyrosine kinase activity in its cy

18、toplasmic portion (Fig 6). Insulin binds insulin receptor leading to GluT4 plasma membrane translocation Glucose influx Glucose catabolism Glycogen synthesis (liver and muscles) Fig. 6 biological effects of insulin Fatty acids synthesis (liver and adipocytes) 4. Insulin actions and effectsInsulin ma

19、inly exerts its effects on liver, muscle and adipose tissues: increase glycolysis and enhance syntheses of glycogen, protein, DNA, RNA and triacylglycerol. Thus, insulin is also considered as a growth hormone.Table 1, Biological and physiological actions of insulinThe metabolic effects of insulin ex

20、erted on these tissues are summarized in the Table 2. Note, as a glucagon antagonist, insulin acts by promoting the dephosphorylation of phosphofructokinase-2/fructose-2, 6-bisphosphatase, thereby increasing the level of fructose-2, 6-bisphosphate which is a key regulator of glycolysis/gluconeogenes

21、is pathways.Table 2, metabolic effects of insulin on different tissuesGerhard Meisenberg and William H. Simmons, Principles of Medical Biochemistry, 2nd Edition, Table 30.1B.GlucagonTogether with insulin, Glucagon plays important roles in maintaining normal blood glucose levels. Fig. 7. Greenspan &a

22、mp; Gardner, Basic & Clin. Endocrinology, pp. 631, Fig. 18-51. Synthesis and secretion¨ Similar to insulin, glucagon is derived from proglucagon peptide encoded by the preproglucagon gene ¨ Glucagon is synthesized and secreted by the a-cells of the islets of Langerhans when the blood g

23、lucose levels fall¨ Proglucagon is a 160 amino acid protein, which is cleaved during processing in the pancreas alpha cells to several peptides, including the 29-amino acid glucagon . ¨ L-cells in the gut also synthesize peptides from the same gene by alternative splicing: glicentin, glice

24、ntin related polypeptide (GRPP), oxyntomodulin, and glucagon like peptide (GLP-1 and GLP-2) (Fig. 7), and the functions of these peptides are not clear Glucagon secretion is stimulated by: § Amino acids and derivatives (especially Arginine and Alanine) § Catecholamines (see later in this l

25、ecture, epinephrine) § Cholecystokinin (CCK) Glucagon secretion is inhibited by:§ Glucose § Insulin o Due to the spatial arrangement of a- and b-cells in the islets, insulin secreted from the b-cells passes by and acts on the a-cells (paracrine effects) before reachingto the distant t

26、issues through the Fig. 8 Insulin and glucagons blood stream (endocrine effects) secretion Greenspan & Gardner, Basic & Clin. Endocrinology, pp. 630-1o The “paracrine effect” of insulin on a-cell is inhibiting glucagon secretion (Fig. 8)2. Glucagon signaling pathway· Glucagon functions

27、through a glucagon receptor (predominantly on liver cells)· Glucagon receptor is a member of the G-protein coupled receptor (GPCR) family· GPCRs are membrane-integrated proteins associate with G-proteins· G-proteins contain three subunits (a-,b-, and g-subunit)· Without ligand, t

28、he a-subunit binds with a GDP, and the G-protein is inactive· Binding of glucagan: o Induces a conformational change of the receptoro The a-subunit dissociates fromb/g-subunits o The a-subunit releases GDP and binds GTPo GTP-bound a-subunit activates adenylate cyclaseo Adenylate cyclase catalyz

29、es the synthesis of cAMP from ATPo The cAMP binds the regulatory subunit (R) of protein kinase A (PKA)o The cAMP binding of R-subunit releases the catalytic subunits (C)o The C-subunits of PKA phosphorylates target proteins+4 cAMP Protein Kinase AFig. 9. Action of Glucagon. Glucagon binds to Glucago

30、n receptor, thus signaling through the second messenger, cyclic AMP, to Protein Kinase AFrom Marks, Basic Med. Biochem., Fig. 43-13, p. 682 and Murray et al. Harpers Biochem. Fig. 44-5, p. 493Note: both Glucagon and Epinephrine act in a similar way by using cAMP to activate PKA.3. Glucagon Effects o

31、n Target Cells“In contrast to insulin, which promotes energy storage in a variety of tissues, glucagon is a hormone making energy available to the tissues between meals, when ingested food is not available for absorption.” As shown in Fig 10.The metabolic effects of glucagons on the LIVER are summar

32、ized in the following table. Note: (1) both the enzyme phosphorylations and the effects on gene expression are mediated by cAMP; (2) The activated gluconeogenesis and repressed glycolysis switch is mediated by the cAMP-dependent phosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase an

33、d decreased cellular concentration of fructose-2,6-bisphosphate.Fig. 10 biological effects of glucagon Greenspan & Gardner, Basic & Clin. Endocrinology, pp. 630-1 Table 3: The metabolic effects of glucagons on the liverGerhard Meisenberg and William H. Simmons, Principles of Medical Biochemi

34、stry, 2nd Edition, Table 30.24. Regulation of blood glucose levels by insulin and glucagons The ratio of insulin to glucagon affects key target tissues by mediating phosphorylation or dephosphorylation (either or both) of key enzymes affecting nutrient metabolism. In addition, this ratio increases o

35、r decreases actual quantities of certain enzymes, thus controlling the flux of these nutrients into or out of storage (Fig 11). During long-term fasting and after the depletion of liver glycogen, net protein breakdown is required to supply amino acids for gluconeogenesis. More importantly, during lo

36、ng-term fasting plasma ketone bodies concentration increased dramatically as shown in Fig 12.Fig. 12 Plasma levels of hormones and nutrients during fasting Gerhard Meisenberg and William H. Simmons, Principles of Medical Biochemistry, 2nd Edition, Fig. 30.1The most important hormonal regulation of b

37、lood glucose is the balance between insulin and its antagonists, especially glucagons. During fasting, the plasma level of insulin falls, whereas first epinephrine, then glucagons, and finally cortisol levels rise. After two days of fasting, glucose levels reduced dramatically, and then stabilized.

38、However, free fatty acid, especially the ketone bodies increase continuously to support the energy requirements of heart and brain tissues. C. Catecholamines (Amine hormones) and metabolisms1.Synthesis and secretion2.Ways of signaling3.Effects on target cells 1. Synthesis The catecholamines (dopa, d

39、opamine, norepinephrine and epinephrine) are synthesized from the amino acid tyrosine. Epinephrine is synthesized mainly in the adrenal medulla.2. Secretion and physiological effect Adrenal medullary catecholamine secretion is increased by stressful stimuli (exercise, angina pectoris, myocardial inf

40、arction, hemorrhage, surgery, hypoglycemia, anoxia, asphyxia, and many more). Epinephrine plays a central role in the short-term stress reactionthe physiological response to threatening, exciting or environmental stresses through the hypothalamic-pituitary-adrenal axis After released to the circulat

41、ion, catecholamines bind to albumin or closely associated protein with low affinity and high capacity Fig. 13. Synthesis of catecholamines from tyrosineSchumm, Essentials of Biochemistry, Fig. 25-9, p. 2923. Ways of signaling· The catecholamines exert their physiologic effects by activating sig

42、naling pathways in their target cells · The family of adrenergic receptors is transmembrane proteins, each with seven hydrophobic regions which spans the cell membrane· Different receptors have different effects· All Beta-type receptors á cAMP, and activation of PKA· Epineph

43、rine is much more potent on beta2-type receptors than is norepinephrine· The signal transduction cascade of b2 receptors is essentially identical to that of the glucagon receptor (see earlier sections). Fig. 14. Human b2-adrenergic receptorMetzler, Biochemistry, Fig. 11-6, p. 5554. Epinephrine

44、effects on glucose metabolisms Inhibit insulin secretion and enhance glucagon secretion Muscle has only receptors for epinephrine Activates adenylate cyclase and increase cAMP Increases glycogenolysis and reduce glycogen synthesis Liver has receptors for both glucagon and epinephrine Together with g

45、lucagons, decrease glucose uptake and increase glucose release increase blood glucose levels Epinephrine effect is quick and short-livedThe effects of norepinephrine and epinephrine have been summarized in the following table. Note the catecholamine effects are exerted either directly by enzyme phos

46、phorylation or indirectly by phosphorylation of phosphofructose-2/fructose-2, 6-bisphosphatase Metabolic effects of norepinephrine and epinephrine (Table 4)Gerhard Meisenberg and William H. Simmons, Principles of Medical Biochemistry, 2nd Edition, Table 30.3Note: The effects of epinephrine on liver

47、and skeletal/heart muscle glycolysis are opposite. Although epinephrine activates protein kinase A in both tissues, the effects of phosphorylation of the downstream enzymes (i.e. phosphofructokinase-2 and fructose2, 6 bisphosphatese) are different. D. Cortisol and other GlucocorticoidsDuring chronic

48、 stress, the hypothalamus of the brain releases corticotrophin releasing factor, which stimulates the secretion of adrenaocorticortropin hormone (ACTH) from the anterior pituitary gland. ACTH then stimulates the secretion of cortisol and other corticoids from the adrenal cortex. · Functional, g

49、lucocorticoids synergize with epinephrine, but there is an important difference. · Epinephrine works through induction of cAMP, whereas the glucocorticoids act through regulation of target gene expression. · Therefore, epinephrine induces its effects in a matter of seconds, but the glucoco

50、rticoid effects are cumulative over hours to days. · The important metabolic actions of cortisol and other corticoids are summarized in the following table.Table 5: Metabolic actions of cortisol and other glucocorticoids Gerhard Meisenberg and William H. Simmons, Principles of Medical Biochemis

51、try, 2nd Edition, Table 30.4E. Appetite-affecting Hormones and Secretagogues Leptin: A hormone affects appetite and weight Deletion of the gene corresponding to the leptin in mice results in obesity The leptin gene is also known as obesity (OB) gene Leptin is mainly synthesized in adipocytes Its syn

52、thesis and secretion is proportional to fat storage Leptin inhibits appetite and enhances energy expenditure, therefore against obesity Leptin receptor: A membrane protein enriched in the hypothalamus Deletion of this gene in mice leads to diabetes (DB) Thus it is also known as DB gene I Interesting

53、ly, the DB mice also develop into obesity DB involved regulation of appetite, energy expenditure and weight control Parabiosis experiments revealed some intriguing findings: Finally, it has been confirmed that OB gene encodes the leptin protein which serves as a hormone and the DB gene encodes a pro

54、tein serves as the leptin receptor Together, they control both appetite and energy expenditure Many different hormones control our body weight and appetite. A new and fascinating area of active research is in the neuroendocrine system, in which circulating hormones convey information about energy ba

55、lance (the difference between energy intake and expenditure) to brain pathways that control eating and energy output. Schwartz, M.W. & G.J. Morton (2002) Keeping hunger at bay. Nature 418:595-7There are many ways of classifying hormones that regulate food intake:· Those that act rapidly to

56、influence individual meals. Examples:o Cholecystokinin § released from small intestine during eating§ promotes sense of fullness§ releasing of bile and digestive enzymes from pancreaso Ghrelin § Secreted from cellslining the stomach§ levels rise just before meals when stomach is empty§ stimulating appetiteo Peptide YY (PYY), a 34 AA peptide, secreted fromthe endocrine cells linin