Lehninger Principles of Biochemistry Fourth Edition Chapter 23: Hormonal Regulation and Integration of Mammalian Metabolism Copyright © 2004 by W. H. Freeman & Company David L. Nelson and Michael M. Cox

Chapter Outline Learn the diverse structures and functions of hormones Learn how different tissues divide labor Learn how hormones regulate fuel metabolism Learn how our body regulate body mass

The diverse structures and functions of hormones

The way hormone get to their target tissues Endocrine: blood Paracrine: diffusion through extracellular space Autocrine: no

Major classes of hormones (p. 886, table 23-1) Peptide hormone – glucacon, insulin, TSHinsulinTSH Catecholamine - epinephrineepinephrine Eicosanoids - prostaglandinprostaglandin Steroid - cortisolcortisol Calcitriol Retinoid – retinoic acidretinoic acid Thyroid Nitric oxide

TSH (thyrotropin-releasing hormone)

Insulin are highly concentrated in secretory vesicles

Catecholamines are highly concentrated in secretory vesicles

Eicosanoids are produced when needed Prostaglandin E1 They are paracrines.

Steroids act through nuclear receptors

Vit. D activates an intestinal Ca 2+ binding protein

RA regulates growth and differentiation by nuclear retinoid receptors

Thyroid hormones act through nuclear receptors

NO is synthesized from arginine Arginine + 1 ½ NADPH + 2O 2  NO + citrulline + 2H 2 O +1 ½ NADP + This reaction is catalyzed by NO synthase, which is found in many tissues and cell types.

How different tissues divide labor

Sugar metabolism in Liver

Amino acid metabolism in liver Glucose-alanine cycle Between meals or prolonged fast

Fatty acid metabolism in liver excess Phospholipids, TG Adipose tissue (bound to serum albumin) Heart & smooth muscle Citric acid cycle Membrane synthesis

Adipose tissues Adipose tissue typically makes up about 15% of the mass of young adult human, with approximately 65% of this mass in the form of triacylglycerols.

glucose pyruvate Acetyl-CoA Fatty acids TAG [ATP] lipase FA epinephrine insulin Adipose tissue FA

Slow-twitch and Fast-twitch muscle Slow-twitch (red) muscle: rich in mitochondria, very dense networks of blood vessels; low tension but highly resistant to fatigue Fast-twitch (white) muscle: fewer mitochondria, less blood vessels; greater tension but quicker to fatigue The ratio of red/white muscle in any individual is genetically controlled.

Muscle mM

Creatinine kinase reaction

3 Glycogen  G 6-P  pyruvate Spend one less ATP Muscle- liver cooperation

Heart muscle Half of the volume of heart muscle is consisted of mitochondria. Fuel: free FA, glucose and ketone bodies

(blood glucose) Brain (  -hydroxybutyrate)    muscle protein gluconeogenesis

How hormones regulate fuel metabolism

Insulin secretion in pancreas

glycogen The well-fed state

The fasting state [Glucose] blood Activate -glycogen phosphorylase -gluconeogenesis (FPBase-1, PEP carboxykinase) Inactivate -glycogen synthase -glycolysis (PFK-1, pyruvate kinase)

Epinephrine : a stress hormone

Cortisol : another stress hormone Cortisol alters metabolism by changing the kinds and amounts of certain enzymes synthesized in its target cell. Cortisol restore blood glucose level and increase glycogen stores Cortisol –Increase adipose tissue fatty acids release from stored TAGs –Increase muscle protein breakdown and export of amino acids –Increase liver gluconeogenesis by stimulating PEP carboxykinase synthesis

Diabetes mellitus Diabetic patients cannot take up glucose efficiently from the blood (GLUT4) Excessive and incomplete oxidation of fatty acid in the liver Acetyl-CoA cannot be completely oxidized by citric acid cycle because of high [NADH]/[NAD+] levels, and accumulation of acetyl-CoA leads to overproduction of ketone bodies.

Acetone is produced spontaneously by ketone bodies in diabetic patients The odor of acetone is often mistaken as alcohol. Ketone bodies will overwhelm the capacity of blood ’ s bicarbonate buffering system  ketoacidosis.

Obesity and the regulation of body mass

The Lipostat theory A feedback signal originating in adipose tissue influencs the brain centers that control eating behavior and activity. Leptin (produced by adipocyte) and leptin receptors (arcuate nucleus of the hypothalamus).

Lack of leptin make mice in a constant state of starvation

Arcuate nucleus

fat-STATs (STATs 3,5,6)