Section VIII.

Section VIII. Tissue metabolism

Many tissues carry out specialized functions:

Ch. 43 – look at different hormones affect metabolism of fuels, especially counter-insulin

Ch. 44 – Proteins and cells of the blood

Ch. 45 – Hemostasis and the clotting cascade

Chapt. 43

Ch. 43 hormone regulationStudent Learning Outcomes:• Describe the role of hormones in regulating fuel

metabolism – appetite, absorption, transport, oxidation• Explain the main functions of insulin• Explain the role of glucagon• Describe the role of epinephrine, cortisol,

somatostatin, growth hormone and thyroid hormone

• Describe how these hormones exert control quickly by changes in phosphorylation state of enzyme, and more slowly by changes of gene expression

Table 1 Major hormones affecting fuel metabolism

Glucose uptake Glucose output GlycogenolyisAnabolic Insulin ↑↑ ↓↓ ↓↓

CounterregulatoryGlucagon - ↑↑ ↑↑

Epinephrine - ↑↑ ↑↑ initial

Glucocorticoid ↓ ↑ -

Growth hormone↓ ↑ -

Thyroid hormone - ↑ -

Somatostatin - - -

I. Insulin

I. Insulin:

Effects on fuel metabolism

(Chapt. 26)

• Stimulates storage of glycogen in liver, muscle• Stimulates synthesis of fatty acids and triagcylglyerols and

storage in adipose tissue• Stimulates synthesis in various tissues of >50 proteins• There are insulinlike growth factors I and II (IGF-1, IGF-II)• Paracrine action: release of insulin from -cells suppresses

secretion of glucagon from -cells.

II. GlucagonGlucagon• Major insulin counterregulatory hormone• Produced as preglucagon in cells of pancreas• 4 peptides in tandem:

Glicentin-related peptideGlucagonglucagon-related peptide 1 (GLP-1)glucagon-related peptide 2 (GLP-2)

• Proteolytic cleavage releases various combinations

• Different forms in different tissues• Signals through G-protein-coupled receptor to cAMP and PKA

III. Somatostatin

Fig. 3

Somatostatin: (growth hormone release-inhibiting hormone)

• Preprosomatostatin is 116 aa• Final cyclic 14-aa peptide (SS-14); • From hypothalmus, also secreted cells of pancreas

• In gut, prosomatostatin SS-28 (28-aa) form

• Inhibits release of many hormones:• Growth hormone, TSH, insulin, glucagon,

• 5 receptors, G-protein receptor family – hormone activates inhibitory G; not stimulate cAMP

Growth hormone

Fig. 1

Growth hormone (somatotropin)stimulates growth:• Made in somatotrophs of anterior pituitary• Direct effects on targets, esp. liver, muscle

• GH receptors are cytosine tyrosine kinases (Janus)

• Indirect, induces insulinlike growth factors (IGF)

Control of secretion of growth hormone

Control of secretion of GH:• GHRH stimulates release

• GH-releasing hormone• Binds receptors on somatotrophs• Signals by cAMP, Ca2+-calmodulin

• GHRIH (somatostatin) inhibits release• GH-release inhibiting hormone

• IGF-1 feedback from liver• Insulinlike growth factor

• Plasma levels of fuels also control

• See also Table 2 list

Fig. 2

GHRH and GHRIH

GHRH stimulates release of growth hormone:• Somatocrinin• 40-, 44-aa peptides• Multiple signaling paths

• cAMP, Ca2+-calmodulin

GHRIH inhibits release:• Somatostatin• Binds G-coupled receptors

• Inhibitory G

Fig. 3

Anabolic effects of growth hormone

Fig. 4

Multiple anabolic effects of growth hormone:• Broad effects on energy metabolism• Uptake, oxidation of fuels

Production, activity of IGFs

Fig. 5

GH stimulates release of IGFs (liver)• GH receptor is cytoplasmic tyrosine

kinase type (Janus)• IGFs are somatomedins• Structure similar to insulin

• (insulinlike growth factors)• IGF-1 70 aa; IGF-II 67 aa

• IGFs bind membrane RTKs• Increase cell proliferation

III C. Epinephrine, norepinephrine

Fig. 26.13

Catecholamines epinephrine, norepinephrine• Neurotransmitters or hormones• Stress hormones increase fuel mobilization• Tyrosine precursor

• Adrenergic receptors• 9 different receptors: 6, 3 receptors work through G-protein coupled, adenylyl cyclase, cAMP, PKA receptors G-protein coupled, PIP2-Ca2+

signal transcduction (Fig. 28.10)• Different receptors on different tissues• Mobilize fuels

Epinephrine

Fig. 6: Epinephrine stimulates fuel metabolism, pancreatic endocrine function.Also stimulates glucagon release to reinforce effects; inhibit insulin

Catecholamines (focus on epinephrine):• Bioamines, stress hormones

Also norepinephrine, dopamine

• Synthesis in adrenal medulla• Act via -adrenergic and -adrenergic receptors

(Ch. 26,28)

Glucocorticoids (GC)

Fig. 7

Cortisol is major Glucocorticooid:

‘counterregulatory’, ↑blood glucose

Neural and endocrine signals:• Acetylcholine & serotonin:• CRH = corticotropin-releasing hormone

(midbrain)• ACTH = adrenocorticotropic hormone • Adrenal gland releases cortisol• Cortisol does negative feedback (but

overridden by stress)

Effects of Glucocorticoids (GC)

Fig. 8 fuel metabolic effects

Glucocorticoids (GC) have diverse effects:• bind intracellular receptors, bind DNA, induce

transcription of target genes• Fuel metabolism effects

often stimulate degradation• Also nonmetabolic effects

(Table 3)

Signal transduction by cortisol, intracellular receptors

Cortisol and thyroid hormone bind intracellular receptors:

• Binding of hormone causes hormone-receptor complex to bind specific DNA sequences, increase transcription from target genes.

Figs. 11.7,8

Thyroid hormone (TH)

E. Thyroid hormone (TH) is derived from tyrosine:

• T3 and T4 made in thyroid acinar cells• signal by binding intracellular nuclear receptors

Fig. 9

Formation of thyroid hormone

Fig. 10

Formation of thyroid hormone (TH):• Protein thyroglobulin secreted into colloid space• Iodination, coupling• Pinocytosis • Digestion by lysosomes

• ~ 10:1 T4:T3

• Synthesis stimulated byTSH in anterior pituitary

• TSH stimulates release T1/2 days in plasma

Regulation of TH levels

Fig. 11

Regulation of TH levels:• TRH = thyrotropin-releasing hormone• TSH = thyroid-stimulating hormone

• TSH binds membrane receptor, ↑cAMP• Also through IP3 + DAG, Ca2+

• T3 & T4 secreted from thyroid

• T3 inhibits release of TSH, TRH

Physiological effects thyroid hormone

Normal TH affects fuel metabolism:Liver: carbohydrate, lipid metabolism

• Increase glycolysis, cholesterol synthesis• Increase sensitivity of hepatocyte to gluconeogenic &

glycogenolyticactions of epinephrine

Adipocytes: • sensitizes adipocyte to lipolytic action of epinephrine • also increase availability of glucose to fat cells

Muscle: increase glucose uptake, stimulate protein synthesis

TH can increase heat production by stimulating ATP utilization in futile cycles (increase heat production by uncoupling)

F. GI hormones affect fuel metabolism

Fig. 12

Many GI hormones affect fuel metabolism:• Direct and indirect effects: produced by many tissues (Table 4,5)• GLP-1, glucagonlike peptide; GIP, Gastic inhibitory peptide • CCK, cholecystokinin has indirect effects

Key concepts

Key concepts:• Insulin is major anabolic hormone• Counterregulatory (counterinsulin) hormones include:

• Glucagon• Somatostatin• Growth hormone has diverse roles

• Catecholamine hormones• Cortisol (glucacorticoid) promtoes survival• Thyroid hormones secretion is highly regulated• Intestines and stomach secrete hormones (incretins)

Review question

Review question.3. A dietary deficiency of iodine will lead to which of the

following?a.A direct effect on the synthesis of thyroglobulin on

ribosomesb.An increased secretion of thyroid-stimulatory hormone

(TSH)c.Decreased production of thyrotropin-releasing hormone

(TRH)d.Increased heat productione.Weight loss