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

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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 regulation Student 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 Glycogenolyis

Anabolic

Insulin

↑↑ ↓↓ ↓↓

Counterregulatory

Glucagon - ↑↑ ↑↑

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 β-cells suppresses

secretion of glucagon from α-cells.

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II. Glucagon Glucagon

• Major insulin counterregulatory hormone

• Produced as preglucagon in α−cells of pancreas

• 4 peptides in tandem:

Glicentin-related peptide Glucagon

glucagon-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 δ 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 Gα; 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, Ca

^2+-

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

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GHRH and GHRIH

GHRH stimulates release of growth hormone:

• Somatocrinin

• 40-, 44-aa peptides

• Multiple signaling paths

•

cAMP, Ca

^2+-

calmodulin GHRIH inhibits release:

• Somatostatin

• Binds G-coupled receptors

•

Inhibitory Gα

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: 6α, 3 β:

β receptors work through G-protein coupled, adenylyl cyclase, cAMP, PKA

α

receptors G-protein coupled, PIP

2

-Ca

²⁺

signal transcduction (Fig. 28.10)

• Different receptors on different tissues

• Mobilize fuels

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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 α-adrenergic and

β-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

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Thyroid hormone (TH)

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

• T

3

and T

4

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 T

₄

:T

₃

• Synthesis stimulated by TSH in anterior pituitary

• TSH stimulates release T

1/2

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, Ca

²⁺

• T

3

& T

4

secreted from thyroid

• T

3

inhibits release of TSH, TRH

Physiological effects thyroid hormone Normal TH affects fuel metabolism:

Liver: carbohydrate, lipid metabolism

•

Increase glycolysis, cholesterol synthesis

•