1. 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

2. 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

3. Table 1 Major hormones affecting fuel metabolism
Glucose uptake Glucose output Glycogenolyis
Anabolic
Insulin ↑↑ ↓↓ ↓↓
Counterregulatory
Glucagon - ↑↑ ↑↑
Epinephrine - ↑↑ ↑↑ initial
Glucocorticoid ↓ ↑ -
Growth hormone ↓ ↑ -
Thyroid hormone - ↑
Somatostatin

4. Effects on fuel metabolism
I. Insulin
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 b-cells suppresses secretion of glucagon from a-cells.

5. Glucagon II. Glucagon Major insulin counterregulatory hormone
Produced as preglucagon in a-cells of pancreas
4 peptides in tandem:
Glicentin-related peptide
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

6. Somatostatin: (growth hormone release-inhibiting hormone)
III. Somatostatin
Somatostatin: (growth hormone release-inhibiting hormone)
Preprosomatostatin is 116 aa
Final cyclic 14-aa peptide (SS-14);
From hypothalmus, also secreted d 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 Ga; not stimulate cAMP
Fig. 3

7. 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)
Fig. 1

8. 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

9. GHRH stimulates release of growth hormone: Somatocrinin
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 Ga
Fig. 3

10. Anabolic effects of growth hormone
Multiple anabolic effects of growth hormone:
Broad effects on energy metabolism
Uptake, oxidation of fuels
Fig. 4

11. Production, activity of IGFs
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
Fig. 5

12. III C. Epinephrine, norepinephrine
Catecholamines epinephrine, norepinephrine
Neurotransmitters or hormones
Stress hormones increase fuel mobilization
Tyrosine precursor
Adrenergic receptors
9 different receptors: 6a, 3 b:
b receptors work through G-protein
coupled, adenylyl cyclase, cAMP, PKA
a receptors G-protein coupled, PIP2-Ca2+
signal transcduction (Fig )
Different receptors on different tissues
Mobilize fuels
Fig

13. Catecholamines (focus on epinephrine): Bioamines, stress hormones
Also norepinephrine, dopamine
Synthesis in adrenal medulla
Act via a-adrenergic and
b-adrenergic receptors
(Ch. 26,28)
Fig. 6: Epinephrine stimulates fuel metabolism, pancreatic endocrine function.
Also stimulates glucagon release to reinforce effects; inhibit insulin

14. Cortisol is major Glucocorticooid: Neural and endocrine signals:
Glucocorticoids (GC)
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)
Fig. 7

15. Effects of Glucocorticoids (GC)
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)
Fig. 8 fuel metabolic effects

16. 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

17. E. Thyroid hormone (TH) is derived from tyrosine:
T3 and T4 made in thyroid acinar cells
signal by binding intracellular nuclear receptors
Fig. 9

18. Formation of thyroid hormone
Formation of thyroid hormone (TH):
Protein thyroglobulin secreted into colloid space
Iodination, coupling
Pinocytosis
Digestion by lysosomes
~ 10:1 T4:T3
Synthesis stimulated by
TSH in anterior pituitary
TSH stimulates release
T1/2 days in plasma
Fig. 10

19. 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
Fig. 11

20. 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)

21. F. GI hormones affect fuel metabolism
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
Fig. 12

22. 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)

23. Review question
Review question.
3. A dietary deficiency of iodine will lead to which of the following?
A direct effect on the synthesis of thyroglobulin on ribosomes
An increased secretion of thyroid-stimulatory hormone (TSH)
Decreased production of thyrotropin-releasing hormone (TRH)
Increased heat production
Weight loss