Transcript The Cell, 5e

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
↑↑
↓↓
↓↓
↓
↓
-
↑↑
↑↑
↑
↑
↑
-
↑↑
↑↑ initial
-
Counterregulatory
Glucagon
Epinephrine
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 b-cells suppresses
secretion of glucagon from a-cells.
II. Glucagon
Glucagon
• Major insulin counterregulatory hormone
• Produced as preglucagon in a-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
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
Growth hormone
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
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 Ga
Fig. 3
Anabolic effects of growth hormone
Multiple anabolic effects of growth hormone:
• Broad effects on energy metabolism
• Uptake, oxidation of fuels
Fig. 4
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
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. 28.10)
• Different receptors on different tissues
• Mobilize fuels
Fig. 26.13
Epinephrine
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
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
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
Signal transduction by cortisol, intracellular receptors
Cortisol and thyroid hormone bind
intracellular receptors:
• Binding of hormone causes hormonereceptor 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
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
Regulation of TH levels
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
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
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
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
ribosomes
b. An increased secretion of thyroid-stimulatory hormone
(TSH)
c. Decreased production of thyrotropin-releasing hormone
(TRH)
d. Increased heat production
e. Weight loss