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2024-04-26 1 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Body growth- effects by the hypothalamus-pituitary PROFESSOR SUZANNE L DICKSON | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 1 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Robert Wadlow (1918-1940) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 272 cm 1936 Class Photo 2
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2024-04-26 2 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Body growth - general • Body growth - endocrine regulation • What are the effects of the GH-IGF-1 axis? • How is the GH-IGF-1 axis regulated? • What are the mechanisms of action of GH and IGF-1? • What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 3 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ø Body growth - general • Body growth - endocrine regulation • What are the effects of the GH-IGF-1 axis? • How is the GH-IGF-1 axis regulated? • What are the mechanisms of action of GH and IGF-1? • What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 4
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2024-04-26 3 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Organ growth (% of size at age 20) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Size obtained (as % adult size) LYMPHOID BRAIN & HEAD – develop early GENERAL – eg skeleton, muscle REPRODUCTIVE – develop late - puberty Age (years) 5 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Genetic – 80% of an individual’s height is genetically determined • Environment: nutrition, illness, stress
- Food provides energy for growth but also vitamins & minerals.
- Growth is a luxury spared in times of famine.
- Injury and disease stunt growth (catabolic state). Factors that affect growth | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 6
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2024-04-26 4 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Genetic – 80% of an individual’s height is genetically determined • Environment: nutrition, illness, stress Factors that affect growth | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Hormones: growth hormone insulin-like growth factor 1 and 2, insulin thyroid hormones androgens - estrogens glucocorticoids – inhibitory (catabolic) 7 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Growth is not continuous – it is episodic • Periods of physiological rapid growth – In infancy – In late puberty (just before growth stops) Growth in humans | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON % adult height age in years INFANCY CHILDHOOD PUBERTY 5 10 15 20 100 75 50 25 8
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2024-04-26 5 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY “Catch-up” growth: pathophysiological after illness or food restriction | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Illness or Food restriction A Normal Growth B Decline in growth C Hyperanabolic phase D Return to normal growth rate CG= catch-up growth 9 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Catch-up growth in relation to a population of children | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Illness or fasting period Normal Normal 5% 95% Gaussian curve (any age) 50% Recovery From illness 95% 5% 10
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2024-04-26 6 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Growth velocity in boys and girls | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 5 10 15 20 25 0 0 2 4 6 8 10 12 14 16 18 20 Age in years BOYS GIRLS Height gain (cm/yr) Growth spurt Why are men taller? 11 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Body growth - general Ø Body growth - endocrine regulation • What are the effects of the GH-IGF-1 axis? • How is the GH-IGF-1 axis regulated? • What are the mechanisms of action of GH and IGF-1? • What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 12
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2024-04-26 7 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Endocrine control of postnatal growth 5 10 15 20 25 0 0 2 4 6 8 10 12 14 16 18 20 Age in years BOYS GIRLS Height gain (cm/yr) Thyroid hormones Growth hormone à ↑IGF-1 Gonadal steroids Estradiol Testosterone à Estradiol (à ERa à ↑ GH à ↑ IGF-1) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 13 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Induction of growth plate closure by steroids in men and women | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Aromatase E2 TàE2 Same hormones that cause the growth spurt, but later! Females: Estradiol acts on ERa in growth plate. Males: Testosterone à Estradiol acts on ERa in growth plate. 14
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2024-04-26 8 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Responsible for the growth spurt at puberty • Stimulate secretion of GH and IGF-1 • T is more anabolic à more pubertal growth in males. • Body weight: T à ↑muscle mass & E à↑fat deposition. • E more potent than T at level of growth plate • E first stimulates the epiphyseal growth plate but then leads to its closure. Patients with precocious (early) puberty have short stature. Androgens (T) and estrogens (E) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 15 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY u Nutrients (dose response) u Insulin – once beta cells have developed u IGF-1 u IGF-2 u Thyroid hormone u Not GH. Endocrine control of prenatal growth (trimester 2-3) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 16
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2024-04-26 9 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY anterior pituitary GH-N, GH gene (somatotrophs) – pulsatile placenta - GH variant – continuous, 3rd trimester, secretion to mother, not fetus, may increase B-glucose and lipolysis in mother à more nutrients for fetus? Growth hormone (GH) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON In addition 3 human placental lactogen (hPL)= human chorionsomatomammotropin (hCG) genes GH-N (pit) GH-V (pla- centa) Mum ↑GH-Và ↓GH-N hCG Gene clusters Maternal circulation 17 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Human GH protein (192 amino acids, 4 a-helices) must be injected (from GH-N gene). Without GH à proportional dwarf - 110 cm. GH tumour: Giant if not adult. 270 cm. à Wide dose response! (maybe also for IGF-1.) Growth hormone therapy | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON GH structure 18
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2024-04-26 10 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Body growth - general • Body growth - endocrine regulation Ø What are the effects of the GH-IGF-1 axis? • How is the GH-IGF-1 axis regulated? • What are the mechanisms of action of GH and IGF-1? • What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 19 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY What does GH do? (One opnion) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 20
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2024-04-26 11 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY What does GH do? (One opnion) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 21 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH is anabolic, lipolytic and diabetogenic Bone growth direct anabolic Local IGF-1 production Liver-derived IGF1 ? ¯ glucose uptake (insulin resistance) diabetogenic glycogenolysis blood glucose GH anabolic Protein synthesis Amino acid uptake Lean body mass FFAs ¯ fat mass lipolytic | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 22
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2024-04-26 12 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON GH-deficient patient before GH therapy GH-deficient patient after 26 weeks GH therapy Bengtsson et al 1993 J. Clin. Endocrinol. Metab. 76:309 GH therapy reduces visceral adiposity in GH-deficiency 23 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • hGH is banned in professional sport • Usually taken for effects to reduce fat rather than to build muscle. • Health risks similar to those of patients with acromegaly (see later). • Common complaints: bloating, joint inflammation, joint pain, diabetes-like symptoms, injection site reactions, carpal tunnel syndrome, breast development in men, increased risk of cancers GH abuse and doping in sport | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 24
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2024-04-26 13 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Body growth - general • Body growth - endocrine regulation • What are the effects of the GH-IGF-1 axis? Ø How is the GH-IGF-1 axis regulated? • What are the mechanisms of action of GH and IGF-1? • What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 25 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Physiological control of GH secretion GH Exercise Fasting Sleep Aging Stress Arginine Lipids GH/IGF-1 Glucose + + + + _ _ _ _ + Gonadal steroids + | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ghrelin + Cortisol _ 26
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2024-04-26 14 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of GH secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 27 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Nutrient control of GH secretion in relation to GH effects | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Amino acids (Arginine) Lipids (FFA) Glucose GH _ + + + _ _ Pituitary anabolic lypolytic diabetogenic 28
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2024-04-26 15 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Implications of pulsatile GH | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Time GH levels GH producing tumor Normal GH pattern GH deficiency X X X Single GH blood samples not good enough How to distinguish? • 24 h GH pattern (golden standard) • Serum IGF-1 as marker of mean 24 h GH • Stimulators or inhibitors X 29 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Effect of arginine or insulin on plasma GH | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Arginine & insulin can be used as provocactive tests for GH release Arg/ insulin hGH µg/ml 100 80 60 40 20 0 -10 0 30 60 90 120 Time (minutes) Normal GH deficient 30
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2024-04-26 16 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucose tolerance test | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Glucose 0 2 4 Hours Normal Acromegaly (nonresponsive to glucose) 35 6 3 0 GH mU/ml 31 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH secretion is increased by gonadal steroids during the growth spurt and then declines | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 32
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2024-04-26 17 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Clock time SLEEP STAGE Plasma GH µg/l Clock time SWS SWS = slow wave sleep GH secretion during sleep | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 33 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Fasting increases GH secretion in man | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Effects: •Keep B-glucose up •Lipolysis •Does NOT increase growth Bergendahl et al, 1999 34
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2024-04-26 18 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH, IGF-1 and fasting | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON IGF-1 stimulated by GH and Nutrition (partly via insulin). FASTING GH B-glucose Lipolysis Fasting blocks GH effects on body growth and IGF-1 à Appropriate response to fasting ¯ IGF-1 ¯ « Body growth Needed for IGF-1 synthesis: GH and food! 35 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Somatotrophs: GHRH and somatostatin regulate GH synthesis & release + cell replication | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON P CREB CREB PKA cAMP Somatostatin GHRH AC +
Pituitary somatotroph 2 GH Secretion 3 Proliferation 1 GH synthesis Pit-1 Pit-1 GH GH G-prot Pit1 is a pituitary-specific transcription factor that is essential for the development of somatotrophs (& lactotrophs & thyrotrophs). 36
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• It is a peptide with a fatty acid group
• Ghrelin treatment stimulates GH release (and food intake)
• Most mice with disrupted ghrelin signalling are not “skinny
dwarfs” although certain models do have a mild phenotype.
• Ghrelin is mainly produced by the empty stomach between
meals
Ghrelin has 2 main roles: 1) food intake and 2) GH
release.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Ghrelin receptors: In GHRH (growth)
and NPY (food intake) neurons
in arcuate nucleus (ARC)
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
Non-Hypothalamic Brain Areas
Taste sensation
Reward behaviour
Olfaction & sniffing
Learning & Memory
Depression
Sleep/wake rhythm
Neuroprotection Sympathetic nervous system
- SNS activity ¯ BAT
- Thermogenesis ¯ Heart
- Cardiac output
- Cardiac contractility
- Vasodilatation Stomach
- Gastric emptying
- Gastric motility
- Gastric acid secretion Pituitary
- GH Ghrelin directly stimulates growth hormone release from the anterior pituitary. It also activates GHRH* neurones in the hypothalamus. GHRH and ghrelin act synergistically to increase GH secretion. Pituitar Hypothalamus
- GHRH *Growth hormone-releasing hormone Physiological effects of ghrelin: GH release | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 38
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2024-04-26 20 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ø Synthetic peptide and non-peptides that release GH e.g. GH-releasing peptide 6 (GHRP-6), MK-0677, ipamorelin, hexarelin. (1980s) Ø NOTE: These ligands are now known to be ghrelin mimetics. Discovered before ghrelin or its receptor. Ø Amplify GH release induced by GHRH Ø Therapeutic potential - but have not become prescribed drugs
for treating certain forms of GH deficiency (when somatotrphs intact) or
for enhancing GH secretion when it could have beneficial effects e.g. in the elderly? GH release Placebo 0.1 ug/kg GHRP 1.0 ug/kg GHRP 1.0 ug/kg GHRH 0.1 ug/kg GHRP plus 1 ug/kg GHRH From Bowers et al., 1990, J JCEM, 70: 975-982. GH secretagogues (ghrelin mimetics) – 1980s-1990s | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 39 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Veldhuis JD et al., 2008, JCEM, 93:3597-603. Ghrelin (like GHRPs) amplifies GH secretion in healthy subjects | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 40
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
Pantel et al., 2006, JCI, 116:760
Loss of constitutive activity of the growth
hormone secretagogue receptor in familial short
stature
Whereas several clinical studies support a role of
ghrelin in regulation growth and height, mice lacking
ghrelin or its receptor mostly do not have growth
abnormalities.
We do not know the role of ghrelin in GH physiology –
it could be important to promote GH release during
fasting (and rescue blood glucose).
Sun et al Mol Cell Biol. 2003;23:7973-81.
Pfluger et al Am J Physiol Gastrointest Liver
Physiol. 2008;294:G610-8
Peris-Sampedro F Mol Metab 2021 13: 1301
Zhao et al., PNAS, 2010;107:7467-72
Those in
red support
a role
in growth
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Not clear that ghrelin is important for growth
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Ghrelin mimetics tested in clinical trials
Many linked to GH release!
42
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2024-04-26 22 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Body growth - general • Body growth - endocrine regulation • What are the effects of the GH-IGF-1 axis? • How is the GH-IGF-1 axis regulated? Ø What are the mechanisms of action of GH and IGF-1? • What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 43 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Endochondral growth Calcifying Hypertrophic Proliferative Geminal Chondrocytes Epiphyseal plate Oestrogens induce closure of the growth plate via Erα, such that no further proliferation or hypertrophy is possible. Growth of long bones before epiphyseal plate closure | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 44
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GH actions to stimulate bone
growth are mediated by
insulin-like growth factor 1
(IGF-1), produced by the liver.
IGF-1 - previously called
somatomedin C.
Salmon & Daughaday, 1957
GH
IGF-1
Somatomedin (IGF-1) hypothesis of GH action on bone
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
GH acts locally within the
epiphyseal plate to promote
growth. No effect via liver IGF-1
on contralateral leg
Direct action of GH?
Locally produced IGF-1
needed
GH
NaCl
Experiment:
Administration of GH to growth
plate of one leg.
Olle Isakssson and coworkers, Science 1982
Challenge to the somatomedin hypothesis - 1
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
46
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2024-04-26 24 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH plus IGF antiserum NaCl Additional Experiment: IGF-1 antiserum (removes IGF-1)
- GH to growth plate of one leg. Result: No increase in growth of injected leg. Conclusion: GH actions require the presence of IGF-1. IGF-1 may be produced locally. Challenge to the somatomedin hypothesis - 2 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 47 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY 0 10 20 30 40 50 0 8 12 16 20 24 Liver IGF-1 knockout Control Days after induction of knockout Body Weight (g) Normal body growth in liver-specific IGF- 1-knockout mice. àLiver-derived IGF-1 may not be important for growth. Sjögren K, Ohlsson C et al, PNAS 1999 Challenge to the somatomedin hypothesis - 3 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 48
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2024-04-26 25 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The local actions of GH within the growth plate require the presence of IGF-1 Green et al, 1985 Maturing chondrocytes IGF1 IGF1 Clonal expansion Early chondrocyte IGF1 mRNA Epiphyseal growth plate GH GH-R Differentiation Prechondrocyte GH Long bone Needed for growth:
- Direct GH effect. and
- IGF-1 (liver or local)
IGF-1 cannot replace
GH if GH deficient.
GH no effect in IGF-1
knockout mice.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Modified somatomedin (IGF-1) hypothesis
49
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
GH actions to stimulate
bone growth are direct on
the bone.
The effects are partly
mediated by local IGF-1.
GH IGF-1 GH IGF-1 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Revised GH action on bone 50
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2024-04-26 26 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH receptor dimerization for biological effect 1 2 inactive 1 2 active 1 2 GH antagonist (pegvisomant, No proper dimerisation) inactive 1 2 GH GH receptor inactive | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 51 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH Receptor signaling: active STAT dimer to nucleus P 1 2 1 2 GH GH receptor P JAK2 P Nucleus Nucleus STAT5b P Phosphotyrosine binding domain STAT : signal transducer and activator of transcription | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 52
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2024-04-26 27 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Serum IGF-1 levels determine sizes of dog breeds Polymorphism near IGF-I gene associated with body size of dog breeds IGF-I IGF-I IGF-I IGF-I IGF-I | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 53 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Derek LeRoith NEJM 1997 Scavenger receptor? The ligands bind mainly to their own receptors , but also to others with lower affinity Insulin- and IGF-I receptors à Biological signaling IGF-II Receptors à Scavenging of ligand INSULIN IGF-1 IGF-2 Metabolic Actions Growth & Differentiation ? Insulin receptor IGF-1 receptor Scavenger rec? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Comparisons between IGF-1, IGF-2, and insulin 54
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2024-04-26 28 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY IGF-IIR IGF-IR Insulin-R insulin IGF-I IGF-II P P P P P P P P IGFBP-2 IGFBP-1 IGFBP-4 IGFBP-6 IGFBP-3 ALS IGFBP-5 ALS " " IGFBP proteases Courtesy of Dr Ricarda Granata IGFBP-3 – ALS (acid-labile subunit) binds most of all IGF-1 in serum. These ”chop up” binding proteins and release IGF-1 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON The insulin-like growth factor (IGF) system 55 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY IGF-1 ALS IGF-BP3 IGF-1 Rec ALS: “acid labile subunit” (old term) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Interactions between IGF-1, IGF-BP3, ALS and BP3 protease BP3 protease 56
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2024-04-26 29 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY IGF-1 stimulates proliferation IGF-1 inhibits apoptosis. In epidemiologic studies: High S-IGF-1 predictor of breast cancer, prostate cancer, colon cancer… Low S-IGF-BP3 – independent predictor of cancer. PSA (IGF BP3 protease) a clinical marker of prostate cancer On the other hand: IGF-1R blockers (e g teprotumumab) do not decrease cancer. IGF-1 is approved by FDA to increase growth in small children, irrespective of cause. Caution. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Beware of IGF-1? 1) Tumors 57 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY 1/3 ↓ food intake ↓GH effect ↓ IGF-1 & insulin ? Animals with ↓IGF-1 all live longer (15-30%!) u Partly starved animals (not monkeys?) u Growth mutants (GHRH-/- (Little) mice, ames dwarf mice, GHR-/-, IGF-1+/- etc.) Genetic growth defects ↑ Longevity | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Beware of IGF-1? 2) Longevity 58
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2024-04-26 30 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Body weight Longevity | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Smaller dogs live longer – IGF-1 involved? 59 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Body growth - general • Body growth - endocrine regulation • What are the effects of the GH-IGF-1 axis? • How is the GH-IGF-1 axis regulated? • What are the mechanisms of action of GH and IGF-1? Ø What can go wrong with GH- IGF-1? Content | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 60
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2024-04-26 31 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Excessive GH production in childhood, or before the epiphyseal growth plates have fused Dose-response 110-270 cm! Cause: Pituitary tumour that starts from a somatotrophic cell. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Gigantism 61 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Excessive GH production in adulthood after the epiphyseal growth plates have fused. Growth of “the tips of the body”. Cause: Pituitary tumor that starts from a somatotrophic cell. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Acromegaly 62
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2024-04-26 32 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Large nose Thick lips Growth of mandible Prominent cheek bones Osteoarthritic vertabral changes Enlarged hand & feet Visual field defects (bitemporal hemianopia) Hirsutism Barrel chest Excessive sweating Often caused by Lack of GTPase activity in G-protein (see next slide) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Clinical features of acromegaly 63 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Arg201 in G-protein changed à No dephosphorylisation by GTPase à No signal termination à 1 GH production, 2 GH release, 3 Somatotroph proliferation Gs- GTP Gs- GDP GDP GTP P GHRH receptor X Adenylate cyclase cAMP Active Inactive + 40% of acromegaly in Europeans. GTPase | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Molecular causes of Acromegaly in a somatotroph 64
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2024-04-26 33 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Pit-1 defect. Snell (dw/dw) Don’t get development of GH, TSH, PRL- producing cells • Prop-1 ”Prophet of Pit” defect. Ames (df/df): GH, TSH, PRL +LH +FSH Pit-1 and Prop-1: master genes. Also in man. Longevity?? • GHRH receptor gene defect ”little” mouse. Identified families in Bangladesh, South America. • GH gene defect. Antibodies against GH unfortunately
……. Continued on next slide
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Known genetic defects with growth defects in which
the body remains in proportion - I
65
UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
• GH receptor gene defect. Laron dwarfism.
IGF-1 treatment partially effective. Have low IGF-1.
• STAT5b gene defect. IGF-1 treatment partially effective.
• IGF-1 gene defect. Mental retardation, deaf. IGF-1 treatment
• IGF-1 receptor gene defect. As for IGF-1 defect. No IGF-1
treatment
• (Fibroblast growth factor-receptor 3 (FGFR3) gene defect.
Achondroplasia, short arms and legs; body not in proportion.
Not linked to GH-IGF-1
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Known genetic defects with growth defects in which
the body remains in proportion - II
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2024-04-26 34 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH somatostatin IGF-1 Target organs ¯ IGF-1 synthesis & release Defective GH gene IGF1-R mutations IGF1-R GH-R GH-R Mutation Laron Dwarfism GHRH-R Ghrelin-R Mutation? GHRH-R Mutation Defective development of somatotrophs “Little” Dwarfism Ghrelin-R GHRH | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Monogenic causes of dwarfism; defective GH axis 67 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Prop-1 Defect: Ames Dwarf mice Human dwarfs (Krk) Pit-1 Defect: Snell Dwarf mice Human dwarfs GH PRL TSH LH, FSH Stem cell Stem cell Pit-1 :
- Mediator of GHRH effect on GH production postnatally
- Inducer of pituitary development prenatally Defect earlier in development, (e g Prop-1 instead of Pit-1) à More hormones lacking. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Dwarf mice and human equivalents: defective pituitary master genes during development 68
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Evidence that the GHRH-receptor, and not down-stream
pathways, is nonfunctional in dwarf “little” mice
40
30
20
10
GH secretion
(% of cell
content)
Little mice
Wild type
Control
dbcAMP
Forskolin
Cholera toxin
GHRH
cAMP
GHRH
AC
GH Secretion
G-prot
Forskolin
Cholera
toxin
GH secretion from pituitaries of Little mice is decreased after GHRH compared to Wild type mice.
In contrast, stimulation of the down stream G-protein –adenylate cyclase (AC) – cAMP signal pathway by cholera
toxin, forskolin or dbcAMP can all stimulate GH secretion in little mice
(Adapted from Jansson JO et al Science 1986)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Little mice
wildtype mice
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
Dwarfism due to mutations
of human GHRH receptor
Effect of Sindh
Mutation (AlaàGlu)
Brazil (intron 1 splice donor)
Leu
D
E
I
I Y
H G V T
S I S
L A V I
F
A
V
L
T I
I
V A L
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R L H C P
R
K
D
W
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W
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A
W
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W
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N
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L
L
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S
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R
A
A
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L
F
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D D T D H
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A
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A
G L G I R
P
L
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L
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Y WW
I
G K
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F L G
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LV
T
L F
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L
T F L
H
Q
N
Y
V
T
S
F
Y
S
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E
A
L
L
E
L
P V P C A V P Y P P F P E S W G T I
T C D R K V A
G S
S
E
S F H S F F D P C P L T V W
G
G
S
A
T
P
W
C
L
L
G
W
T
A
P
C
G
L
T
T
N
P
M
E
E
A
A
Q
L
C
A
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D
E
R
L
Q
T
I
F
D
C
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P H M H
C
L
K
S
T
L
V S V
Y
N
H
A A
F A
L
V
A E A
F
T S
W L
M
S
S
T F I
S
P
K
S
L
F
L
F
L
L
N
I
I Y
G I H
F L P
F
I
T S
P
D
NH2
COOH
Sindh
His
Glu
Ala
Cys
Phe
Spain
Pakistan
USA
USA
D 4
Japan
Gly
Asp
Stop
Glu
Little mouse
little mouse
-/- and -/+ littermates
Little mouse
AspàGlu
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
GHRH receptor
70
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2024-04-26 36 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GH receptor deficiency (Laron dwarfism) 1 2 GH GH receptor inactive X X • GH treatment ineffective • IGF-1 only small effect (lack of cells with IGF-1 rec in growth plate when no GH?) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 71 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY IGF-1 and IGF-1 receptor deficiency IGF-1 gene defect IGF-1 receptor gene defect Chernausek S et al NEJM 2003 Woods KA et al NEJM 1996 Intrauterine growth defect Chernausek S et al NEJM 2003 Woods KA et al NEJM 1996 Intrauterine growth defect autosomal recessive | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 72
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Causes of dwarfism unrelated to GH-IGF axis
Thyroid hormone deficiency in childhood (Cretinism).
Retardation of mental development & growth.
Thyroid hormones are permissive for growth.
Excess glucocorticoids - stunts growth.
Glucocorticoids are permissive for growth, but inhibitory in
high doses.
Genetic diseases:
Pygmy mouse, HMGA2 (high-mobility group A2), a transcription factor
for e g cycline A.
Human SNP 0.5 cm height.
Achondroplasia (next slide)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
Achondroplasia: Selective shortening of long bones in dogs & humans
Hypothesis: Gain of function mutation in fibroblast growth factor receptor-3
(FGFR-3). FGFR3 prevents stem cell proliferation and differentiation.
Gain of function à Autosomal dominant disease. 80% new mutations.
Diego Velázquez (1599-1660).
Museo del Prado, Madrid
(Achondroplasia “No chondrocyte proliferation”
Not responsive to GH or IGF-1 treatment.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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2024-04-26 38 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Summary • Prenatal, postnatal and pubertal body growth is regulated by different hormones. • Postnatal longitudinal body growth is regulated by a hypothalamus – pituitary – liver – bone axis. • GH is diabetogenic and lipolytic in addition to growth promoting. • GH- IGF-1 axis is regulated by feeding, amino acids, lipids and glucose. • GH- IGF-1 in relation to tumour growth is a concern, but few alarming data at present. • Dwarfism can be due to defects of various hormones and receptors in the GHRH - GH- IGF-1 – FGFR3 axis. Diagnos for right treatment. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 75