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Unit 3 Physiology: Control of Growth and Body Mass (Leff)
2 forms of GH that result from differential splicing
o 20 kDa (176 AA) GH and 22 KDa (191 AA) GH
o Difference is 14 amino acids
o Not clear what the difference is between the 2
Gene Expression:
GH is part of a gene cluster of closely related genes on cs17
Gene encodes:
o Human GH (191 AA)
o pvGH (191 AA, 93% homologous with hGH)
Thought to be a major regulator of fetal growth (GH itself does NOT control fetal growth; GH
levels are actually low during fetal development)
Has same affinity for GH receptor as GH itself
o Human CS1 and CS2 (191 AA each, 84% homologous)
Human chorionic somatomammotropin
Relevant only in embryonic development
Produced by the placenta
o Human PRL (199 AA, 16% homologous)
Gene is differentially spliced, resulting in the pre-22 kDa or pre-20 kDa growth hormone mRNA (in the nucleus)
Enters RER where it is transcribed to the pre-pro-hormone, and is then transported to the Golgi where it is
converted to the pro-hormone
Eventually stored in secretory granules in the somatotrophic cells of the anterior pituitary, awaiting signal to be
Episodic Production:
Higher GH levels exist at night during non-REM stages of sleep
o Earlier in the night
o Slow wave/deep sleep
This is used in treatment as therapeutic GH is administered at night when endogenous GH is normally produced
Factors Affecting GH Production:
Increase GH Production:
o Fasting (hypoglycemia, low circulating free FAs)
o High protein diet (elevated circulating AA)
o Exercise (obviously not mediating growth here, but serves a function)
o Deep sleep (non-REM sleep)
Decrease GH Production:
o Stress/Anxiety (causes release of glucocorticoids which suppresses downstream GH effects; does not
affect GH production)
Direct (Acute) Effects of GH:
These effects are mainly diabetogenic (ant-insulin effects); do not commonly play a role in normal individuals
Short-term effects (minutes to hours)
o Increases glucose uptake in muscle
o Increases lipolysis in fat
o Increases gluconeogenesis in liver
o Causes insulin resistance muscle, fat and liver
GH itself does NOT have growth promoting activity
Indirect Effects of GH Mediated by IGF-1:
The primary mediatory of growth-promoting effects of GH is IGF-1 (produced in the liver when stimulated by GH)
Causes chronic effects of GH, which are all related to growth:
o Increased DNA, RNA and protein synthesis
o Increase in cell size and number
o Increase in organ size
o Increase in organ function
o Increase in linear growth (has a direct effect on osteoblasts, causing bone building process to be
Cell Signaling Pathway:
Growth hormone receptor is a JAK/STAT receptor
Growth hormone binds to a pair of receptors, causes dimerization and autophoshorylation of the receptor
This autophosphorylation leads to phosphorylation of janus kinases associated with the receptor
STATs bind to the phsophorylated receptor, and become phosphorylated by the janus kinases
Phosphorylated STATs move to the nucleus to act as transcription factors and modulate gene expression
o Increase expression of IGF-1 and IGFBPs
Highly homologous with insulin
o In lower animals, only have one hormone that carries out activities of IGF-1 and insulin
o “C peptide” in IGF-1 is shorter and is NOT cleaved out of the IGF-1 gene product
There also exists an IGF-2 molecule
o Function is not totally clear
o May be limited to specific periods of growth
IGF-1 Receptor:
Very similar structure to the insulin receptor (also a tyrosine kinase)
Has similar signaling to the insulin pathway
o At very high concentrations of insulin (ie. in severe hyperinsulinemia associated with type II diabetes),
insulin can bind IGF-1 receptor causing undesirable effects
IGF-2 receptor has also been characterized
o Mannose-6-phosphate receptor
o Does not induce cell signaling inside the cell
o IGF-2 can also bind the IGF-1 receptor in some circumstances
IGF-1 and Growth:
Most rapid growth occurs in early childhood, but is not mediated by IGF-1 (what does mediate this growth is
unclear; might be IGF-2, placental lactogens etc.)
IGF-1 primarily mediates pubertal body growth
o IGF-1 levels increase during childhood and peak at puberty
Cells in the arcuate nucleus secrete GHRH (stimulate GH release)
o Causes fusion and release of GH by somatotrophs
GHRH binds GHRH receptor (Gs coupled receptor) which activates adenylate cyclase,
increasing cAMP and PKA, causing Ca++ influx
o Circadian rhythm plays a role in GHRH production (increasing GH secretion during the night)
Cells in periventricular region release somatostatin (inhibit GH release)
o Somatostatin binds somatostatin receptor (Gi coupled receptor) which inactivates adenylate cyclase ,
decreasing cAMP and PKA (prevent Ca++ influx into cell, therefore preventing docking and fusion of GH
GH Feedback:
o Feeds back to inhibit somatotrophs in anterior pituitary, therefore inhibiting GH release
o GH is removed rapidly from circulation
IGF-1 Feedback:
o Feeds back to inhibit somatotrophs in anterior pituitary, therefore inhibiting GH release
o Feeds back to inhibit GHRH secretion fro arcuate nucleus
o Feeds back to stimulate somatostatin release (inhibit GH release)
o IGF-1 has a longer half life in circulation than GH
Thyroid hormone
Sex steroids
Tissue and cell-specific growth factors promote growth (have hormone like effects):
Nerve growth factor (NGF)
Fibroblast growth factor (FGF)
Angiogenesis factor
Vascular endothelial growth factor (VEGF; repairs vascular endothelium)
Epidermal growth factor (EGF)
Hepatocyte growth factor (HGF)
GH Excess: caused by tumor of somatotrophs in anterior pituitary (usually treatable)
o Hyperglycemia
o Insulin resistance
o Reduced body fat/increased lean body mass
o Acromegaly in adults (epiphyseal plates have been fused)
o Gigantism in kids (followed by acromegaly later in life)
GH Deficiency:
o Short stature
o Hypoglycemia
o Increased body fat
o Reduced lean body mass (muscle mass)
Laron Dwarfism: mutation in the receptor for GH (cannot induce production of IGF-1)
2 genes, the when defective, cause obesity: Ob gene and Db gene
Experiments performed in mice:
o Ob defective mouse attached to normal mouse
Ob mouse became slender, normal mouse remained normal
Therefore, Ob mouse must have a defective hormone that normally reduces body weight
(because it became slender after being able to receive the normal mouse’s hormone)
o Db defective mouse attached to normal mouse
Db mouse remained fat, normal mouse became anorexic
Therefore, Db mouse must have a defective receptor for the normal hormone that reduces
body weight (because it remained fat even after receiving hormone from the normal mouse)
It also must have normal functioning hormone since the normal mouse became anorexic
(received extra weight reducing hormone from the Db mouse)
Physiological Effects of Leptin:
Leptin affects appetite (reduces appetite)
Does NOT affect metabolic processes (receptors for leptin are in the CNS)
Giving leptin to Ob mouse (with defective hormone) decreased food intake dramatically
Giving leptin to the Db mouse (with the defective receptor) had no effect on food intake
Hormonal Regulation of Appetite:
Leptin is secreted at all times from all adipose tissue in the body
o Amount of leptin produced is proportional to the amount of body fat a person has
Leptin is only secreted by adipose tissue
o Gene for leptin is expressed only in adipose tissue
Receptors for leptin are located in the arcuate nucleus of the hypothalamus on 2 populations of neurons
o Anorexogenic neurons (POMC/CART, decrease appetite)
o Orexigenic neurons (AGRP/NPY, increase appetite)
Leptin stimulates anorexigenic neurons and inhibits orexigenic neurons
Other Hormones Playing a Role: Ghrelin and CCK (released from the gut)
Clinical Use of Leptin:
o Leptin is only effective at decreasing appetite and body weight in people that have a defect in the
leptin gene (very rare)
o Obese individuals actually have more leptin than normal sized individuals
Thought is that hyperleptinemia leads to leptin resistance in a similar fashion to
hyperinsulinemia causing insulin resistance in diabetes