Lecture 12: Growth and Body Size

List the growth hormones.

• growth hormone releasing hormone (GHRH)

• growth hormone (GH)

• insulin-like growth factor 1(IGF-1)

Review the hypothalamic-pituitary axis:

What negatively regulates GH secretion?

somatostatin

Where is somatostatin made?

small-bodied neurons in the PVN

What type of peptide is somatostatin (more specifically than a peptide hormone)?

tetradecapeptide

Where is GHRH produced?

small-bodied neurons in the arcuate nucleus

How many amino acids does GHRH have?

44 amino acids

Which receptor does somatostatin act on?

SSTR

Briefly describe SSTR.

a GPCR, specifially through G-inhibitory to reduce cAMP

What is the receptor for GHRH?

GHRHR

Briefly describe GHRHR.

a GPCR that acts through G-stimulatory to increase cAMP and PKA

What stimulates GH release?

GHRH

List the process of GHRH and somatostatin.

1. neurosecretory cells in the arcuate nucleus secrete GHRH, a 43 amino acid peptide that reaches the somatotrophs via the hypophyseal portal blood supply

2. cells in the periventricular region release somatostatin, a hormone that is a potent inhibitor of GH secretion, into the portal blood supply

3. GHRH causes somatotrophs to synthesize and release GH

4. somatostatin inhibits the release of GH by somatotrophs

How does GHRH stimulate transcription of GH?

acts on PROP1, CREB, and PIT1

How many amino acids does GH have?

191 amino acids

True or False: GH is part of a hormone family with prolactin and human placental lactogen.

true

What is 50% of GH bound to?

GH-binding protein (GHBP)

What is the half-life of unbound GH?

20 minutes

Briefly describe GH release.

pulsatile release with a peak right before waking

What type of receptor is GHR? Which pathway does GHR act through?

a tyrosine kinase receptor; acts through the JAK-STAT pathway

Where is GHR found in (which organs/tissues)?

• liver

• adipocytes

• muscle

True or False: There is type I and type I insulin-like growth factors.

true

What regulates IGF1 transcription? Where does this occur?

GH regulates IGF1 transcription in the liver

True or False: Of 29 amino acids in IGF-1, 13 are homologous with the insulin B domain.

true

True or False: Insulin receptors and IGF-1 receptors are tyrosine kinase receptors.

true

Where is circulating IGF-1 produced

primarily in the liver (endocrine effects)

What is the function of IGF-1?

main mediator of the growth promoting effects of GH

Where else can IGF-1 be produced to have paracrine/autocrine effects?

the bone and muscle

What percentage of IGF1 is bound to binding proteins?

90%

True or False: There are 6 IGFBPs which regulate the biological actions of IGF-1 and IGF-2.

true

What does IGFBPs increase IGFs half-life to?

12 hours

What are IGFBPs degraded by?

IPGFBP proteases

What type of complex are IGFBPs? What are the different subunits?

ternary complex with IGFBP-3, IGF1, and acid labile subunit

What are the 3 actions of GH and IGFs? Which hormone does what?

• increase linear growth by IGF action

• increase protein synthesis and organ growth mainly through IGF action

• diabetogenic (raises blood glucose) by GH action

When does GH-IGF1 increase linear growth?

affects height starting after birth and continuing until the end of puberty

When do GH-IGF1 levels decline?

during aging

True or False: The pubertal peak rate of growth corresponds to the peak serum concentrations of IGF-1.

true

What are the specific functions of how GH-IGF1 increases linear growth?

• stimulate growth of bones, cartilage, and soft tissue

• regulate metabolism of chondrocytes (cartilage making cells)

• stimulate osteoblast replication (mitogenic) and collagen and bone matrix synthesis

• acts to increase length of bones until epiphyseal plate closes

• stimulate appositional growth after epiphyseal plate closes

How does GH action increase organ growth?

in almost all organs, GH increases amino acid uptake and ultimately protein synthesis

How does GH cause short-term increase in blood glucose?

antagonizes insulin action in adipose and muscle (causes insulin resistance)

What does GH decrease phosphorylation of? What does this upregulate?

decrease IRS and PI3K phosphorylation—upregulating inhibitors

What does GH induce to inhibit PI3K?

p85-alpha

What are the diabetogenic actions of GH in fat?

• increases lipolysis and serum levels of free fatty acids (HSL)

• decreases glucose uptake

What is the diabetogenic action of GH in the liver?

gluconeogenesis

What are the diabetegenic action of GH in the muscle?

• increases amino acid uptake and protein synthesis (anabolic)

• decrease glucose uptake

True or False: GH shifts metabolism to lipid use to spare the muscle.

true

Which factors play into increased longevity with decreased GH/IGF-1 levels?

• less proliferation

• better insulin sensitivity

• better immune system

What are the other growth promoting hormones?

• thyroid hormones

• sex steroids

What does a thyroid hormone deficiency before closure of epiphyseal plate cause?

dwarfism

True or False: Thyroid hormone is needed for optimal GH levels.

true

True or False: Estrogen and androgen stimulate growth but promote closure of epiphyseal plate.

true

What does a mutation in PROP1 cause in both mice and humans?

dwarfism

What does GH insensitivity block?

cancer and diabetes

What is gigantism due to?

excess GH before closure of epiphyseal plates

What is gigantism most often due to?

GH-secreting pituitary tumor

What is acromegaly due to?

excess GH after closure of epiphyseal plates due to GH secreting tumor

What are the treatments for GH secreting tumors?

• octreotide: somatostatin analog

• pegvisomant: GHR blockade

True or False: ALP1 mutations have also been detected in about 15% of patients with FIPA (familial isolated pituitary adenoma).

true

What does AIP stand for?

aryl hydrocarbon interacting protein