Physiology Exam 4 Lecture 12B [The Hypothalamus and Pituitary Gland: Miller]

Location of the hypothalamus

At the base of the brain, below the thalamus and in contact with the pituitary

The hypothalamus is comprised of

multiple nuclei with different neuronal population/functions

The hypothalamus maintains

homeostasis for multiple physiological systems

Hypothalamus monitors:

Energy homeostasis: monitors nutrient levels and regulate appetite

Blood osmolarity: Monitors and regulates thirst

Body temperature

Body clock- regulates sleep/ wake cycles

Blood glucose- senses glucose and modulates its concentration

The hypothalamus is part of the __________ organs

circumventricular

Unlike most of the brain the circumventricular organs have

fenestrated capillaries that permit blood sampling

The hypothalamus can sense _____, ______, _____ etc in the blood and acts to maintain them at the ideal setpoint

Hormones, nutrients, ions

The hypothalamus acts largely through the secretion of

hormones or more precisely neuro-hormones

SUMMARY: The hypothalamus is located at

the base of the brain and just above the pituitary

SUMMARY: The hypothalamus regulates a large number of basic physiological functions such as

energy homeostasis

Hormonal release of pituitary hormones

Circadian rhythms

Insulin sensitivity

Immune homeostasis

SUMMARY: The vasculature of the hypothalamus is less tight than the rest of the brain allowing for

the hypothalamus to measure blood hormones

Energy Homeostasis

Balance between energy intake and energy expenditure

- Regulated by the hypothalamus

Hormones secreted by the ____, ___, and ____ tissues inform the hypothalamus on energy state

Stomach, pancreas, and adipose

Main hormonal regulators of energy

Leptin

Insulin

Ghrelin

Leptin is secreted by

adipose tissue

Leptin informs the hypothalamus on the

amount of reserve available

The more fat in the body the higher the level of circulating

leptin

Insulin is secreted by

the pancreas after a meal

Insulin informs the hypothalamus that

food was consumed

Insulin acts on the

liver, muscle and adipose tissue to lower blood glucose

Ghrelin is secreted by

the stomach before a meal

Ghrelin is the only peripheral hormone that

promotes food intake

(called the hunger hormone)

GLP-1 is secreted by

intestines after eating

GLP-1 is one hormone that promotes

satiety, and also acts on the pancreas to release insulin and suppress glucagon

When MC4R neurons are activated they make you feel

Full/satiated

When MC4R are stimulated

You eat less

Signal to use more energy to increase metabolic rate

Neurons residing in the arcuate nucleus

POMC

NPY/AGRP

When POMC are stimulated by Insulin or leptin they activate

MC4R neurons

Result

- Reduce food intake

- increase energy expenditure

When NPY/AGRP are stimulated by Ghrelin they inhibit

MC4R neurons

Result:

- Increase appetite

- Decrease energy expenditure

The acruate nucleus of the hypothalamus is comprised of 2 main types of neurons:

- AGRP/NPY neurons: orexigenic (increase food intake)

- POMC neurons: anorexigenic (decrease food intake)

Insulin and leptin decrease food intake and increase energy expenditure by activating _____ and inhibiting

POMC, AGRP

Ghrelin causes hunger by activating

AGRP neurons

Insulin, Leptin, and Ghrelin are hormones. They are secreted in the blood and act on the hypothalamus through there specific

receptors

Both AGRP and POMC neurons project to MC4R neurons which integrate those signals to

regulate appetite and metabolic rate

Mutations in MC4R causes severe obesity becuase

The hypothalamus is no longer able to properly integrate the information from the peripheral hormones

Hypothalamus does not properly respond to insulin or leptin

Constant state of hunger

Mutation in leptin also causes obesity

Loss of leptin signals the brain that energy reserves are low

Constant state of hunger

Can be treated by leptin replacement therapy

SUMMARY: Ghrelin is secreted by the ______ when no food has been consumed

stomach

SUMMARY: Leptin is secreted by _____ and informs the hypothalamus about the amount of energy reserves

adipose tissue

SUMMARY: Insulin is released by the ____ and indicates the consumption of food containing sugars

pancreas

SUMMARY: The 2 major neuron types of the arcuate nucleus are the

AGRP/NPY

POMC

SUMMARY: The AGRP/NPY neurons synapse on MC4R neurons and

inhibit their activity

SUMMARY: The POMC neurons synapse on MC4R and

stimulate their activity

SUMMARY: Ghrelin activates the

AGRP/NPY neurons

SUMMARY: Leptin and insulin activate the

POMC neurons

SUMMARY: The MC4R neurons activity creates

satiation (not eating behavior)

SUMMARY: Inhibition of MC4R creates

turns on feeding behavior

SUMMARY: Mutations of the MC4R or the Leptin hormone cause a condition of

constant hunger which leads to morbid obesity

Ghrelin is produced in

endocrine cells in the lining of the stomach

Ghrelin is produced as a pro-hormone that is cleaved by a

prohormone convertase to produce ghrelin

Ghrelin is further modified by an enzyme ____ which acetylates serine 3

GOAT

Acetylated ghrelin is the

Active hormone

Ghrelin signals

hunger

The Ghrelin receptor is a

GPCR

The Ghrelin receptor is expressed in ____________ neurons, ____________, and in ___________-

NPY/AGRP, Somatotropes of the pituitary, and in specialized cells of the pancreas

The ghrelin receptor can activate several ________ which differ by target

G-proteins

Ghrelin is essential for survival during

starvation periods

Ghrelin acts at several targets with the goal of maintaining normal

blood glucose during starvation (increases blood glucose)

Ghrelin acts on the brain to

increase food intake

Ghrelin stimulates the release of ______ from the pituitary which in turn stimulates glucose output from the liver

Growth Hormone (GH)

Ghrelin inhibits _______ secretion from the pancreas

insulin

All of Ghrelins actions result in increasing the

circulating blood glucose

Ghrelins badass flow map (IMAGE)

Insulin is produced by

β-cell of the endocrine islets of the pancreas

Insulin is produced as a preprohormone and processed by cleavage of

the signal peptide and the c-peptide

Insulin is comprised of an

α-chain and a β-chain linked by disulfide bonds

The insulin receptor belongs to the family of

RTK

The insulin receptor is a

tetramer (dimer of dimers)

The cytosolic regions of the insulin receptor contain

kinase domains

Insulin binding brings the two cytosolic regions of the receptor closer which allows it to

autophosphorylate

Insulin is secreted after a meal to promote the storage of

excess glucose in adipose tissue and muscle

Insulin acts on the hypothalamus to

decrease food intake and signal satiety

Resistance to insulin signaling results in

Uncontrolled hyperglycemia and results in Diabetes Mellitus type II

The complete loss of insulin secretion due to an autoimmune destruction of β-cell is referred to as

Type I Diabetes

without regular insulin injection, a patient with type I diabetes cannot survive

Leptin is secreted by

adipocytes

Unlike the insulin receptor the leptin receptor does not have

intrinsic kinase activity

Leptin binding causes a change of conformation of the receptor which allows it to recruit cytosolic kinases of the _____ family and activate them

JAK

JAK kinases in turn phosphorylate ________ on the receptor

tyrosines

Phosphorylated tyrosines then recruit signaling proteins like _________

STAT3

The blood level of Hormones that regulate energy are regulated by

energy needs

Ghrelin hormone levels:

elevated before meals and falls after a meal is consumed

Insulin hormone levels:

Low before meals, picks up immediately after food consumption and falls again when blood glucose level is returned to normal

Leptin hormone levels:

Depend on the amount of adipose tissue in the body more so than the acute energy state.

- Not greatly influenced by meal times

SUMMARY: Ghrelin is a hormone secreted by the

stomach and induces hunger

SUMMARY: Ghrelin is secreted as a _______ that has to be acylated by _______ to be active

Prohormone, GOAT

SUMMARY: Ghrelin acts on the

Brain, anterior pituitary, and pancreas to increase the level of glucose in the blood

SUMMARY: Insulin is released by the

beta cells of the pancrease, usually after a meal, so as to decrease blood glucose levels

SUMMARY: Insulin binds to a tetrameric receptor in the

RTK family

SUMMARY: Insulin is critical for life and a decreased sensitivity to it causes

Type II diabetes mellitus

SUMMARY: A complete absence of insulin causes

Type I diabetes mellitus

SUMMARY: Leptin is secreted by

fat cells and signals to the hypothalamus about the status of energy stores

SUMMARY: The leptin receptor activates the

JAK/STAT pathway and affects both cellular biochemistry and gene expression

The pituitary Gland is broken down into two parts the

Anterior (Adenohypophysis)

Posterior (Neurohypophysis)

Derived embryonically from an out pouching from the roof of the mouth (glandular tissue)

Adenohypophysis

Derived embryonically from an outgrowth of the brain (neural tissue)

Neurohypophysis

The pituitary stock (infundibulum) is very important because

1. Connects the blood circulation from the hypothalamus to the anterior pituitary

2. Connects the hypothalamus to the posterior pituitary - a number of neurons from the hypothalaumus project their axons into the posterior pitutary through the infundibulum

Hypothalamic-Hypophyseal Portal system (IMAGE)

Hypophysiotrophic hormones are released into hypothalamic capillaries which join the

hypothalamic-hypophyseal portal system

The vascular link passes into the anterior pituitary where it branches into

anterior pituitary capillaries

The hypophysiotropic hormones leave the blood across the anterior pituitary capillaries and control the release of

anterior pituitary hormones, which are released systemically

Posterior Pituitary (IMAGE)