Transcript Lehninger Principles of Biochemistry 5/e

Signaling by the
neuroendocrine system
Neuronal signals
Electrical signals
Neurotransmitters
~a micrometer
Endocrine signals
Hormones secreted into the bloodstream,
A meter or so
Both neurotransmitters and hormones interact
with specific receptors.
Two general mechanisms of
hormone action
Peptide and amine hormones
Fast
Plasma membrane receptor
Effectors: intracellular signaling
Gene expression
Steroid and thyroid hormones
Slower
Enter the cells
Nuclear receptors: transcription factor
Gene expression
Insulin
A small protein, 5.8 kDa
Important in glucose metabolism
Mature insulin
A larger precursor
preproinsulin
Remove a 23 aa signal
sequence
Formation of three
disulfide bonds
Proinsulin
Remove the C peptide
Mature insulin
A and B chains.
Proteolytic processing of the pro-opiomelanocortin (POMC)
precursor
a long polypeptide that undergoes
cleavage
a series of specific proteases
ACTH
β- and γ-lipotropin
α-, β-, and γ-MSH
CLIP
β-endorphin
Metenkephalin
Catecholamine hormones
Water soluble
Epinephrine (adrenaline)
Norepinephrine (noradrenalin)
Neurotransmitters: neurons
Hormones: adrenal glands
Eicosanoid hormones
Paracrine
Prostaglandins
Contracting smooth muscle
Pain, inflammation
Antiinfflamatory drugs
Steroid hormones
Endocrine tissues, adrenal cortex
Cytochrome P-450
Glucocorticoids
Carbohydrate
Mineralocorticoids
Electrolytes
Testosterone
Estrogen
Sexual development
Sexual behavior
Reproductive functions
The major endocrine glands
Hypothalamus
Coordination center
Regulatory hormones
Pituitary gland
via blood vessels and neurons
Posterior pituitary
Neurons from hypothalamus
Anterior pituitary
Hypothalamic hormones in blood
The major endocrine systems and their target tissues
Neuroendocrine origins of
hormone signals
Neuroendocrine origins of
hormone signals
The hypothalamus-pituitary
system.
Anterior pituitary
Releasing factors into a blood
vessel .
The anterior pituitary releases the
appropriate hormone.
Posterior pituitary
Hormones synthesized in neurons
arising in the hypothalamus.
Two hormones of the
posterior pituitary gland
Oxytocin acts on the smooth
muscle of the uterus and
mammary gland, causing uterine
contractions during labor and
promoting milk release during
lactation.
Vasopressin (also called
antidiuretic hormone) increases
water reabsorption in the kidney
and promotes the constriction of
blood vessels, thereby increasing
blood pressure.
Cascade of hormone release
In each endocrine tissue, a stimulus from
the level above is received, amplified,
and transduced into the release of the
next hormone in the cascade.
The cascade is sensitive to regulation at
several levels through feedback
inhibition by the ultimate hormone.
Specialized metabolic functions of mammalian tissues
Metabolic pathways for
glucose 6-phosphate in
the liver
Carbohydrates, proteins, fats
Broken down
Fats in epithelial cells
triacylglycerol (TAG)
Blood capillaries to the liver
Kupffer cells: immune
Hepatocytes: transform dietary
nutrients into fuels and
precursors
Metabolism of amino
acids in the liver
Metabolism of fatty acids in
the liver
The liver is a distribution
center.
Adipocytes of white adipose tissue
Adipocytes of white and brown adipose tissue
BAT: mitochondria are prominent. Thermogenic
WAT: larger and contain a single huge lipid droplet. Store and supply
fatty acids
Distribution of brown
adipose tissue in a newborn
infant
At birth, human infants have brown
fat to protect the major blood
vessels and the internal organs.
This brown fat recedes over time,
so that an adult has no major
reserves of brown adipose.
Insulin regulation in the liver: The well-fed state
calorie-rich meal glucose, fatty acids, and
amino acids entering
liver.
Insulin - glucose uptake
by tissues.
Some glucose - exported
to brain, adipose, muscle
tissue.
In liver, excess glucose
oxidized to acetyl-CoA fatty acids – TAG in
VLDLs to adipose and
muscle tissue.
very-low-density
lipoprotein
The endocrine system of the
pancreas
Exocrine cells:
digestive enzymes in
the form of zymogens
Clusters of endocrine
cells, the islets of
Langerhans.
The islets contain α, β,
and γ cells, each cell
type secreting a specific
peptide hormone.
Glucose regulation of insulin secretion by pancreatic β cells
blood glucose level up
glucose uptake
glucose 6-phosphase
[ATP] up
closing K+ channels
Depolarizing
voltage-gated Ca2+ channels
open
Ca2+ flow
[Ca2+] up
insulin release by exocytosis
ATP-gated K+ channels in β cells
(a) The octameric structure: four identical Kir6.2 subunits and four SUR1
(sulfonylurea receptor) subunits
(b) The structure of the Kir6.2 portion of the channel. Three K+ ions (green)
are shown in the region of the selectivity filter.
Sulfonyluria drugs
Type 2 diabetes mellitus
Binds to SUR1
Closing the channels, stimulating insulin release
The fasting state: the glucogenic liver
After some hours without a meal
Glucagon from pancreas
glycogen – glucose
gluconeogenesis
amino acids from proteins in
muscle.
glycerol from TAGs in adipose
tissue.
fatty acids - ketone bodies – other
tissues, the brain.
Fuel metabolism in the liver during prolonged fasting or in
uncontrolled diabetes mellitus
After depletion of stored
carbohydrates, proteins
become an important
source of glucose (1 to 4).
Fatty acids from adipose
tissue - ketone bodies the brain (5 to 8).
Plasma concentrations of fatty acids, glucose, and ketone
bodies during the first week of starvation
[glucose] down
[ketone bodies] up
an energy source
during a long fast.
Fatty acids cannot
serve as a fuel for the
brain; they do not cross
the blood-brain barrier.
Diabetes
6% of the US population
Type 1 diabetes
Autoimmune destruction of pancreatic b cells
Insulin deficiency
Insulin dependent
Early in life, quick and severe symptoms
Type 2 diabetes
Slow, mild, typically in older, obese individuals
Insulin is produced
Insulin-response system is broken
Insulin-resistant
Diabetes vs. obesity
Obesity and the regulation of body mass
Body mass index (BMI)
30% obese
35% overweight
Obesity vs. diabetes
Set-point model for maintaining
constant mass
adipose tissue up - leptin inhibits feeding and fat synthesis,
stimulates oxidation of fatty acids.
adipose tissue down - a lowered
leptin production - a greater food
intake and less fatty acid
oxidation.
Obesity caused by defective leptin production
ob/ob mice, no leptin
ate more food
less active, 67 g
ob/ob mice
Injected with leptin
35 g
Hypothalamic regulation of food
intake and energy expenditure
Adipose – leptin
Leptin receptor
in arcuate nucleus of hypothalamus
Appetite - Fuel intake - down
Energy spending – up
Heat
Sympathetic nervous system
Blood pressure, heart rate,
thermogenesis
Hormones that control eating
Leptin - adipose tissue
Insulin – pancreas
Anorexigenic
neurosecretory cells - α-MSH
- eat less, burn fuel
Orexigenic neurosecretory cells to inhibit the release of
NPY – eat more
The gastric hormone ghrelin
-NPY release
These two opposing signals
are balanced.
The JAK-STAT mechanism of leptin signal transduction in
the hypothalamus
Leptin binding - dimerization of the
leptin receptor
JAK - Tyr phosphorylation of Rc.
STAT – p-Rc – dimerization –
nucleus – transcription - feeding
behavior and energy expenditure.
A possible mechanism for cross-talk between receptors for
insulin and leptin
Insulin receptor - Tyr
kinase
Leptin receptor – Phos
by JAK
Both phosphorylate
insulin receptor
substrate-2 (IRS-2)
PI-3K - inhibition of food
intake.
Ghrelin
Ghrelin
Peptide hormone from stomach
Appetite stimulant between
meals
Injection of ghrelin – intense
hunger
Insulin
Insulin levels rise immediately
after each meal, in response to
the increase in blood glucose
concentration.