Transcript Chapter 12 - Clayton State University

Section 5
Advanced Metabolism
Chapter 16
Integration of Metabolism
Section 16.1: Overview of Metabolism
Anabolic and catabolic reaction pathways that use
carbohydrates, lipids, and proteins as energy and
biosynthetic precursors must be precisely regulated
Except during youth, illness, or pregnancy, the
animal’s tissues exist in a metabolic steady state
(anabolic is approximately equal to catabolic)
Section 16.1: Overview of Metabolism
Figure 16.1 Overview
of Metabolism
Section 16.1: Overview of Metabolism
Intracellular communication is believed to play a
significant role in maintaining metabolic balance
Intracellular communication occurs by means of
chemical signals
Once released into the extracellular environment,
each chemical signal is recognized by a specific cell
(target cell)
In animals, the nervous and endocrine systems are
responsible for controlling metabolism
Section 16.1: Overview of Metabolism
Figure 16.2 Structure of the
Thyroid Hormones T3 and T4
Regulation by the endocrine system involves the
release of hormones (endocrine hormones) from glands
into the blood, which then travel to target cells
An example is thyroid-stimulating hormone (TSH) that
stimulates follicular cells from the thyroid to release T3
and T4
T3 stimulates glycogenolysis in the liver
Section 16.2: Hormones and Intracellular Communication
Peptide Hormones
In mammals many metabolic activities are controlled
by peptide hormones
They initiate their action by binding to receptors on the
outer surface of the target cell’s plasma membrane
Synthesis and secretion of many of these hormones
are regulated by a complex cascade controlled by the
central nervous system
Sensory signals are received by the hypothalamus, an
area of the brain that integrates the nervous and
endocrine systems
Section 16.1: Overview of Metabolism
Intracellular actions are
often triggered by second
messengers (e.g., cAMP)
Second messengers often
act to modulate an enzyme
cascade in order to amplify
the signal and response
Figure 16.3 Signal Transduction
Section 16.2: Hormones and Intracellular Communication
Animals employ several mechanisms to prevent excess
hormone synthesis and release, most notably negative
feedback
For example, T3 and T4 inhibit TSH release
Target cells also possess a desensitization mechanism to
decrease the number of receptors for the hormone
Downregulation is a decrease in receptor number in
response to a specific signal
For example, type 2 diabetes is due to a decrease in
functional insulin receptor (insulin resistance)
Section 16.2: Hormones and Intracellular Communication
There are two types of
receptors that water-soluble
hormone molecules bind to:
G-protein-coupled receptors
and receptor tyrosine kinases
G-protein-coupled receptors
(GPCRs), the largest known
receptor family, are composed of
seven membrane-spanning
helices
Figure 16.4 The G-ProteinCoupled Receptor and G Protein
N-terminus has a domain for
ligand binding and C-terminus
has a segment for interacting
with G proteins
Section 16.2: Hormones and Intracellular Communication
GPCRs respond to
neurotransmitters as well as
hormones
G proteins (heterotrimeric
GTP-binding proteins) are the
molecular switches that
transduce ligand binding to
intracellular signals
Figure 16.4 The G-ProteinCoupled Receptor and G Protein
Composed of an a, b, and g
subunit
The a subunit binds GTP
Section 16.2: Hormones and Intracellular Communication
G proteins are attached to the membrane by myristoyl
and/or palmitoyl groups
The bg subunits inhibit the a subunit
The bg subunit promotes association of the a subunit
with the GPCR and prevents GDP/GTP exchange
G-protein activation occurs when a ligand binds the
GPCR
Causes a conformational change leading to
GDP/GTP exchange, mediated by a guanine
nucleotide exchange factor (GEF)
Followed by GTP-a subunit dissociation
Section 16.2: Hormones and Intracellular Communication
GTP-as activates adenylate cyclase
while GTP-ai inhibits the enzyme
Adenylate cyclase produces the
second messenger cyclic AMP
(cAMP)
There are other second messengers:
calcium ions, cGMP, and
phosphatidylinositol components
Figure 16.5 Structure of
the Second Messenger
Molecule Cyclic AMP
(cAMP)
Section 16.2: Hormones and Intracellular Communication
cAMP—generated from
ATP by adenylate cyclase in
response to hormonereceptor interaction
The G protein Gs
stimulates cAMP production
when glucagon, TSH, and
epinephrine bind their
receptors
Figure 16.6 The Adenylate Cyclase
Second Messenger System That
Controls Glycogenolysis
Section 16.2: Hormones and Intracellular Communication
A Gs undergoes GDP/GTP
exchange once the ligand
binds to the receptor
GTP-as subunit dissociates
and activates adenylate
cyclase to produce cAMP
Figure 16.6 The Adenylate Cyclase
Second Messenger System That
Controls Glycogenolysis
Section 16.2: Hormones and Intracellular Communication
GTP hydrolysis mediated
by GTPase activating
protein (GAP) inactivates
the G protein (GDP-as)
Activated adenylate
cyclase synthesizes a
number of cAMP molecules
(signal amplification)
cAMP diffuses into the
cytoplasm and binds and
activates c-AMP-dependent
protein kinase (PKA)
Figure 16.6 The Adenylate Cyclase
Second Messenger System That
Controls Glycogenolysis
Section 16.2: Hormones and Intracellular Communication
PKA then phosphorylates
and thereby alters the
activity of key regulatory
enzymes
cAMP target proteins are
different depending on the cell
type
Glucagon and epinephrine
both activate glycogen
degradation in the liver in
cAMP-dependent fashion
Figure 16.6 The Adenylate Cyclase
Second Messenger System That
Controls Glycogenolysis
Section 16.2: Hormones and Intracellular Communication
The Phosphatidylinositol
Cycle, DAG, and Calcium—
mediate the actions of
hormones and growth
factors
Figure 16.7 The Phosphatidylinositol
Pathway
Examples include
acetylcholine, TSH,
vasopressin, GRH, and
epinephrine
Phosphatidylinositol-4,5bisphosphate (PIP2) is cleaved
by phospholipase C into DAG
and IP3
Section 16.2: Hormones and Intracellular Communication
Hormone receptor complex
activates the G protein that
activates phospholipase C
DAG product activates
protein kinase C (PKC),
which activates specific
regulatory enzymes
IP3 diffuses to the
calcisome (SER) where it
binds to a calcium channel
Causing calcium release
Figure 16.7 The Phosphatidylinositol
Pathway
Section 16.2: Hormones and Intracellular Communication
cGMP—synthesized from GTP by guanylate cyclase
Guanylate cyclase is activated by atrial natriuretic
peptide and bacterial enterotoxin
Atrial natriuretic peptide (ANF) is released by heart
cells in response to increased blood volume
Lowers blood pressure via vasodilation and
diuresis
Bacterial enterotoxin activates another type of
guanylate cyclase in intestinal cells and causes
diarrhea
Section 16.2: Hormones and Intracellular Communication
Receptor Tyrosine Kinases (RTKs)
—a family of transmembrane
receptors that bind ligands such as
insulin and epidermal growth
factor
Binding of ligand to the external
domain activates the tyrosine
kinase domain
Insulin receptor has two domains:
the extracellular a and the b,
which has a transmembrane
domain and the tyrosine kinase
domain
Figure 16.8 The Insulin Receptor
Section 16.2: Hormones and Intracellular Communication
Figure 16.9a Simplified Model
of Insulin Signaling
Insulin receptor substrate 1 (IRS1) is one of the
proteins phosphorylated by the insulin receptor
Phosphorylated IRS1 then binds and activates proteins
like phosphatidylinositol-3-kinase, which
phosphorylates PIP2
PIP3 then triggers a kinase cascade, including PKB
activation
Section 16.2: Hormones and Intracellular Communication
Figure 16.9b Simplified Model
of Insulin Signaling
PKB stimulates glycogen synthesis and inhibits
lipolysis
PKB activates mTOR, which is a central kinase sensor
that integrates hormonal activity, nutrient availability,
stress, and energy status
This is controlled by an autoregulatory pathway
Section 16.2: Hormones and Intracellular Communication
Growth Factors
Rigorous control of cell growth and cell division is
essential for survival of multicellular organisms
Growth factors (hormone-like polypeptides) and some
cytokines regulate growth, proliferation, and
differentiation
Examples of growth factors: epidermal growth factor
(EGF), platelet-derived growth factor (PDGF), and
insulin-like growth factor 1 and 2 (IGF-1 and IGF-2)
Examples of cytokines: interleukins and interferons
Section 16.2: Hormones and Intracellular Communication
Epidermal growth factor is a mitogen (stimulator of
cell division) for a large number of epithelial cells
Triggers cell division of epidermal and gastrointestinal
lining cells by binding TKRs
Platelet-derived growth factor is secreted by blood
platelets during the clotting reaction
Stimulates mitosis and collagen synthesis in fibroblasts
during wound healing
Section 16.2: Hormones and Intracellular Communication
IGF-1 and IGF-2 are polypeptides that mediate the
growth-promoting action of growth hormone (GH)
When GH binds to its cell surface receptor, IGF-1 and
IGF-2 are the major stimulators of growth in animals
In addition to stimulating cell division, IGF-1 and IGF2 promote (to a lesser degree) the same metabolic
processes as insulin
Section 16.2: Hormones and Intracellular Communication
Interleukin 2 (IL-2) promotes cell growth and
differentiation and regulates the immune system
Bind to activated T cells to make numerous identical T
cells
Interferons act as growth inhibitors and are produced
by a variety of cells in response to antigen, mitogens,
viral infection, and certain tumors
Type I interferons protect cells from viral infections by
phosphorylating and inactivating a protein necessary for
protein synthesis (eIF2a)
Type II are produced by T lymphocytes and inhibit the
growth of cancer cells
Section 16.2: Hormones and Intracellular Communication
Steroid and Thyroid Hormone Mechanisms
Signal transduction pathways of the hydrophobic steroid
and thyroid hormones result in changes in gene expression
Hydrophobic hormone molecules are transported in the
blood by attaching to transport proteins (e.g., albumin and
sex hormone-binding protein)
Upon reaching their targets, they can diffuse through the
plasma membrane and bind intracellular receptors
Receptor-ligand complex migrates to the nucleus as a
homodimer binds to a hormone response element and
activates transcription
Section 16.2: Hormones and Intracellular Communication
Figure 16.10 Model of
Steroid Hormone Action
Within a Target Cell
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Each organ in the mammalian body contributes to
the individual’s function in several ways:
Consumers of energy or supplying energy-rich
nutrients
Signal molecules offer an important control
mechanism for integrating these processes
Nutrient transport across cell plasma membranes is
also an important feature of organ function
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Gastrointestinal Tract
Most obvious role is digestion of carbohydrate, lipids,
and proteins into molecules small enough for
absorption
Enterocytes need large amounts of energy for active
transport and lipoprotein synthesis
The GI tract also produces hormones that stimulate
appetite (e.g., ghrelin) or promote satiety (e.g.,
cholecystokinin and leptin)
Insulin secretion from pancreatic b-cells
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Liver
Performs a stunning variety of metabolic activities
Key roles in carbohydrate, lipid, amino acid
metabolism, and blood glucose levels
Also detoxification and reduces fluctuations in
nutrient availability
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Muscle
Skeletal muscle constitutes about one-half of the
body’s mass and therefore consumes a large fraction of
generated energy
Cardiac muscle requires glucose in the fed state and
fatty acids in the fasting state
Insulin activates glucose transport into skeletal and
cardiac muscle through GLUT4 translocation
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Adipose Tissue
The role of adipose tissue is primarily the storage of
energy in the form of triacylglycerols
Lipid metabolism is controlled by the hormones
insulin and epinephrine
Adipocytes and macrophages within adipose tissue
secrete peptide hormones (adipokines)
Leptin is a satiety-inducing protein
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Brain
Ultimately directs most metabolic processes in the
body
Sensory information is integrated in several areas in
the brain, which then direct activities
The hypothalamus plays a pivotal role in energy
balance
The brain uses glucose as its sole fuel and uses up to
20% of the body’s energy resources
Section 16.3: Metabolism in the Mammalian Body: Division of Labor
Kidney
Several roles significant to maintaining a stable
internal environment:
1. Filtration of blood plasma
2. Reabsorption of electrolytes
3. Regulation of blood pH
4. Regulation of the body’s water content
Section 16.4: The Feeding-Fasting Cycle
Despite their constant requirements for energy,
mammals only consume food intermittently
This is possible because of the elaborate
mechanism for storing and mobilizing energy-rich
molecules derived from food
Section 16.4: The Feeding-Fasting Cycle
Animals must have
metabolic integration and
the regulatory influence
of hormones
Substrate
concentrations are also
an important factor in
metabolism
Figure 16.11 Nutrient
Metabolism in Mammals
Section 16.4: The Feeding-Fasting Cycle
Figure 16.11 Nutrient
Metabolism in Mammals
Postprandial state is after a meal when nutrient
levels are high, while postabsorptive is after an
overnight fast when nutrient levels are low
Section 16.4: The Feeding-Fasting Cycle
The Feeding Phase
The feeding phase involves food movement, digestion,
and absorption into the blood and lymph in the
gastrointestinal tract
This is controlled by the enzyme-producing cells of
the digestive organs, the nervous system, and several
hormones
Smooth muscle contraction propels the food along the
tract and is controlled by sympathetic and
parasympathetic nerves
Hormones such as gastrin, secretin, and
cholecystokinin (CCK) also contribute to the digestive
process
Section 16.4: The Feeding-Fasting Cycle
In the early postprandial state,
sugars and amino acids are
absorbed and transported in the
portal blood to the liver
Most lipid molecules are
transported in the lymph as
chylomicrons
Chylomicrons pass to the
bloodstream, which provides
triacylglycerol to muscle and
adipose tissue
Figure 16.12 The Early
Postprandial State
Section 16.4: The Feeding-Fasting Cycle
Chylomicron remnants then
deliver the phospholipids,
cholesterol, and few remaining
triacylglycerol molecules to the
liver
Cholesterol is used to make
bile acids, and fatty acids are
used to synthesize
phospholipids
The phospholipids, lipids, and
protein are then incorporated
into lipoproteins for export to
tissues
Figure 16.12 The Early
Postprandial State
Section 16.4: The Feeding-Fasting Cycle
Glucose movement from the small intestine to the
liver stimulates b cells in the pancreas to release
insulin
Insulin release triggers glucose uptake, glycogenesis,
fat synthesis and storage, and gluconeogenesis and
generally stimulates protein synthesis
Substrate supply and allosteric effectors can also
affect these processes
Section 16.4: The Feeding-Fasting Cycle
The Fasting Phase
Glucagon is released as
glucose and insulin levels fall
back to normal
Prevents hypoglycemia by
stimulating glycogenolysis
and gluconeogenesis in the
liver
Figure 16.13 The Early
Postabsorptive State
Section 16.4: The Feeding-Fasting Cycle
If a fast becomes prolonged
(e.g., overnight), maintenance
of blood glucose levels occurs
by fatty acid mobilization
Alternative to glucose for
muscle, conserving glucose
for the brain
Figure 16.13 The Early
Postabsorptive State
Section 16.4: The Feeding-Fasting Cycle
Extraordinarily long fasting (starvation) leads to
metabolic changes to ensure adequate glucose
availability for glucose-requiring cells (e.g., brain)
Additional fatty acids from adipose tissue and ketone
bodies from the liver are mobilized
Section 16.4: The Feeding-Fasting Cycle
Glycogen is depleted after several hours, so
gluconeogenesis plays an important role
Large amounts of amino acids from muscle protein
are used for this purpose
After several weeks, the brain becomes adapted to
using ketone bodies as an energy source
Section 16.4: The Feeding-Fasting Cycle
Feeding Behavior
Regulating feeding behavior
involves hormone and
neuronal signals as well as
sensory input from the
environment (i.e., the five
senses)
Both are integrated in the
brain to regulate appetite
Figure 16.14 Feeding
Behavior in Humans
Section 16.4: The Feeding-Fasting Cycle
The primary neural circuits
controlling appetite are in the
hypothalamus
Primary neurons are in the
arcuate nucleus (ARC)
Depending on the signal
(peptide hormone) produced
by the ARC, it can lead to
appetite suppression or
stimulation
Figure 16.15 Apetite-Regulating
Neurons in the Arcuate Nucleus
(ARC)
Section 16.4: The Feeding-Fasting Cycle
Insulin also reduces intake
via the same neurons that
the hypothalamus uses
AMPK seems to mediate
the appetite-regulating
integration of the
hypothalamus
AMPK is inhibited by
insulin and leptin binding
to their receptors
Figure 16.15 Apetite-Regulating
Neurons in the Arcuate Nucleus
(ARC)
mTOR also regulates ARC
nutrient-sensing neurons