Transcript Homeostatic Control of Metabolism

Homeostatic Control of
Metabolism
Food Intake
• How does your body know when to eat?
• How does your body know how much to eat?
• Two ‘competing’ behavioral states:
– Appetite = desire for food
– Satiety = sense of fullness
Hypothalamic Centers
• Feeding center – tonically active
• Satiety center – inhibits feeding center
Figure 11-3
Regulation: Classic Theories
• Glucostatic theory: glucose levels control the
feeding and satiety centers in hypothalamus
– Low [glucose] – satiety center suppressed
– High [glucose] – satiety center inhibits feeding center
• Lipostatic theory: body fat stores regulate the
feeding and satiety centers
– Low fat levels  increased eating
– Recent discovery of leptin and neuropeptide Y provides
support
Peptides Regulate Feeding
• Input to hypothalamus:
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–
–
Neural from cerebral cortex
Neural from limbic system
Peptide hormones from GI tract
Adipocytokines from adipose tissue
Peptides Regulate Feeding
Note the diversity
of peptide origins!
cholecystokinin =
Peptides Regulate Feeding
inhibition
Figure 22-1
We Eat To Do Work
• Energy input = energy output
– Energy output = work + heat
– 3 categories of work:
• Transport work – moving molecules from one side of
membrane to the other
• Mechanical work – movement
• Chemical work – synthesis and storage of molecules
– Short-term energy storage – ATP
– Long-term energy storage – glycogen, fat
Metabolism
= sum of all chemical reactions in the body
• Anabolic pathways – synthesize large
molecules from smaller
• Catabolic pathways – break large molecules
into smaller
Metabolism
• Divided into two states:
– Fed (or Absorptive) state
• After a meal
• Anabolic – energy is stored
– Fasted (or Post-absorptive) state
• Molecules from meal no longer in bloodstream
• Catabolic – storage molecules broken down
Fate of Ingested Molecules
• Immediate use in energy production: nutrient
pools
• Synthesis into needed molecules (growth,
maintenance)
• Storage for later use
• Fate depends on type of molecule:
carbohydrate, protein, or fat
DIET
Fats
Carbohydrates
Proteins
Build
proteins
Free fatty acids + glycerol
Lipogenesis
Excess
stored
Fat
stores
Glucose
Glycogenesis
Lipogenesis
Excess glucose
Excess
stored
Body
protein
Glycogen
stores
Lipolysis
Urine
Glycogenolysis
Glucose pool
Free fatty
acid pool
Many
immediately
used
Excess nutrients
Metabolism in
most tissues
Amino
acids
Protein
synthesis
Many
immediately
used
Gluconeogenesis
Range of normal
plasma glucose
Amino acid
pool
Excess converted
in liver
Brain
metabolism
Figure 22-2
What Controls This?
• Hormones control metabolism by altering
enzyme activity and molecule movement
• Push-pull control: different enzymes catalyze
forward and reverse reactions
Push-Pull Control
INSULIN
enzyme 1 enhanced,
enzyme 2 inhibited
enzyme 1 inhibited,
enzyme 2 enhanced
GLUCAGON
Figure 22-4
Metabolism is Controlled by Ratio of
Insulin and Glucagon
Anabolic
Catabolic
Figure 22-9
Fed State
Many
immediately
used
1 Liver glycogen
becomes glucose.
Fasted State
Liver
glycogen
stores
Free fatty
acids
Glycogenolysis
-oxidation
Energy
production
Glucose
2 Adipose lipids
become free
fatty acids and
glycerol that
enter blood.
Triglyceride stores
Free fatty
acids
Glycerol
Gluconeogenesis
Ketone
bodies
Energy production
Glycogen
Gluconeogenesis
Proteins
Pyruvate
or
Lactate
Glucose
Amino
acids
Ketone
bodies
Energy production
3 Muscle glycogen can be used for energy.
Muscles also use fatty acids and break
down their proteins to amino acids that
enter the blood.
4 Brain can use
only glucose and
ketones for energy.
Figure 22-7
Pancreas – Islets of Langerhans
Figure 22-8
Insulin
• Origin in β cells of
pancreas
• Peptide hormone
• Transported dissolved
in plasma
• Half-life ~5 min
• Target tissues: liver,
muscle, adipose tissue
Insulin
• Secretion promoted by:
– High plasma [glucose] (> 100 mg/dL)
– Increased plasma amino acids
– Feedforward effects of GI hormones
• Glucagon-like peptide-1 (GLP-1)
• Gastric inhibitory peptide (GIP)
• Anticipatory release of insulin
– Parasympathetic input to β cells
• Secretion inhibited by:
– Sympathetic input
– Reduced plasma [glucose]
Insulin Mechanism of Action
Extracellular
fluid
1 Insulin binds to tyrosine
kinase receptor.
Insulin
1
2 Receptor phosphorylates
insulin-receptor substrates (IRS).
3 Second messenger pathways
alter protein synthesis and
existing proteins.
GLUT4
2
IRS
IRS
P
3
Nucleus
Second
messenger
pathways
4
Transport
activity
Enzymes
or
5
Transcription
factors
4 Membrane transport
is modified.
5 Cell metabolism is
changed.
Changes in
metabolism
Figure 22-11
Insulin Lowers Plasma Glucose
1. Increases glucose transport into most insulinsensitive cells
2. Enhances cellular utilization and storage of
glucose
3. Enhances utilization of amino acids
4. Promotes fat synthesis
Insulin Increases Glucose Transport
• Required for resting skeletal muscle and
adipose tissue
• Moves GLUT-4 transporters to cell membrane
• Exercising skeletal muscle does not require
insulin for glucose uptake
• In liver cells, indirect influence on glucose
transport
Insulin Increases Glucose Transport:
Skeletal Muscle & Adipose Tissue
GLUT-4 transporters moved to cell membrane
Figure 22-12
Insulin Increases Glucose Transport:
Indirect in Liver Cells
Insulin activates hexokinase, keeps IC [glucose] low
Figure 22-13
Insulin Enhances Utilization and
Storage of Glucose
• Activates enzymes for:
– Glycolysis – glucose utilization
– Glycogenesis – glycogen synthesis
– Lipogenesis – fat synthesis
• Inhibits enzymes for:
– Glycogenolysis – glycogen breakdown
– Gluconeogenesis – glucose synthesis
Insulin Enhances Utilization of
Amino Acids
• Activates enzymes for protein synthesis in
liver and muscle
• Inhibits enzymes that promote protein
breakdown (no gluconeogenesis)
• Excess amino acids converted into fatty acids
Insulin Promotes Fat Synthesis
• Inhibits β-oxidation of fatty acids
• Promotes conversion of excess glucose into
triglycerides
• Excess triglycerides stored in adipose tissue
Energy
storage
Glucose
metabolism
Figure 22-14
Glucagon
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Origin in α cells of pancreas
Peptide hormone
Transported dissolved in plasma
Half-life ~5 min
Target tissues: mostly liver
α cells require insulin to uptake glucose
Glucagon
• Secretion promoted by:
– Low plasma [glucose] (< 100 mg/dL)
– Increased plasma amino acids
– Sympathetic input
• Secretion inhibited by increased [glucose]
• Inhibition by insulin??
Glucagon Raises Plasma Glucose
• Main purpose is to respond to hypoglycemia
• Activates enzymes for:
– Glycogenolysis – glycogen breakdown
– Gluconeogenesis – glucose synthesis
Response to Hypoglycemia in Fasted State
Figure 22-15
Diabetes Mellitus
• Family of diseases
• Chronic elevated plasma glucose levels
= hyperglycemia
• Two types:
– Type 1 – insulin deficiency
– Type 2 – ‘insulin-resistant’ diabetes; cells do not
respond to insulin
Type 1 Diabetes
• ~10% of cases
• Absorb nutrients normally, but no insulin
released – what happens?
• Cells shift to fasted state, leading to glucose
production!
• Results in hyperglycemia and cascading
effects
Figure 22-16
Type 2 Diabetes
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~90% of cases
Target cells do not respond normally to insulin
Delayed response to ingested glucose
Leads to hyperglycemia
Often have elevated glucagon – why?
– No uptake of glucose by α cells
– Release glucagon
• Exercise and modified diet help treat – why?