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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:
– 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

Free fatty acids + glycerol


Build
proteins
Excess
Protein
stored Glycogenesis Amino synthesis
Glucose Excess acids
Lipogenesis

Fat Lipogenesis
stores Excess glucose stored
Glycogen Body
stores protein
Lipolysis Urine
Glycogenolysis
Glucose pool
Gluconeogenesis
Free fatty
Range of normal
acid pool
plasma glucose Amino acid
Many pool

immediately Excess converted


used Many
in liver
Metabolism in immediately
Brain
most tissues used
Excess nutrients 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
Fasted State 2 Adipose lipids
becomes glucose. become free
fatty acids and Triglyceride stores
glycerol that
enter blood.

Liver Free fatty Free fatty


Glycerol
glycogen acids acids
stores
Glycogenolysis -oxidation
Gluconeogenesis

Energy Ketone
production bodies Energy production
Glucose

Glycogen Proteins

Gluconeogenesis
Pyruvate
or
Lactate
Amino
Ketone acids
Glucose
bodies

Energy production
3 Muscle glycogen can be used for energy.
4 Brain can use Muscles also use fatty acids and break
only glucose and down their proteins to amino acids that
ketones for energy. enter the blood.
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
Insulin 1 Insulin binds to tyrosine
fluid
kinase receptor.

1
2 Receptor phosphorylates
insulin-receptor substrates (IRS).

3 Second messenger pathways


GLUT4 alter protein synthesis and
2 existing proteins.
IRS IRS P Transport
4
3 activity 4 Membrane transport
is modified.
Second
Nucleus messenger
pathways Enzymes or
5 Cell metabolism is
5 changed.
Transcription
factors Changes in
metabolism

Figure 22-11
Insulin Lowers Plasma Glucose
1. Increases glucose transport into most insulin-
sensitive 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 Glucose
storage metabolism

Figure 22-14
Glucagon
• 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
• ~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?