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

Figure 22-1

inhibition

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

Figure 22-2

CarbohydratesFats

Free fatty acids + glycerol

Fatstores

Glucose

Excess glucose

Glycogenstores

Aminoacids

Proteins

DIET

Lipogenesis

Brainmetabolism

Range of normalplasma glucose

Gluconeogenesis

Bodyprotein

Glycogenolysis

GlycogenesisProteinsynthesis

Metabolism inmost tissues

Free fattyacid pool

Urine

Excess nutrients

Lipolysis

Glucose pool

Amino acidpool

Lipogenesis

Many immediately

used

Excess stored

Excess converted in liver

Build proteins

Many immediately

used

Excess stored

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

Figure 22-4

enzyme 1 enhanced, enzyme 2 inhibited

enzyme 1 inhibited, enzyme 2 enhanced

INSULIN

GLUCAGON

Metabolism is Controlled by Ratio of Insulin and Glucagon

Figure 22-9

Anabolic

Catabolic

Fed State

Many immediately used

Figure 22-7

Liverglycogen

stores

Energy production

Free fattyacids

Free fattyacids

Glycerol

Aminoacids

KetonebodiesGlucose

Adipose lipidsbecome freefatty acids andglycerol thatenter blood.

Muscle glycogen can be used for energy.Muscles also use fatty acids and breakdown their proteins to amino acids thatenter the blood.

Brain can useonly glucose andketones for energy.

or

Triglyceride stores

Glycogen

Pyruvate

Lactate

Energy production

Glucose

Proteins

Ketonebodies

Gluconeogenesis

Gluconeogenesis

1 2

34

Energyproduction

Liver glycogenbecomes glucose.

-oxidationGlycogenolysis

Fasted State

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

PIRSIRS

Secondmessengerpathways

Transcriptionfactors

Enzymes or

Transportactivity

Changes inmetabolism

Nucleus

Extracellularfluid Insulin

GLUT4

Insulin binds to tyrosinekinase receptor.

Receptor phosphorylatesinsulin-receptor substrates (IRS).

Second messenger pathwaysalter protein synthesis andexisting proteins.

Membrane transportis modified.

Cell metabolism ischanged.

1

2

3

4

5

1

2

34

5

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

Figure 22-12GLUT-4 transporters moved to cell membrane

Insulin Increases Glucose Transport:Indirect in Liver Cells

Figure 22-13Insulin activates hexokinase, keeps IC [glucose] low

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

Figure 22-14

Glucose metabolism

Energy storage

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

Figure 22-15

Response to Hypoglycemia in Fasted State

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?