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

Excess converted in liver Metabolism in most tissues DIET Fats Carbohydrates Proteins Build proteins Free fatty acids + glycerol Excess stored Protein synthesis Glycogenesis Excess stored Amino acids Glucose Fat stores Lipogenesis Excess glucose Lipogenesis Glycogen stores Body protein Lipolysis Urine Glycogenolysis Glucose pool Gluconeogenesis Free fatty acid pool Range of normal plasma glucose Amino acid pool Many immediately used Excess converted in liver Many immediately used Metabolism in most tissues Brain metabolism Excess nutrients 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

Fasted State Figure 22-7 1 Liver glycogen becomes glucose. 2 Adipose lipids become free fatty acids and glycerol that enter blood. Triglyceride stores Liver glycogen stores Free fatty acids Free fatty acids Glycerol Glycogenolysis -oxidation Gluconeogenesis Energy production Ketone bodies Energy production Glucose Glycogen Proteins Gluconeogenesis Pyruvate or Lactate Amino acids Ketone bodies Glucose 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: Secretion inhibited 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 Insulin binds to tyrosine kinase receptor. 1 2 Receptor phosphorylates insulin-receptor substrates (IRS). 3 Second messenger pathways alter protein synthesis and existing proteins. GLUT4 2 IRS IRS P Transport activity 4 3 4 Membrane transport is modified. Second messenger pathways Nucleus Enzymes or 5 Cell metabolism is changed. 5 Transcription factors Changes in metabolism Figure 22-11

Insulin Lowers Plasma Glucose Increases glucose transport into most insulin-sensitive cells Enhances cellular utilization and storage of glucose Enhances utilization of amino acids 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 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?