Flashcards in Metabolism Deck (139):
What is homeostatic eating?
What is non-homeostatic eating?
Homeostatic: Eating when energy fuels are depleted, and non eating when energy fuels are sufficient.
Non-homeostatic: Eating in the absence of hunger, and eating despite large fat reserves.
Which type of eating is also considered metabolically-driven eating?
Which type of eating is also known as "hedonic" eating?
How many centers in the hypothalamus are responsible for homeostatic eating?
2. The "hunger/feeding" center, and the "satiety" center.
What is the glucostatic theory?
- Intake regulated by glucose levels, monitored by centers in the hypothalamus.
- Plasma glucose low -> Satiety center suppressed -> Feeding center dominant.
What is the lipostatic theory?
Signal from fat stores to brain modulates eating behaviour.
What does leptos mean?
What is the relationship between leptin and the "ob" and "db" genes?
In the 1950's, a spontaneous mutation arose in a mouse colony that made the mice more obese, voracious eaters.
In the 1990's, the mutation was identified to be in the "ob" gene, and mice who were "ob/ob" or "db/db" had dysfunctional leptin receptors.
What is the purpose of leptin?
What happens to the stomach during increased appetite?
Increase in ghrelin, secreted by cells of an empty stomach.
What happens to the stomach during decreased appetite?
Increase in stretch, causing an increase in acid from the acid-sensing ion channels).
What happens to the upper small intestine during decreased appetite?
- Increase in CCK (in response to fat/protein in lumen).
- Increase in glucose in lumen.
What happens to the lower small intestine/colon during decreased appetite?
- Increased peptide YY (PYY), inhibits release of neuropeptide Y.
- Increased GLP-1
What are PYY and GLP-1 triggered by?
Macronutrients in lumen and also neural reflex from upper small intestine.
What is neuropeptide Y a key neurotransmitter in the stimulation of?
What interacts to influence appetite?
Many hormones, neuropeptides, and products of adipocytes.
What is metabolic rate?
Glucose + Oxygen + ADP + Pi -> Carbon Dioxide + Water + ATP + Heat
True or False: The rate of CO2 produced to O2 consumed is the same for all macronutrients.
What are some factors that affect metabolic rate?
- Lean muscle mass
- Activity level
- Hormones, gut peptides
What are the 3 possible fates of ingested biomolecules?
1) Metabolized to provide energy to fuel mechanical work.
2) Used in synthesis reactions for growth and maintenance of tissues.
3) Stored as glycogen (liver, skeletal muscles) or fat.
What are the 2 states of metabolism?
1) Fed/absorptive state
2) Fasted/postabsorptive state
What is the fed/absorptive state?
Anabolic. Products of digestion being absorbed and used for synthesis or stored.
What is the fasted/postabsorptive state?
Catabolic. Body taps into stores.
What are the 3 nutrient pools available for immediate use?
1) Free fatty acid pool
2) Glucose pool
3) Amino acid pool
What is lipogenesis?
The formation of fat.
What happens to the direction of metabolism if there is no regulation of enzymatic activity?
No net synthesis of A or B.
The pathway will simply cycle back and forth.
What happens to the direction of metabolism during a fed-state?
Net glycogen synthesis.
Under the influence of insulin, enzyme activity for the forward reaction increases. Enzymes for glycogen breakdown are inhibited.
What happens to the direction of metabolism during a fasted-state?
Net glucose synthesis.
Under influence of glucagon, enzymes that break down glucose are more active, and enzymes for glycogen synthesis synthesis are inhibited.
Where does glycolysis occur? Where does the citric acid cycle occur?
Glycolysis occurs in the cytoplasm, whereas the CAC occurs in the mitochondria.
What is the destination(s) of carbohydrates (glucose)?
Travels to the liver, where 70% passes through to the brain, muscles, and other tissues. The other 30% moves into hepatic cells.
What is the purpose of glycogen?
Provides ready energy source in skeletal muscles.
It is the main source of glucose in the postabsorptive state.
How much glycogen does the liver keep on supply?
~ 4 hour supply.
What is the destination(s) of amino acids?
Travels through the liver to:
- Pass through and used for synthesis of structural proteins, enzymes, hormones, amines...
- Some move out of sinusoids into hepatic cells, for the synthesis of liver enzymes, plasma proteins, lipoproteins...
If not used for protein synthesis, what can amino acids be used for?
They can be deaminated and their carbon skeletons re-deployed:
- Converted to key metabolites that lead to pathways that generate glucose.
- Converted to acetoacetate but can't enter CAC. Instead, use to make fatty acids.
What are gluconeogenic AA's?
Converting key metabolites that lead to pathways that generate glucose.
I.e. Acetoacetate, pyruvate, CAC intermediates.
What are ketogenic AA's?
Those used to make fatty acids (reverse of beta-oxidation).
Produce ketone bodies.
What is the process of fat synthesis?
1) Glycerol can be made from glucose through glycolysis.
2) Fatty acids made when 2-carbon acyl units from acetyl CoA linked together.
3) One glycerol + 3 fatty acids -> triglycerides. Occurs in smooth ER.
4) Even with zero dietary cholesterol, cholesterol can and will be synthesized from acetyl CoA.
What is the transport of fats from the intestine to the blood?
Fats (triglycerides) exit the intestine via the lymph as chylomicrons (formed in enterocytes) and eventually reach systemic circulation.
What are chylomicrons?
Particles consisting of a fatty core (triglycerides, cholesterol esters) and an outer coating of amphipathic and hydrophilic molecules (free cholesterol, phospholipids, apoproteins).
What are apoproteins involved in?
Delivery to certain cell types.
What happens to fats as it passes through capillaries in key organs?
They're "harvested", mostly through the action of lipoprotein lipase (lpl), expressed by endothelial cells lining capillaries.
True or False: Free fatty acids travel in the blood unbound.
False. Bound to serum albumin.
What happens to fat as it's being removed?
The remaining particle becomes smaller and more dense (less fatty).
What is the density of fat particles from lowest to highest?
- Chylomicron remnant
What are the 3 possible fates of a fat particle taken up by liver?
2) Store (triglycerides)
3) Export (release into circulation)
Which type of fat particle can only be taken into cells by receptor-mediated endocytosis?
What is the process of fasted-state metabolism?
1) Liver glycogen -> glucose
2) TG's in adipose -> FFA's and glycerol -> Enter blood.
3) Glycogen used for energy. Muscles also use fatty acids and break down their proteins to AA's that enter blood.
4) Brain can use only glucose and ketones for energy.
What are the 2 options for the formation of glucose 6-PO4 from glycogen?
1) Splitting off glucose by addition of Pi.
2) Splitting off glucose then spending an ATP to phosphorylate.
True/False: Only the liver has the enzymes to generate free glucose for export to plasma.
How can muscle contribute to plasma glucose?
Only indirectly by exporting pyruvate or lactate.
What is the process of AA catabolism?
1) AA' s are deaminated, giving rise to intermediates.
2) Intermediates can either directly enter glycolysis or CAC, OR
3) Be sent to the liver to be converted to glucose (gluconeogenesis).
What is proteolysis?
Breakdown of muscle protein.
What is the process of lipolysis?
1) Lipase digests TG's into glycerol and fatty acids.
2) Glycerol becomes a glycolysis substrate.
3) Beta-oxidation chops 2-carbon acyl units off of free fatty acids.
4) Acyl units become acetyl CoA and can be used in CAC.
What happens if lipolysis proceeds faster than acetyl CoA can be used in TCA Cycle?
Ketone bodies are formed.
What are ketone bodies typically used for?
What kind of diet generates ketone bodies?
Can enter blood and serve as energy substrates for brain during times of starvation.
Typically generated by low carb, high fat/protein diets.
When can ketogenesis become dangerous?
Certain ketone bodies (acetoacetic acid, beta-hydroxybutyric acid) are strong metabolic acids that can disrupt acid/base balance, leading to ketoacidosis.
What do we mean by "metabolism"?
A set of life-sustaining chemical transformations within the cells of living organisms.
What are the islet of langerhans?
Tiny clusters of cells scattered throughout the pancreas. Contain alpha cells (glucagon), D cells (somatostatin), and beta cells (insulin).
What is the Insulin to Glucagon ratio in a fed state?
What about a fasted state?
Fed state: glucagon:INSULIN
Fasted state: GLUCAGON:insulin
Which processes are increased during a fed state?
- Glucose oxidation
- Glycogen synthesis
- Fat synthesis
- Protein synthesis
Which processes are increased during a fasted state?
What are the relationships between plasma glucagon levels, plasma glucose levels, and plasma insulin levels, and meals?
Plasma glucagon levels are at its max just before a meal, then rapidly declines.
Plasma glucose levels sharply reach its max almost an hour after a meal, then slowly declines to fasting levels.
Plasma insulin levels sharply reach its max approx. 30 min after a meal, then slowly declines.
What is the fasting level of glucose?
What are some factors that affect insulin release?
- Increased plasma glucose
- Increased plasma AA's
- Increased GLP-1, GIP
- Increased parasympathetic activity
What are the targets of insulin?
- Striated muscle
- Adipose tissue that express a GLUT4 transporter
What processes occur as a result of insulin secretion?
- Increased glucose transport into GLUT4-expressing target cells
- Increased glucose metabolism
- Increased glycogenesis
- Increased fat & protein synthesis
What are some features of pancreatic beta cells?
- They have GLUT2 transporters.
- They have K+ leak channels.
- They have voltage-gated Ca2+ channels.
- They have secretory vesicles of insulin waiting for release signal.
True/False: K+ leak channels in a beta cell are always open.
False. They're usually open, but close when ATP binds to them.
How does GLUT2 transporters move glucose into the beta cell?
By facilitated diffusion.
What is the process of a beta cell at rest (when blood glucose is low)?
1) Low blood glucose.
2) Metabolism slows.
3) Decreased ATP.
4) K+/ATP channels open.
5) Cell at resting membrane potential. No insulin is released.
What is the process of a beta cell when its releasing insulin?
1) High blood glucose.
2) Metabolism increases.
3) Increased ATP.
4) K+/ATP channels close.
5) Cell depolarizes and calcium channels open.
6) Ca2+ enters the cell.
7) Exocytosis of insulin.
What are the components of an enzyme coupled Receptor Tyrosine Kinase (RTK)?
- 2 alpha subunits: Extracellular. Binding site for insulin.
- 2 beta subunits: Penetrate through the plasma membrane.
What happens when RTK's are activated?
RTK's transfer phosphate groups from ATP to tyrosine residues on target proteins.
What is the Insulin mechanism of action?
1) Insulin binds to tyrosine kinase receptor (RTK).
2) RTK phosphorylates insulin-receptor substrates.
3) Second messenger pathways alter protein synthesis and existing proteins.
4) Membrane transport is modified.
5) Cell metabolism is changed.
What are insulin's effects in muscle and adipose tissue during a fasted state vs. a fed state?
In a fasted state, there's no insulin, so there's no GLUT4 transporters on the membrane.
In a fed state, the insulin binds to receptors, and GLUT4 transporters are inserted into the membrane, allowing glucose to move into the cell.
What are insulin's effects in hepatocytes during a fasted state vs. a fed state?
In a fasted state, blood glucose and insulin levels are both low, so hepatocytes make glucose and export it via GLUT2 transporters.
In a fed state, blood glucose and insulin levels are high, so the gradient favours glucose import via GLUT2. Insulin signalling activates hexokinase glucose -> glucose 6-PO4, to keep free glucose [low] in cell.
Insulin is ___________ (anabolic/catabolic)?
When insulin is low or absent, __________ pathways predominate.
What is the main function of glucagon?
Where is it produced?
To prevent hypoglycemia.
Produced by alpha cells of pancreas.
Glucagon acts via ... ?
A G protein-coupled receptor, cyclic AMP
During an overnight fast, how much of the glucose from the liver comes from glycogenolysis? How much from gluconeogenesis?
75% from glycogenolysis.
25% from gluconeogenesis.
What is the endocrine response to hypoglycemia?
- Activate pancreatic alpha cells
- Inhibit pancreatic beta cells
Causes increase in glucagon, and decrease in insulin, which ultimately results in increased glucose.
What is diabetes mellitus?
A group of diseases characterized by elevated blood glucose (hyperglycemia), resulting from:
- Inadequate insulin secretion (Type 1).
- Abnormal target cell responsiveness (Type 2).
What are considered normal levels of plasma glucose?
Which type of diabetes is more common? What was it once called?
Type 2. Once called "mature onset" diabetes.
What are some characteristics of Type 2 diabetes?
- Acute symptoms not as severe as Type 1, but metabolism is not normal.
- Often co-occurs with atherosclerosis and hypertension (metabolic syndrome).
- At least 3 of: Central obesity, hypertension, fasting blood glucose > 110 mg/dL, elevated fasting triglycerides, and/or low plasma HDL.
What is insulin resistance?
Delayed response to a glucose "challenge" (oral glucose tolerance test).
Can be coupled with low, normal, or high insulin secretion.
With all of these homeostatic pathways, how can we still become obese?
Larger animals have significant energy stores to go without food for relatively long periods, but food restriction and fat depletion eventually lead to "hungry brain".
Evolutionarily, there was also a constant struggle to find enough food for survival, which resulted in very strong defence of the lower limits of adiposity.
What is "hungry brain"?
A powerful effector mechanism that are adaptable, flexible, and learns from experience.
In the modern environment, what are some factors that lead modern humans to be more obese than ever?
- Overstimulate food intake through advertising, social cues, stress.
- Procuring food is no longer demanding/dangerous.
- Exceeding the upper limits of body weight is no longer a disadvantage in terms of predatory/prey relationships.
- Many obese humans become leptin-resistant.
What does the adrenal gland produce?
- Cortisol, corticosterone
- Weak androgens
- Catecholamines (mostly epinephrine)
What does "ad renal" mean?
On the kidneys.
What are the 5 regions of the adrenal gland (from outermost to innermost)?
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
- Adrenal medulla
Which region of the adrenal gland secretes catecholamines?
Which region of the adrenal gland secretes steroid hormones?
All 3 "Zona"'s, which make up the adrenal cortex.
Which region of the adrenal gland secretes glucocorticoids?
True/False: Cortisol is secreted in a circadian rhythm.
What are the target cells of glucocorticoids?
Receptors expressed by all nucleated cells.
What are the effects of glucocorticoids?
1) Prevention of hypoglycemia.
2) Suppress immune response.
By increasing expression of enzymes, and receptors for other regulatory hormones.
Are the effects of glucocorticoids short or long term effects?
Mostly longer-term (genomic) effects.
Glucocorticoids are __________ for full effects of glucagon and epinephrine.
What did Hans Selye do?
Developed concept that a wide variety of stressors caused a generic response:
- Adrenal hypertrophy
- Atrophy of thymus/lymph nodes
- GI ulcers
He noted that failure to cope with/adapt to stresses caused diseases of adaptation.
Led to many breakthroughs wrt the HPA-axis.
Where does norepinephrine come from? What about epinephrine?
Norepinephrine comes from sympathetic post-ganglionic neurons.
Epinephrine comes from adrenal medulla.
How are epinephrine and glucagon similar? How are they different?
Effects are similar, but the receptors for epinephrine are expressed on a broader range of target cells.
What is hypercortisolism?
Primary: Cortisol-secreting adrenal tumors (not regulated by ACTH).
Secondary: Pituitary tumor that over-secretes ACTH.
Iatrogenic: Secondary to cortisol therapy for other conditions.
What is hypocortisolism?
Primary adrenal insufficiency (Addison's disease).
- Adrenal gland does not develop normally.
- Mutations in key steroidogenic enzymes.
- Adrenal gland damaged/destroyed (autoimmune).
Secondary: Lack of ACTH.
What do follicular cells secrete?
What do C cells produce?
What is thyroid hormone?
An amino acid derivative (tyrosine) containing iodine.
Which macromolecule's mechanism of action is most similar to the mechanism of action for thyroid hormone?
Steroids. Both bind to nuclear receptors.
Is thyroid hormone lipophilic or lipophobic?
What are the 2 main types of thyroid hormone?
T4: Main circulating type
T3: Most active form, converted at target cell by deiodinases.
What is the purpose of thyroid hormone?
- Essential for normal growth/development, esp. nervous system.
- Provide substrates for oxidative metabolism.
- Increase oxygen consumption and generation of heat.
- Interact with other hormones to modulate carbohydrate/protein/lipid metabolism.
True/False: Thyroid hormone is essential at all ages.
False. Not essential in adults, but does affect quality of life.
What is hypothyroidism?
- Decreased oxygen consumption
- Decreased metabolic rate (cold intolerant)
- Neurological effects, fatigue
- Effects on nail, skin, hair
What is the most common cause of hypothyroidism?
Iodine deficiency -> enlarged thyroid gland -> goitre
What is hyperthyroidism?
- Increased oxygen consumption
- Increased heat production (heat intolerant)
- Muscle weakness (catabolism)
- Neurological/cardiac effects
- Exophthalmos (protruding eyes)
What is the most common cause of hyperthyroidism?
Autoantibodies that resemble TSH overstimulate thyroid gland (not subject to negative feedback regulation).
What does the control of growth depend on?
- GH, and other hormones
- Adequate nutrition
- Absence of chronic stress
True/False: The effects of Growth Hormone are indirect.
False. Can be direct or indirect.
Direct: Target cells express GH receptor.
Indirect: Mediated by insulin-like growth factors produced by liver or target cells themselves.
What are the metabolic actions of growth hormone on carbohydrates?
Indirect effects lead to increase in plasma glucose.
What are the metabolic actions of growth hormone on fats?
Increased lipolysis and increased oxidation.
Catabolic wrt CHO's and fat. "Anti-insulin".
What are the metabolic actions of growth hormone on protein?
Increased AA uptake, increased protein synthesis, but decreased oxidation for energy.
Anabolic wrt proteins. "pro-insulin".
How does growth hormone actually affect growth?
- Increased proliferation and differentiation of chondrocytes, which lead to cartilage and bone growth.
- Increased muscle growth.
- Increased growth of other soft tissues.
What happens if there's a deficiency in growth hormone secretion?
What happens if there's an excess in growth hormone secretion?
Depends on whether the excess secretion is before or after closure of growth plates of long bones.
What are some ethical issues raised with the growing availability of bioengineered human GH?
- How tall is tall enough?
- How to predict when children will be "too short"?
- Used as performance enhancing drug.
What is extracellular calcium involved in?
- Contraction of cardiac and smooth muscle.
- Clotting cascade.
What is intracellular calcium involved in?
Muscle contraction, signalling pathways.
What is calcium a component of?
Extracellular matrix of bones and teeth.
What is the purpose of osteoblasts?
Lay down Ca-PO4
What is the purpose of osteoclasts?
Secrete enzymes/H+ that dissolve mineral matrix -> Resorption.
How much of ingested calcium is absorbed?
1/3, absorbed by paracellular and transcellular routes.
Which route of calcium intake is hormonally regulated?
Which organ is the primary source of Calcium output?
Kidneys. Freely filtered, but most reabsorbed, at distal nephron only.
Which hormone is the main regulator of plasma [Ca2+]?
What does it do?
Parathyroid hormone (PTH).
It increases gut absorption (via transcellular route), renal reabsorption, and bone resorption.
Which vitamin assists PTH?
When is PTH released?
In response to decreased plasma Ca2+.