3: Lipids + Carbohydrates Role in Health + Disease

maintaining homeostasis requires metabolic regulation that coordinates the use of _______ _______

nutrient pools

homeostasis adjusts the ______ and _______ rates to maintain physiological levels while also meeting essential demands

production consumption

How is homeostasis analogous to a bucket with a hole?

• water going into the bucket = what we produce from our diet (energy consumed)

• hole on the side = clearance and oxidation (energy expended)

• water left in bucket = macromolecules left in blood and tissues (energy stored)

the ability to maintain adequate, but not excessive, energy stores

caloric homeostasis

if fuels are consumed in excess of energy needs, the fuels are STORED

excess energy molecules are ultimately converted to ________ which are stored in __________

triacylglycerols

adipocytes

triacylglycerols represents energy that is _________

fuel is expended as ________, _________, and _______ which are oxidized in the citric acid cycle

stored

amino acids, fatty acids, monosaccharides

excessive energy storage beyond what is needed during fast leads to an accumulation of _______________ leading to enlarged ___________ which increase _________ ___________

triacylglycerols

adipocytes

body weight

In 24 hours you …

• consume 120 moles of dietary fatty acids

• oxidize fatty acids for energy at 2 moles per hour

• excrete (via urine + feces) at an average rate of 0.5 moles per hour

the concentration of free fatty acids is the SAME at the beginning and end of the day

Assuming no changes in other fatty acid consumption routes, what must be the effect on triglyceride pools in this person?

120- 2(24) - 0.5(24) = 60 remaining fatty acids to be stored

each triglyceride = 3 fatty acids so

60 fatty acids /3 = + 20 triacylglycerols to storage pool

energy balance is controlled by both BEHAVIORAL and BIOCHEMICAL factors

list some examples of each

behavioral = diet, exercise

biochemical = short term + long term signals, resting metbaolic rate + hormones

which organ plays a KEY role in caloric homeostasis

where does it send short term andlong term signals to?

Brain

• GI tract

• B cells of pancreas

• fat cells

what is the difference between the short term and long term signals sent from the brain to the GI tract, pancreas, and fat cells?

both signals target the brain’s ______ _________, a group of neurons in a region of the ___________

short = active DURING meal

long = report on OVERALL energy status of body

arcuate nuerons hypothalamus

small peptide hormones secreted from the ____________ signal distal organs such as the _______ and __________

from: small intestine

to: pancreas and brain

what are two examples of short term signals that relay feelings of satiety from the gut to various regions of the brain, REDUCING the urge to eat

cholecystokinin (CKK)

Glucagon like peptide - 1 (GLP-1)

CCK and GLP-1 are released are small hormones released by the __________ that bind to their GPCRs in the _________ ________ which relay hunger/satiety signals

small intestine

peripheral neurons

satiety

GLP-1 signals both the _________ and ______ while CKK signals the __________

GLP-1 = brain AND pancreas (increase insulin)

CKK = brain

stimulates the secretion of pancreatic enzymes and bile salts from the gall bladder

CCK

ENHANCES glucose- induced insulin secretion and INHIBITS glucagon secretion

GLP-1

Does insulin increase or decrease the following:

• ___________ glycogen

• ____________lipogenesis

• ____________lipolysis

• increase

• increase (from triacylglycerides from fatty acids to be stored)

• decrease

how does insulin effect the muscle?

• increase glucose uptake

• increase glycogen synthesis

what does insulin stimulate the ADIPOSE TISSUE to do?

• increase lipogenesis

• decrease lipolysis

• increase glucose uptake and storage

what does insulin stimulate the LIVER to do?

• increase glycogen synthesis

• decrease glucose release to the bloodstream

• decrease gluconeogenesis

• increase lipogenesis

what does insulin stimulate the BRAIN to do?

• inhibit hepatic glycogenoLYSIS

• inhibit lipolysis

• decrease appetite

_____________ decreases energy storage activating ______ to catalyze the hydrolysis of triacylglycerols to fatty acids

glucagon

lipases

What do GLP-1 Agonists like the following do?

• Mounjaro

• Wegovy

• Trulicity

• Ozempic

• increase insulin release from pancrease

• inhibit glucagon release from pancreas

• DECREASE rate of stomach emptying (digestion)

• increase satiety (fullness)

do GLP-1 agonists increase or decrease the rate of stomach emptying (digestion)?

DECREASE digestion to decrease your appetite

signal molecule that communicates the status of triacylglycerol stores

leptin

what is the difference between GLP-1 and leptin?

leptin communicates the amount of TRIACYLGLYCERIDE stored in the body

insulin communicates the status of GLUCOSE in the blood

leptin is secreted from ________ in direct proportion to the amount of _____ present

adipocytes \

fat

when leptin binds to its receptors it increases the sensitivity of the ________ and the ______ to INSULIN

stimulating the ____-________ of FATTY ACIDS

decreasing triacylglycerol synthesis

muscle and liver

b-oxidation

does leptin increase or decrease triacylglycerol synthesis?

DECREASE

increases b-oxidation of fatty acids using them for energy

adipokine secreted by adipose tissue in direct relation to fat mass

leptin

SEQ Leptin Action

1. fat mass increases

2. leptin inhibits appetite stimulating peptides _______ and _________ secretion

3. Leptin activates ________- producing neurons which increases ________ expression suppressing appetite

2. NPY and AgRP

3. POMC- —→ MSH

which hormones when stimulated induce appetite?

• NPY

• AgRP

a psychological condition experienced after an evening meal and throughout night’s fast

fasted-fed cycle

what are the three stages of the fasted-fed cycle?

1. well - fed (POST prandial)

2. early fasting (POST absorptive)

3. refed state

during which part of the fasted-fed cycle are the following levels at their highest

• glucagon

• insulin

• glucose

• liver glycogen

• fasted

• fed

• fed

• fed

what do each of the curves represent if the x axis going from left to right represents hours of starvatio?

blue = insulin

purple = glucagon

green = glucose

red = glycogen in liver

state that immediately follows the absorption of glucose from the previous meal when blood-glucose concentration begins to drop

leads to

• _______ in insulin secretion

• _______in glucagon secretion

post-absorptive (early fasting)

• decreased

• rise

what happens to insulin and glucagon levels in the post-absorptive state?

post absorptive is another word for fasted state

• decrease insulin

• increase glucagon

what are the 5 roles of glucagon

1. increase glycogenolysis (glycogen breakdown)

2. decrease glycogen synthesis

3. inhibit fatty acid synthesis

4. increase gluconeogenesis in LIVER

5. BLOCK glycolysis (use a different source for ATP)

PYRUVATE—>

**oxaloacetate**

phosphoenolpyruvate (PEP)—>

Fructose 1,6- bisphosphate —>

**fructose 1,6- biphosphate 1 (FBP1)**

Fructose 6- Phosphate

Glucose 6- Phosphate—>

**Glucose 6-phosphatase**

GLUCOSE

the following describes the events of which process?

glycolysis

GLUCOSE

*hexokinase / glucokinase*

glucose 6- phosphate —>

fructose 6- phosphate —>

* phosphofructokinase 1 *

fructose 1,6- bisphosphate —_>

phosphoenolpyruvate (PEP) —->

*pyruvate kinase*

PYRUVATE

the following describes the events of which process?

glycolysis

__________ and ___________ are reciprocally related

glycolysis and gluconeogenesis

which enzyme is key in the regulation of glycolysis?

which enzyme is key in regulation of gluconeogenesis?

• phosphofructokinase

• fructose 1, 6 bisphosphotase

does the following conversion occur in the fasted or fed state?

Fructose 6- phosphate —→

** PHOSPHOFRUCTOKINASE ENZYME *

Fructose 1, 6- bisphosphate

fed — glycolysis

does the following conversion occur in the fasted or fed state?

Fructose 1, 6 bisphosphate —→

**Fructose 1,6 bisphosphatase enzyme **

Fructose 6-phosphate

fasted— gluconeogenesis

is this the key step in glycolysis or gluconeogenesis ?

does the following occur in the fasted or fed state ?

glycolysis

fed

is this the key step in glycolysis or gluconeogenesis ?

does the following occur in the fasted or fed state ?

gluconeogenesis

fasted

SEQ: eating after LONG fast

1. does the liver immediately absorb glucose from the blood?

2. is the liver in a gluconeogenesis state or glycogenolysis state?

3. what happens to the excess glucose that remains after glycogen stores are replenished?

1. NO leaves glucose in the blood for other tissues

2. still gluconeogenesissis

3. glucose is used to synthesize fatty acids

the conversion of frucose 6-phosphate to fructose 1,6-bisphosphate by phosphofructokinase is

• inhibited by?

• activated by?

• inhibited by Citrate + ATP (dont need to do glycolysis)

• activated by AMP and F-2, 6-BP

the conversion of 1,6-bisphosphate to fructose 6-phosphate to fructose by Fructose 1,6 bisphosphotase is

• inhibited by?

• F-2, 6-BP

• AMP

disease resulting from the disruption of caloric homestasis

• overproduction of glucose by liver and UNDERUTILIZATION by organs — stays in blood

where does this disease gets its name from?

diabetes mellitus

frequent urination

10 hour fast

• no dietary glucose

• constant glucose concentration

• glucose oxidized for energy 2000 moles per hour

• no excretion of glucose

• gluconeogenesis = 100 moles per hour

• glyycogen consists of 1,000 glucose molecules

assuming no change in glucose production or consumption, what must the effecr be on liver glycogen pools in this person by the end of this fast

100 (10) - 2000 (10) = -19000 moles of glucose

-19000/1000 = -19 moles of glycogen

diabetes leads to increased _______ elevation and slower ___________ after a meal

glucose

clearance

which curves respond to a patient with diabetes? what is noticibely different with those with diabetes vs. those without

black = healthy

colored = diabetic

levels of glucose in the blood are larger AND sustained don’t go down as quick as healthy individual

diabetic individuals have HIGHER levels of insulin, but they are resistant to them

which type of diabetes is insulin- dependent?

type 1

these patients rely on medicinal insulin as they do not produce them on their own as opposed to type 2 individuals who HAVE insulin but have grown resistant

diabetes caused by the destruction of the insulin secreting B cells of the pancreas

• _______ disorder

• begins before age ______

• autoimmune

• 20

type _____ diabetes occurs later on in life than type ___ diabetes and accounts for 90% of cases in the world

what is a predisposing factor of this form of diabetes?

2 1

obesity

cluster of pathologies including

• insulin resistance

• hyperglycemia

• dyslipidemia (high triacylglycerols)

predecessor of type ___ Diabetes

metabolic syndrome

2

conditions in which tissues OTHER THAN adipose tissues accumulate fat

which tissues often accumulate fat?

often results in _______ resistance and _______ failure

hepatic steatosis

liver and muscle

insulin pancreatic

storage capacity of _______ ________ can be exceeded leading to lipid accumulation in other tissues such as … leading to ______ ____________

adipose tissue

• blood vessels

• liver

• pancreas

• muscle

excess tissue triglycerides can disrupt signal-transduction pathways leading to _________

insulin resistance

excess fat accumulation in peripheral tissues

SEQ events leading up to insulin resistance:

1. overnutrition + inactivity

2. increased _______ ______ supply —→

3. increased _____ ______

4. increased triacylglycerols and mitochondrial overload

what follows increased levels of triacylglycerol?

what is the consequence of mitochondrial overload?

2. fatty acids

3. fatty- acetyl coA

• increased DAG and Ceramide

• decreased glucose uptake by transporter GLUT4

what happens during a mitochondrial overload following an excess of fatty acids

• decreased _______

• increased _____-_______

• increased ______

• increased ______

what does all of this lead to?

• decreased free CoA bc/ now all acyl-CoA

• increased B-oxidation (TCA cycle flux)

• ROS

• acylcarnitines

decreased glucose uptake by GLUT4

what three downstream factors are increased due to increased fatty acid supply leading to decreased GLUT-4 uptake and insulin resistance ?

the following stimulate stress-induced _______ ________

1. DAG (diacylglycerols)

2. Ceramides

3. Mitochondrial overload

serine kinases

ketogenic diets are used as therapeutic option for which demographic?

children with drug-resistant epilepsy

keto diets are rich in _______ and low in __________ with adequate amounts of proteins

rich in fat

low in carbohydrates

research in mice studies suggests keto diets can be used to

• improve memory

• extend lifespan

• weight loss

SEQ Regular Diet / NOT ketogenic

1. eat carbohydrate —> ________levels rise

2. pancreas secrete ______ and ______is stored in tissues

3. _________

1. glucose

2. insulin glucose

3. energy

Ketogenic Diet:

1. eat ____—> glucose level falls

2. ______ releases stored __________

3. ______ ______ travel to liver

4. liver produces _______ that give ENERGY

1. fat

2. lipases triacylglycerols

3. fatty acids

4. ketones

would you want high or low insulin levels on a ketogenic diet and why?

LOW bc/ insulin promotes lipogenesis (formation of triacyl glycerides from fatty acids)

the goal of ketogenesis is to promote lipolysis and covert stored triacylglycerols into fatty acids to be converted into ketones and used for energy

the liver will not produce _____ ______ if there is insulin present

ketone bodies

the liver produces ketone bodies from _______ ______ when _______ signaling is low

acetyl CoA

insulin

what three molecules are known as ketone bodies?

1. acetoacetate

2. acetone

3. d-3-hydroxy-butyrate

SEQ Ketogenesis starting from acetyl-CoA from fatty acids

1. acetyl-CoA

2. —> acetoacetyl CoA using enzyme ____________

3. —> 3-hydroxy-3methyl-glutaryl CoA using ________

4. —> Acetoacetate using ________________ CLEAVAGE enzyme

5. —> D-3-Hydroxy-butyrate using ________

6. OR acetoacetate decarboxylated into

2. 3-ketothiolase

3. hydroxymethylglutaryl CoA synthase

4. hydroxylmethylglutaryl CoA

5. D-3 hydroxybutyrate dehydrogenase

6. acetone

the _________ converts _________ into ketone bodies

liver fatty acids (specifically acetyl CoA from them)

what is the primary fuel that predominates during starvation?

ketone bodies from fatty acids

SEQ Ketone formation:

1. _______ acids —>

2. __________ ________ —>

3. ketone bodies into blood stream—>

4. ketone go to cells of _______ , ___________, ___________

5. ketones converted into _______________ which goes into the citric acid cycle

6. what is produced at the end of the citric acid cycle?

1. fatty

2. acetyl CoA

   4. heart, renal cortex, brain

   5. acetyl CoA

   6. H2O + CO2 + ATP

dietary consumption of ______ _____ increases cardiovascular disease

trans fats

changing in relative risk of coronary heart disease for each ___% energy from carbohydrate that is isocalorically replaced with fatty acids

what are the different types of fatty acids that exists?

1

trans fat

saturated

monounsaturated

polyunsaturated

most dietary trans fats derive from industrial _________ ____________ vegetable oils which are less expensive that ______ fats and nonhydrogenated vegetable oils

partial hydrogenated

animal

what are some advantages of partial hydrogenated vegetable oils over nonhydrogenated vegetable oils?

what is a popular example of a partially hydrogenated vegetable oil?

• longer half life

• greater solidity at room temp

• stability during repeated deep-frying temperature

margarine

are naturally occurring fats cis or trans?

are cis or trans fatty acids a straight chain?

cis (carbons of double bond same side)

trans = straight chain = processed

full hydrogenation of cis fatty acids leads to the formation of

partial hydrogen of ciis fatty acids leads to the formation of

• full = saturated fat

• partial = unsaturated fat

trans fats are made through the partial hydrogenation of cis fats and unsaturated fats are made from full hydrogenation of cis fats

what is meant by hydrogenation?

adding H2 gas to oil with high heat and pressure

dietary trans fats are dangerous because of their interactions with which types of cells?

reactions with these cell types ultimately leads to _____________(fatty plaque build up) and ____________

• macrophages

• endothelial cells

• hepatocytes

• adipocytes

ATHEROSCLEROSIS and INFLAMATION

• increased lipid and lipoprotein levels

• systemic inflammation

• endothelial function

• adiposity

• glucose— insulin homeostasis

are all metabolic risk factors associated with _____________

trans fatty acids (TFA)

___________ molecules have a rigid planar steroid ring structure with a polar _____ that interacts with the hydrophilic head of phospholipids

cholesterol

hydroxyl (OH)

what happens once the OH of cholesterol interacts with the polar head group of the phospholipid bilayer?

cholesterol‘s hydrophobic ring structure is implanted into the hydrophobic tails and increases stiffness with its rigidity

the 27 carbon atoms of cholesterol are synthesized from ____________ in a step process in the ______ and _________

acetyl CoA

3

liver and small intestine

is cholesterol only introduced in the body through diet?

NO can be synthesized de novo as well

the rate of cholesterol synthesis is mediated primarily by changes in the amount and activity of ________ _____ which is the enzyme that catalyzes the synthesis of ____________ (intermediate)

HMG CoA

mevalonate

what is 3-hydroxy-3-methylglutaryl CoA reductase?

HMG CoA

enzyme that catalyzes synthesis of cholesterol intermediate (mevalonate)

does cholesterol travel freely though the blood stream?

no MUST be transported with lipoprotein

the means by which cholesterol and triacylglycerols are transported in body fluids to tissues for use as fuel or for storage

lipoproteins

fatty acid constituents of the triacylglycerol components of the lipoprotein particles are incorporated into phospholipids for ____________ ___________

membrane synthesis

cholesterol is a precursor to many _______ hormones BUT its nucleus is unable to be degraded by _____ so it MUST be used or excreted by the ______

steroids

cells

liver

lipoprotein particles consist of

• a core of ___________ lipids

• shell of more _______- lipids and proteins

protein components of lipoprotein particles (_______) have 2 roles

• solubilizing _______ lipids

• containing cell- targeting _______

• hydrophobic

• polar

• hydrophobic

• signals

particles that are a major carrier of cholesterol in the blood and regulate de novo cholesterol synthesis in peripheral tissues

Low-Density Lipoproteins