Integration of Metabolism Flashcards
Glucose 6P acts as a metabolic junction point in what 4 pathways?
(1) Gluconeogenesis (RLE: Glucose 6 Phosphatase) -> Glucose
(2) Glycogenolysis (RLE: Glycogen Synthase) -> Glycogen
(3) Glycolysis (RLE: PFK1) -> Pyruvate
(4) PPP (RLE: Glucose 6P Dehydrogenase) -> Ribose 5P
Pyruvate acts as a metabolic junction point in what 4 pathways?
(1) Pyruvate Dehydrogenase -> ACoA
(2) Lactate Formation (RLE: Lactate Dehydrogenase) -> Lactate
(3) Nucleotide Metabolism (RLE: ALT) -> Alanine
(4) CAC via PDC -> OAA
ACoA acts as a metabolic junction point in what 3 pathways?
(1) CO2
(2) FA
(3) Ketone bodies
When are short term signals active?
During a meal
What is the function of long term signals?
Report overall energy status of body
i.e. Leptin secreted if not enough TAG stores
Where do these signals originate?
- GI tract
- Beta cells of pancreas (insulin)
- Adipocytes (leptin)
What is the primary target organ of the signals?
Brain - arcuate nucleus in hypothalamus
What are the two satiation signals?
- Glucagon like Peptide (GLP-1)
- CCK
Where are GLP-1 signals secreted from?
L cells in the intestine
Where are CCK signals secreted from?
Small intestine
What do both GLP-1 and CCK lead to increases in?
- increased insulin secretion
- increased insulin biosynthesis
- increased satiety
What do both GLP-1 and CCK lead to decreases in?
- decreased food intake
- decreased body weight
CCK
- short-term signal
- family of peptide hormones
- secreted into blood by cells in duodenum and jejunum regions of small intestine as a postprandial satiation signal
- binds to GCPR located in peripheral neurons
- leads to feeling of satiety
- also helps with digestion, stimulating secretion of pancreatic enzymes and bile salts from gallbladder
GLP-1
- short term signal
- hormone
- secreted by intestinal L cells
- binds to GPCR
- potentiates glucose-induced insulin secretion by beta cells of the pancreas
- inhibits glucagon secretion
Where is Ghrelin secreted from?
Stomach
Where does Ghrelin act?
Regions of the hypothalamus
What is the role of Ghrelin?
Stimulates apetite via GPCR on hypothalamus
Ghrelin secretion increases ___ a meal and ____ afterwards
- before
- decreases
What two key signal molecules regulate energy homeostasis over the time period of hours or days?
- Leptin
- Insulin
Leptin
- long term signal
- hormone
- secreted by adipocytes
- reports on status of TAG (decreases signal if high TAG stores)
Insulin
- long term signal
- secreted by beta cells of pancreas
- reports on status of blood glucose
Leptin makes tissues more sensitive to ___
Insulin
Increased adipose tissue means increased __ release
Leptin
Adipose tissue is considered what type of tissue?
Endorcine
What hormones does adipose tissue secrete?
- Adipokines (ex. leptin, adiponectin)
- RBP4 (retinol binding protein)
- resistin
What 3 effects does binding of Leptin to its receptors (located all over the body) and subsequent signaling result in?
(1) increase sensitivity of muscle and liver to insulin
(2) stimulates beta oxidation of FAs
(3) decreases TAG synthesis
Increased adipose tissue means decreased __ release
Adiponectin
Most important location of Leptin receptor:
Hypothalamus
How does Leptin regulate body weight?
(1) inhibits food intake
(2) stimulates energy expenditure
What 3 characteristics do leptin knockout mice display?
- hyperphagia (overeating)
- hyperlipidemia
- insensitivity to insulin
NPY
- Neuropeptide Y
- found in hypothalamus
- inhibited by leptin
AgRP
- Agouti-released Peptide
- found in hypothalamus
- inhibited by Leptin
POMC
- Propiomelanocortin
- found in hypothalamus
- activated by leptin
MSH
- Melanocyte Stimulating Hormone
- found in hypothalamus
- directly stimulated by POMC (which responds to increase in leptin)
Leptin pathway when there is an increase in fat cell mass
(1) increased leptin expression
(2) increased leptin action in hypothalamus
(3) (a) inhibition of NPY and AgRP producing neurons
(b) activation of POMC producing neurons
(4) (a) decrease in NPY and AgRP expression
(b) increase in MSH expression
(5) decrease in food intake
Enlarged adipocytes secrete higher levels of __ antagonizing hormones which contributes to __ resistance
INSULIN
Leptin and insulin resistance contribute to __
obesity
What two hormones that are produced by adipocytes promote insulin resistance?
RBP4 and Resistin
Name of group of proteins that contribute to insulin resistance (may also play a role in leptin resistance too!)
Suppressors of Cytokine Signaling (SOCS)
3 actions SOCS take to inhibit receptor function
- bind to insulin receptor
- bind to other components of insulin signaling pathway (bind to IRS-1 thus prohibiting phosphorylation of it and activation)
- enhance proteolytic degradation of the receptor
Phosphorylation of what intracellular component of insulin receptor leads to activation of pathway?
IRS-1
Characteristics displayed by SOCS knockout mice
- enhanced sensitivity to leptin
- resistant to weight gain even on high fat diet
Metabolic Syndrome
- cluster of pathologies that include insulin resistance, hyperglycemia, and dyslipidemia
- often leads to obesity and liver steatosis (accumulation of TAGs in organs)
- often precedes type 2 DM
HMG CoA Synthase
- rate limiting enzyme in ketogenesis
- converts acetoacetyl-CoA into HMG CoA which is then converted to Acetoacetate
Glycolysis
- rate limiting enzyme: PFK-1 (Glucose 6P -> Fructose 6P)
- occurs in cytoplasm during fed state
- conversion of glucose to 2 pyruvate
- inhibited by glucagon
- stimulated by insulin
Glucoenogenesis
- rate limiting enzyme: Fructose 1,6 Bisphosphatase (Fructose 1,6BP -> Fructose 6P)
- occurs in liver, kidney and small intestine when glucose and glycogen stores are depleted (starvation, exercise, keto diet)
- conversion of 2 pyruvate to glucose
- activated by glucagon
Galactose Metabolism
- rate limiting enzyme: GALT (Galactose 1P + UDP Glucose -> UDP-Galactose + Glucose 1P)
- feeds into glycolysis or gluconeogenesis
PPP
- rate limiting enzyme: Glucose 6P Dehydrogenase (Glucose 6P —-> Ribulose 5P)
Glycogenesis
- rate limiting enzyme: Glycogen Synthase (catalyzes transfer of UDP-glucose to non-reducing end of glycogen chain)
- glycogen formation
- occurs in fed state in liver and muscle
- activated by insulin
Glycogenolysis
- rate limiting enzyme: Glycogen Phosphorylase (catalyzes cleavage of glucose residues as a glucose 1P from non-reducing end of glycogen)
- glycogen breakdown
- occurs in low energy state / hungry state
- activated by glucagon
Fatty Acid Synthesis
- rate limiting enzyme: Acetyl-CoA Carboxylase (Acetyl CoA -> Malonyl CoA)
- occurs in fed state
- activated by insulin
- inhibited by glucagon and epinephrin
TAG Synthesis
- promoted by excess carbs and fats
- stored in adipose tissue
- occurs in liver and adipose tissue
TAG Degradation
- promoted by glucagon and epinephrine
- releases FAs into blood
- occurs in adipocytes
Ketogenesis
- rate limiting step: HMG CoA Synthase (Acetoacetyl CoA -> HMG CoA)
- formation of ketones
- occurs in mitochondrial matrix of liver cells
- used by muscle and kidneys under normal conditions, skeletal muscle when fasting, and brain when starving
- RBCs can’t use ketone bodies for energy!
- forms acetone which is exhaled or excreted in urine
Effects of Excess FAs in Muscle
- excessive TAG synthesis
- increased cytoplasmic levels of diacylglycerol increase (activation of PKC -> phosphorylation of IRS -> IRS unable to transduce insulin signal)
- ceramide accumulates in cytoplasm which inhibits glucose uptake and glycogen synthesis
- net result: diet induced insulin resistance
Effects of Insulin Resistance in Muscle on Pancreas
- Beta cells respond to insulin resistance by making and secreting more insulin
- machinery becomes overwhelmed and unfolded/misfolded proteins accumulate which activated the unfolded protein response (UPR)
- UPR continues and triggers apoptosis of Beta cells, which leads to cessation of insulin secretion
- pancreatic failure if severe
Glucagon
- restores blood-glucose levels by stimulating glycogen breakdown and gluconeogenesis in the liver, and mobilization of TAGs and degradation to form FAs
- secreted when blood glucose levels drop — insulin levels also drop
Primary fuel choice after 2 days of starvation
Glucose
Primary fuel choices after 2+ days of starvation
still glucose but both ketone bodies and FAs are rising
After how many days of starvation do ketone bodies become the primary fuel source?
~5 days
When do ketone bodies become the major fuel for the brain?
After several weeks of starvation
How does exercise alter the cell’s biochemistry?
release of Ca2+ from SR acts as second messenger to activate nuclear transcription factors that stimulate mitochondrial biogenesis
What happens to FAs during exercise?
FAs act thru a signal transduction pathway to influence a set of genes that increased the fatty oxidation capability of mitochondria
Increased mitochondrial biogenesis and increased FA oxidation prevent __ insensitivity
Insulin
Serine/Thyronine Kinase AMP-Activated Protein Kinase Complex (AMPK)
- senses cellular ATP levels
- if low energy, AMPK phosphorylates multiple enzymes and growth control nodes to increase ATP generation and decrease ATP consumption
- complex consists of 3 protein subunits (heterotrimers) comprised of a catalytic α subunit that carries the protein kinase activity, and regulatory β and γ subunits
- inactivated by ATP
- activated by AMP
