Starve- Feed Cycle 515

week 6

obesity

The unlimited capacity to store calories in the form of glycogen and triacylglyerol results in the most typical form of malnutrition:

protein malnutrition and starvation

other forms of malnutrition are:

cardiovascular death

obesity, together with insulin resistance, Dyslipidemia, and hypertension constitutes the metabolic syndrome and contributes to the high rate of ____

liver

The central organ involved in these metabolic interrelationships is the liver and the peripheral tissues are brain, muscle, adipose tissue, kidney, and red blood cells

Brain

glucose is virtually the sole fuel for the human brain, except during prolonged starvation

Muscle

the major fuels are glucose, fatty acids, and ketone bodies

Adipose tissue

synthesis and degradation of triacyglycerols.

Adipose tissue needs glucose (from liver, via glycolysis) to _____ triacyglycerols

synthesize

Liver

the metabolic activities of the liver are essential for providing fuel to the brain, muscle,, adipose tissue and other peripheral organs

liver

a major concept preceding a detailed analysis of the starve-feed cycle is established by the control of glucose level by the ____

4 stages

The starve-feed cycle has __ ___

well-fed state

Stage 1 of the Starve-Feed Cycle

the ______ _____ ______ in which the diet provides the energy requirements

early fasting state

Stage 2 of the Starve-Feed Cycle

the ____ _____ ____ in which hepatic glycogenolysis is the most important source of blood glucose

fasting state

Stage 3 of the Starve-Feed Cycle

The _____ _____ in which amino acids are used to synthesis glucose (gluconeogenesis)

early-refed state

Stage 4 of the Starve-Feed Cycle

The ___ ____ ____ is charactered by a normal metabolism of fat and re-establishment of a normal glucose metabolism

The well-fed state

amino acids

Fats

Glucose

Amino acids, fats, and glucose obtained from the diet are metabolized as follows:

_____ ______ are released into portal blood, but there is a small amount of metabolism in the gut

_____ (triacylglycerols) in the form of chylomicrons are secreted into lymphatics and, by way of the subclavian vein, into the blood

______ passes from the intestinal epithelial cells to the liver by way of the portal vein

amino acids

____ _____ from dietary protein are transported to liver by portal blood.

protein synthesis; amino acids; lipogenesis

a) A normal concentration of amino acids usually passes through the liver without metabolism and is distributed to peripheral tissues mainly for ____ _____

b) When the conc of amino acids is unsually high (high protein diet), liver retains some ___ ____ for protein synthesis, metabolism to CO2, and H2O, and urea synthesis. Some intermediates of amino acid metabolism are used for fatty acid synthesis (___) in liver

Fats; chylomicrons

1. The well-fed state

____ present in the diet are delivered to peripheral tissues via ____ fats synthesized in the liver are released from this organ in the form of very low density lipoproteins (VLDL)

lipoprotein lipase

1. The well-fed state

Both chylomicrons (from gut) and VLDL (from liver) circulate in the blood and are acted up by

glucose

The synthesis of triacylglycerols in adipose tissue requires glucose (as a source of glycerol-P)

Glucose

1. The well-fed state

Liver distributes most of ____ to other organs

Brain

1. The well-fed state

____ depends almost solely on glucose where it is metabolized to CO2 and H2O

adipose tissue

1. The well-fed state

___ ____ converts most of glucose into triacylglycerides

red blood cells

1. The well-fed state

____ _____ ___ metabolize glucose via glycolysis to lactate

muscle

1. The well-fed state

_____ stores glucose as glycogen and metabolizes it to lactate via glycolysis

lactacte

_____ originating from erthrocytes and myocytes is taken up by liver in the well-fed state, wehere it is used for the synthesis of fat

cori cycle ; interrrupted

__ ___the conversion of glucose to lactate in peripheral tissues followed by conversion of lactate back to glucose in liver) is _____ in the well-fed state

gluconeogenesis

2. the early fasting state - In the early stages of fasting, hepatic glycogenolysis is crucial for maintenance of blood glucose. Lactate, pyruvate, and amino acids are used for the formation of glucose (___)

Cori Cycle, Alanine Cycle

2. the early fasting state The ___ ____ and the ___ ___ become important in maintaining plasma glucose levels and represent important energy sources for muscle and erythrocytes

Hepatic gluconeogenesis

3. Fasting State

___ ___ occurs at expense of protein degradation in muscle (glutaminolysis) and triglyceride degradation in adipose tissue. the synthesis of glucose from alanine in liver is closely linked to urea cycle

Hepatic ketogenesis

__ ___ occurs at expense of the fatty acids released from triglyceride degradation in adipose tissue

3. this is the fasting state

succinyl-CoA transferase (SCOT)

3. Fasting state

Hepatic ketogenesis in the fasting state is determined by the following:

the liver can synthesize ketone bodies but cannot use them for energy because it lacks ___ ___ ___

ketone bodies

3. Fasting state

Hepatic ketogenesis in the fasting state is determined by the following:

Ketone bodies severe as a secondary energy source in the brain during fasting. During fasting (or starvation), the brain uses ____ ____ as an energy source because it has succinyl-CoA transferase (SCOT) activity

gluconeogenic mode

4. Early refed state

Shortly after fuel is absorbed from the gut, triacylglycerol ( in chylomicrons) is metabolized by peripheral tissues (adipose tissue and muscle) as in the well fed state. The liver, however, remains in the ___ ___ a few hours after feeding; glucose-6-P formed by gluconeogenesis in the liver is stored as glyocgen instead of being hydrolyzed to free glucose and release in the blood. therefore, during the early-refed state, the liver aims at restoring the glycogen stores.

Hepatic gluconeogensis

Fasting and Starvation:

____ ______ occurs at the expense of protein degradation in muscle and triglyceride degradation in adipose tissue

urea cycle

Glucose synthesis from alanine in the liver is closely linked to __ ___

Hepatic ketogenesis

occurs at the expense of the fatty acids released from triglyceride degradation in adipose tissue

(Fasting and Starvation_

B- oxidation ; oxaloacetate

The breakdown of fatty acids via ___ ___ to acetyl-CoA is followed by the entrance of the latter into the tricarboxylic acid cycle, where it is oxidized to CO2. This is dependent upon the presence of _____ , the acceptor of acetyl-CoA, which condenses with acetyl-CoA to form citrate.

starvation ; fuel for the brain

During ______ metabolism shifts to provide _____ _____ ___ i.e. hepatic glucose metabolism glucose is shifted towards gluconeogenesis, making oxaloacetate unavailable to condense with acetyl-CoA. Acetyl CoA conc increases and its fate is diverted to the formation of ketone bodies

marasmus

Starvation leads to a syndrome known as ____, which is not restricted to particular age group but is common in children under 1 year of age in developing countries.

ketogenesis

in marasmus, the liver mobilizes fat as an energy source for ____

glutaminolysis; gluconeogenesis

Muscle temporarily provides amino acids (___) to the liver for glucose synthesis (___)

brain

metabolizes glucose and ketone bodies. ultimately energy and protein reserves are exhausted and the child starves to death

adults

can suffer marasmus as a result of diseases that prevent swallowing (cancer of the throat or esophagus) or interfere with access to food (dementia or stroke)

AMPK

is a nutrient and energy sensor that maintains energy homeostasis; it monitors cellular energy status by sensing increases in the AMP/ATP, and ADP/ATP ratios

AMPK

regulates energy balance by activating catabolic pathways that generate ATP while conserving ATP by downregulating anabolic pathways

whole-body level

AMPK regulates metabolism and energy balance at the ___ ____ ___ via effects on the hypothalamus

a-subunit, regulatory b- and y- subunits

AMPK occurs as a complex comprising a catalytic __ _____

AMP

(allosteric regulator) binds to the y- subunit that acts as an energy sensor

liver kinase B1 (LKB1); Ca/calmodulin-dependent kinase kinases (CaMKKs),

Binding of AMP promotes phosphorylation of the a-subunit by upstream kinases: ____ (this introducing a link between AMPK and cancer) and ___, especially CaMKKB

type 2 diabetes

Some of the metabolic effects that ensue following AMPK activation are particularly relevant to the treatment of ___ _____ __

Catabolic pathways

are activated by AMPK: glucose uptake via GLUT4 and GLUT1, glycolysis, fatty acid uptake, fatty acid oxidation, mitochondrial biogenesis, and autophagy

anabolic pathways

are inhibited by AMPK: fatty acid, triglyceride, cholesterol, glycogen, protein, and rRNA synthesis; transcription of lipogenic enzymes, transcription of gluconeogenic enzymes

neural control ; ghrelin ; leptin

the ___ ____ of caloric intake to balance energy expenditure is controlled by two hormones, released by the stomach (___), and adipose tissue (___)

neuronal control

The neural control of caloric intake to balance energy expenditure is controlled by two hormones, released by the stomach (ghrelin) and adipose tissue (leptin)

Ghrelin

acts on Agouti-Related Protein expressing (AgRP) neurons that generate the neuropeptide Y (NPY)

Leptin

acts on Pro-Opio-Melano Cortin- expressing (POMC) neurons.

AgRP

____ neurons induce feeding

POMC

_____ neurons inhibit feeding

feeding

the primary appetite control center is the hypothalamus (arcuate nucleus) in which neuropeptide Y and AgRP neurons induce ___

POMC

__ neurons inhibit feeding.

stomach

the AgRP system contains a receptor for the hormone ghrelin, released by the ___

adipose tissue

The POMC neurons contain a receptor for the hormone leptin which is released by ____ ____

presynaptic neurons

In the fasting state, ghrelin, a “hunger signal” activates AMPK in the ___ ____ acting upstream of NPY/AgRP neurons via the Ca2+/calmodulin-activated kinase-B (CaMKKB)

in the fasting state

CaMKKB causes the release of Ca2+ from intracellular stores and the continous release of neurotransmitter on the NPY/AgRP neurons

promote

The NPY/AgRP _____ promote feeding (and inhibit the POMC neurons, which inhibit feeding

POMC neurons ; opioids

are stimulated by the “satiety signal”, leptin, deprived from adipose tissue. the binding of leptin to the leptin receptor in POMC neurons promotes the release of ____ that inhibits AMPK in the presynaptic neurons upstream od the NPY/AgRP neurons, switching them back to an inactive state

mTOR

links nutrient abundance with growth and the accumulation of energy storesin anticipation of future nutrient shortage.

activated

When nutrients are available, mTOR is ____, driving anabolism, as well as energy storage and consumption.

fasting

During _____ mTOR must be suppressed to avoid conflicting metabolic signals.

Chronic overfeeding

____ ____ can lead to excessive mTOR activation and metabolic derangements (as observed in obesity)

2

mTOR (mammalian Target of Rapamycin) is a kinase consisting of ___ distinct protein complexes

MTOR Complex t 1 (mTORC C1)

contains the protein raptor, this complex is sensitive to rapamycin.

growth and nutrients (amino acids)

mTOR C1 promotes C1 promotes cell growth and proliferation by stimulating nutrient uptake and metabolism and integrating inputs from various sources, such as ___ ___ ____

insensitive

MTOR complex 2 (mTORC2) contains the protein rictor and is ____ to rapamycin. mTOR C2 helps activate Akt (insulin signaling) and it regulates the actin cytoskeleton via Rho0family GTPases. Akt (insulin signaling) activates mTORC1 indirectly by phosphorylating other intermediates

future

mTOR links nutrients abundance with growth and the accumulation of energy stores in anticipation of ___ nutrient shortage

growth factors ( such as insulin and insulin growth factor (IGF), amino acids, and energy signals (through AMPK)

The ultimate effects of mTOR are to promote mRNA translation and to inhibit autophagy; this is carried out by intergrating nutrients signals generated by (A) ____ (B) _____ and (C) _____

cancer

mTOR is ubiquitously expressed within cells and is a validated target in the treatment of ___

cell growth, proliferation, and survival

mTOR integrates signals from growth factors and nutrients to promote ___, ____, ____

upregulated

mTOR signaling is ___ in benign and malginant neoplaastic disorders

Drugs

____ targeting mTOR activity are anticipated to be helpful for the treatment of different cancers

FDA- approved mTOR inhibitors

Everolimus, Temsirolimus, Sirolimus

Everolimus

used to treat several cancers

Temsirolimus

derivates of rapamycin are used to treat advances renal-cell carcinoma and mantle-cell lymphoma

sirolimus

derivates of rapamycin are used to treat metastatic malignant epithelioid tumors

resistance

FDA approved mTOR inhibitors are associated with ___; major challenge in cancer therapy

metformin

combining ____ with mTOR inhibitors also shows promise. ____ an antidiabetic drug, has been shwo to enhance the therapeutic effects of rapamycin an mTOR inhibitor

ULK1

____ complexes senses nutrient signals to activate autophagy

Authophagy

is active under energy and nutrient deprivation, there it plays a central role in starvation. degrades and recycles damaged and redundant organelles and macromolecules providing building blocks and energy to support cell survival under stress

regulates

the UL 1 complex ____ autophagy and consists of the ULK1 protein, Atg13 (autophagy-related gene 13) and focal adhesion kinase interacting protein of 200kD (FIP200)

AMPK

activates ULK1 through phosphorylation

autophagy

triggered by the ULK1 complex and included several other factors, such as PI3K class III, beclin 1, and LC3-ii which anchors to the membrane and interacts with the cargo (organelles, cytosolic proteins, etc) through receptors that recognize the cargo

lysosomes

once the autophagosome is formed, it fuses with ____ whose proteolytic enzymes degrade the cargo

non selective

__ ___ autophagy degrades cytosolic proteins and organelles

mitophagy

selectively degrades mitochondria

feedback

as a kinase triad, AMPK, mTOR, and ULK1 control energy and nutrient homeostasis through ____ mechanisms

AMPK

is activated when the cellular organismal energy levels decrease, resulting in stimulation of catabolism and inhibition of anabolism for energy production

nutrient sufficiency (amino acids)

leads to the activation of mTOR; these nutrients are used for cell growth

During nutrient starvation,

the cell degrades macromolecules and organelles (autophagy) to yield energy; autophagy is regulated by the ULK1 complex