Week 9: Integration of Metabolism

What is the central theme of metabolism?

Energy homeostasis

Which systems facilitate communication around the body?

Nervous, endocrine, vascular

What are the two general divisions of metabolic pathways?

Catabolic and anabolic

What are two key intermediates that tie metabolic pathways together?

Pyruvate, acetyl-CoA

What is the largest determinant for the flow of metabolic molecules within a cell?

Energy level

Regulatory metabolic enzymes are mostly (unidirectional/bidirectional)

Unidirectional

How are the majority of important metabolic enzymes controlled?

Allosteric regulation

Malonyl-CoA ___ FA synthesis and ___ FA breakdown

Stimulates, inhibits

Malonyl-CoA is needed for the first step of the synthesis of ___ and ___.

Fatty acids, sterols

Malonyl-CoA allosterically controls which enzyme needed for fatty acid transport?

Carnitine acyltransferase I

What enzyme mediates cellular levels of malonyl-CoA?

AMP-dependent protein kinase (AMPK)

What happens to excess acetyl-CoA if energy is not needed by the cell?

Carboxylated to form malonyl-CoA

What molecule and what hormone increase muscular malonyl-CoA?

Glucose, insulin

Increased malonyl-CoA results in a decrease of what process?

Beta-oxidation

In lipogenic tissues (liver, adipose tissue), malonyl-CoA is a co-substrate for what enzyme?

Fatty acid synthase

When cellular energy is low, cytosolic ___ increases

Fatty acyl-CoA

An increase in cellular fatty acyl-CoA phosphorylates and activates what enzyme, and inactivates what other enzyme?

AMPK, acetyl-CoA carboxylase

What process does acetyl-CoA carboxylase catalyze?

Carboxylation of acetyl-CoA to form malonyl-CoA

Malonyl-CoA is also thought to be a signaling molecule to what cells? (to release ___)

Pancreatic beta-cells (to release insulin)

Low cellular glucose, high ATP usage, and metabolic stress phosphorylates what enzyme?

AMPK

What other dietary component can activate AMPK?

Phytochemicals

In response to low energy, AMPK increases the translocation of what transporter? (facilitates ___ uptake)

GLUT4 (facilitates glucose uptake)

AMPK stimulates ___ in cells that only express it; this transporter is already in the membrane

GLUT1

What enzyme does AMPK phosphorylate to stimulates cardiac glycolysis?

PFK2

What does PFK2 produce, and what glycolytic enzyme does it stimulate?

2,6 BP, PFK

What enzymes does AMPK inhibit? (processes)

PEP CK, glucose-6-phosphatase (gluconeogenesis and glycogenesis)

With regard to fatty acids, what process does AMPK promote?

Fatty acid uptake

With regard to fatty acids, what processes does AMPK inhibit?

Synthesis of TAGs, PLs, cholesterol

Which protein-synthesizing enzyme is inhibited by AMPK?

mTOR

What is the delineation in fasting time before mechanisms of serum glucose homeostasis start to change?

18 hours

What are the four phases of the fed-fast cycle?

Fed, postabsorptive, fasting, starvation

When does the fasting state occur after a meal?

18 hours to 2 days

When does the postabsorptive state occur after a meal?

3-18 hours

What is the primary indicator of the fed state?

Insulin

As far as we know, do RBCs and the brain have glycogen stores?

No

Low blood glucose stimulates the release of ___ from ___

Glucagon, pancreatic alpha cells

What is the main target organ of glucagon?

Liver

What do muscle tissue and the liver use for fuel when serum glucose levels drop?

Fatty acids

What process is the major provider of glucose to the blood during the postabsorptive state?

Hepatic glycogenolysis

Which process is upregulated, but not in total control, during the postabsorptive state?

Gluconeogenesis

What is the general purpose of the glucose-alanine cycle?

Transport carbon and nitrogen from muscle to liver

What are the typical substrates left once the glucose-alanine cycle shifts to the liver?

Pyruvate, glutamate

During the postabsorptive state, TAGs are broken down. What happens to the free glycerol that is left?

Shuttled into gluconeogenesis

What glucogenic compound does glycerol-3-phosphate isomerize into as it enters gluconeogenesis?

DHAP

Which hormones shift the body towards gluconeogenesis?

Glucagon and cortisol

What provides most of the substrates for gluconeogenesis?

Proteins from muscle breakdown

Which two amino acids cannot contribute to gluconeogenesis?

Leucine and lysine

Which amino acid is particularly prevalent during the fasting state?

Alanine

Which process starts to occur during the fasting state as fatty acids are depleted?

Liver ketogenesis

What is the top priority during the starvation state?

Glucose to tissues that need it

What is the second priority during the starvation state?

Preserve proteins, shift to FAs/ketones

The brain and heart start to use ___ as fuel after 3 days of starvation

Ketones

After how long are ketones the primary source of fuel for the brain?

Several weeks

Degradation of ___ accelerates after TAG stores have been depleted

Proteins

Glucose reserves are exhausted in how much time?

1 day

How many calories are stored in the fuel of a well-fed, 70 kg human?

161,000 kcal

What is the primary determinant of starvation time?

Stored TAGs prior to starvation

Which gluconeogenic precursor is provided by RBCs?

Lactate

What are the two major amino acids typically released from muscle tissue?

Alanine and glutamine

What organ (besides the liver) begins to contribute to gluconeogenesis after a certain point?

Kidneys

Once TCA cycle intermediates are used, depletion of which intermediate ultimately shifts the body towards ketogenesis?

Oxaloacetate

When does the plasma concentration of fuel molecules experience the sharpest drop?

Fed state

What two things have the most profound effect on metabolic pathways?

Amount and frequency of food consumption

What are the products of the two major fates of pyruvate?

Acetyl-CoA, lactate

During the TCA cycle, acetyl-CoA combines with ___ to form ___

Oxaloacetate, citrate

The citrate synthase reaction occurs because the ___ is NOT permeable to acetyl-CoA

Mitochondrial membrane

Generally, fuel molecules released by peripheral tissues travel where for processing?

Liver

Glucose is ___ in hepatocytes to prevent diffusion back into the bloodstream

Phosphorylated

Most hepatic G6P is used for ___ rather than fuel for the liver itself

Glycogenesis

Which sugar in the diet can be isomerized to make more G6P?

Galactose

Where are hepatic fatty acids primarily derived from?

Chylomicron remnants

Hepatic fatty acids can be assembled into ___ and released into circulation via ___

TAGs, VLDL

Aside from glucose, what is a major fuel source for the liver?

Fatty acids

Acetyl-CoA that is not used for energy is converted into ___

Ketones

What are the major fuel sources for muscle?

Glucose and FAs

After prolonged fasting, muscles can also use ___ as fuel

Ketones

Muscle contains which glucose transporter?

GLUT4

What percentage of glycogen in the body is stored in muscle?

75%

Rapid burst of muscle activity result in the production of ___

Lactate

Fuel is released from adipose tissue in the form of ___

FFAs

The level of what in the blood determines if FAs are released?

Glucose

Does the brain use fatty acids as fuel?

No

What is the exclusive source of fuel for RBCs?

Glucose

What percentage of the energy used by the body is required by the kidneys?

10%

What renal process characteristically requires lots of energy?

Reabsorption

The renal cortex typically uses ___ for fuel

FAs

The renal medulla typically uses ___ as fuel

Glucose

The renal cortex possesses ___ enzymes

Gluconeogenic

What can contribute to up to half of the circulating glucose during prolonged starvation through gluconeogenesis?

Renal cortex

___ produced in the renal medulla can be used for gluconeogenesis in the cortex

Lactate

What structure primarily regulates growth?

Anterior pituitary

What structure primarily regulates water balance and milk ejection?

Posterior pituitary

What structure regulates gene expression, tissue differentiation, and development?

Thyroid

Which hormones regulate glucose homeostasis, Na+ retention, BP regulation, stress response, and protein anabolism?

Adrenal hormones

Which hormones regulate carbohydrate metabolism?

Pancreatic hormones

Hypothalamic, hypophyseal, pancreatic, and GI hormones are classified as ___

Peptides

Adrenal and gonadal hormones are classified as ___

Steroids

Thyroid hormones and catecholamines are classified as ___

Amino acid derivatives

Peptides and amino-acid derived hormones have receptors ___

At the plasma membrane

Steroid and thyroid hormones have ___ receptors

Intracellular