Regulation of Energy Homeostasis

Cellular Level to Organism Level - Bio 311 - Lecture 12 - EXAM 2

What metabolites are responsible for allosteric regulation of ATP production?

1. ATP

2. ADP

3. AMP

   1. powerful allosteric regulator

What is AMP-activated protein kinase (AMPK)?

A protein kinase that acts as a cellular energy sensor and regulator of energy homeostasis in individual cells and whole-body energy metabolism

• serine/threonine kinase

Regulates ATP-consuming and ATP-generating pathways by phosphorylating key enzymes

Calcium acts as a ____ to stimulate ATP production, preparing cells for specialized function.

second messenger

What effect does a 10% increase in [ATP] have on ATP utilizing enzymes?

• Greatly reduces the activity of ATP utilizing enzymes

• Also leads to a dramatic increase in [AMP}

Which of the following is the most sensitive indicator of intracellular ATP level change: ATP, ADP, AMP?

AMP

High level of ATP ____ (inhibits/promotes) the committed step of glycolysis to prevent excess glucose degradation (waste)

inhibits

Low level of ATP ____ (inhibits/promotes) ATP production

promotes

What step in glycolysis is considered the commitment step?

Fructose-6-phosphate —> fructose 1,6-bisphosphate

• via PFK-1

While ATP is a product of glycolysis, it is a ____ (positive/negative) effector on PFK-1.

Negative

• do not spend glucose in glycolysis if there is plenty of ATP

F2,6BP is a _____ (positive/negative) modulator of PFK-1.

positive modulator

If AMP is high and ATP is low, what pathway should be used?

Glycolysis

If AMP is low, what pathway should be used?

Gluconeogenesis

What is the single most important enzyme/regulator of glycolysis?

PFK1

Pyruvate Kinase is ____ (promoted/inhibited) by ATP.

inhibited

In what conditions is the PDH complex allosterically inhibited?

An energy-sufficient metabolic state

• [ATP]/[ADP]

• [NADH]/[NAD+]

• [Acetyl-CoA]/[CoA]

What conditions can limit the rate of flow through the citric acid cycle?

• availability of the citric synthase substrates

• oxaloacetate and acetyl-CoA

• NAD+

  • depleted by its conversion to NADH, slowing the three NAD-dependent oxidation steps

    • Feedback inhibition by succinyl-CoA, citrate, and ATP

In muscle tissue, Ca2+ signals…

Contraction

• stimulates energy-yielding metabolism to replace the ATP consumed by contraction

The TCA cycle is regulated at…

1. initial step

2. two decarboxylation steps

ADP producuded by synthetic reactions is converted to ___ and ____ by _____

ATP + AMP

• via adenylate kinase

AMPK is activated by…

AMP

What conditions may inhibit ATP production?

• hypoxia

• glucose starvation

• metabolic poisons

Inhibiting ATP production will ____ (raise/lower) [AMP], ___ AMPK (Activate/hinder), and ____ (stimulate/block] catabolism

• Raise [AMP]

• Activate AMPK

• Stimulate catabolism

When [ATP] is ____ (high/low), ATP ____ (promotes/prevents) AMP binding to AMPK, which ____ (lowers/raises) AMPK activity and ____ (speeds up/slows) catabolism

• high

• prevents

• lowers

• slows

What are the functions of AMPK in lipids?

1. enhances fatty acid transport to mitochondria

2. Repress ACC (Fatty acid synthesis)

3. Lowered malonyl CoA stimulates beta oxidation of fatty acids

What are the functions of AMPK in glucose?

1. Enhance glucose transport

2. Enhance glycolysis

AMPK is activated by…

• elevated [AMP]

• decreased [ATP]

• Exercise

• Sympathetic nervous system (SNS)

• peptide hormones produced in adipose tissue

  • leptin, adiponectin

What is the influence of AMPK on the brain/hypothalamus?

stimulates food intake

What is the influence of AMPK on the heart?

• promotes fatty acid oxidation

• promotes glucose uptake

• promotes glycolysis

What is the influence of AMPK on adipose tissue?

• inhibits fatty acid synthesis

• inhibits lipolysis

What is the influence of AMPK on the liver?

• inhibits fatty acid synthesis

• inhibits cholesterol synthesis

• inhibits glycogen synthesis

What is the influence of AMPK on the pancreatic β cells?

• inhibits insulin secretion

What is the influence of AMPK on skeletal muscle?

• promotes fatty acid uptake and oxidation

• promotes glucose uptake

• promotes mitochondrial biogenesis

In a “normal” situation, intracellular calcium level is ____ (low/high).

Low

____ increases intracellular and intra-mitochondria calcium levels

Biosignaling

• influx from outside of cells, calcium channels open

• release from intracellular storage oF ER

Calcium ___ (stimulates/hinders) ATP production by…

stimulates

• activates calcium/calmodulin kinases, which phosphorylates metabolic enzymes

What major hormones are released by the thyroid?

• T3

• T4

What major hormone is released by adipose tissue?

Leptin

What major hormones are released by the adrenal glands?

• epinephrine (adrenaline) —> adrenal medulla

• glucocortisol —> adrenal cortex

How does the hypothalamus-pituitary system regulate energy metabolism?

• release of hypothalamic factors into arterial blood

  • stimulated by signals from connecting neurons

  • carried through a capillary network

• release of anterior pituitary hormones (tropins)

• Release of posterior pituitary hormones (vasopressin, oxytocin)

  • stored in nerve endings until ready to be released

• Veins carry hormones to systemic blood

What is the function of the hypothalamus?

• receives and integrates signals from the central nervous system

• synthesizes several factors that regulate the function of the pituitary

  • pituitary = upstream regulator of thyroid and adrenal glands

• synthesizes some peptide hormones

What is the function of α-MSH?

• promotes the feeling of satisfaction

  • suppresses food taking

How does AMPK affect α-MSH?

AMPK activation is associated w/ lack of energy and decreased mood

• suppresses the release of α-MSH

• Promotes food taking

The following hormones are responsible for basal metabolism rate.

Thyroid hormones, T3/T4

The following hormones are responsible for stress response metabolism.

epinephrine and glucocorticoids

The following hormones are responsible for carbon storage and homeostasis.

Leptin and adiponectin

What are the common examples of plasma membrane receptors? Provide examples and their synthetic path.

• Peptide

  • Ex - insulin, glucagon

  • Path: proteolytic processing of prohormone

• Catecholamine

  • Ex - epinephrine

  • Path: from tyrosine

• Eicosanoid

  • Ex - Prostaglandin E₂

  • Path: from arachidonate

What are the common examples of nuclear receptors? Provide examples and their synthetic path.

• Steroid

  • Ex - testosterone

  • Path: from cholesterol

• Vitamin D

  • Ex - Calcitriol

  • Path: from cholesterol

• Retinoid

  • Ex - Retinoic acid

  • Path: from vitamin A

• Thyroid

  • Ex- Triiodothyronine (T₃)

  • Path: from TYR in thyroglobulin

What is the common example of a cytosolic receptor? Provide an example and their synthetic path.

Nitric oxide

• Ex - nitric oxide

• Path: from arginine + O₂

Put the following in order:

• Thyroxine (T₄)

• Thyroglobulin - Tyr

• Proteolysis

• Triiodothyronine (T₃)

• Thyroglobulin - Tyr - I

• Thyroglobulin - Tyr

• Thyroglobulin - Tyr - I

• Proteolysis

• Thyroxine (T₄) and Triiodothyronine (T₃)

Tyr-Thyroglobulin is stored in the…

follicular lumen

Tyr-Thyroglobulin is released to circulation by…

Proteolysis

• forms T4

This hormone is the major active form of thyroid hormone.

Triiodothyronine (T₃)

Thyroid hormones require ___ for synthesis.

Iodine

Thyroid hormones bind to this type of receptor.

Nuclear Receptors

Thyroid hormones stimulate metabolism via…

transcriptional regulation

Thyroid hormones act on the following organs and have the following effects:

• Liver, muscle and adipose

  • the number and size of mitochondria

  • glucose uptake

    • cellular respiration

Hyperthyroidism is commonly caused by…

Graves’ disease

Hypothyroidism is commonly caused by…

Iodine deficiency

What hormone is responsible for the acute stress response?

Epinephrine (adrenaline)

Epinephrine and Norepinephrine are synthesized from…

the amino acid L-tyrosine

Epinephrine and Norepinephrine bind to…

extracellular receptors and generate secondary messengers

• similar to peptide hormones

What is the goal of epinephrine?

increase ATP in skeletal/cardiac muscle

What is the impact of epinephrine on hepatocytes?

Similar to Glucagon

• increases G6P

• Stimulates Glc to blood

• Inhibits glycolysis

  • Promotes gluconeogenesis

What is the impact of epinephrine on myocytes?

• Promotes ATP level

• Promotes glycolysis

• Inhibits gluconeogenesis