Principles of metabolic integration

Coordination: Tissues in our body are connected by the neuro-endocrine system

Division of labor: different organs perform different and often complementary metabolic functions:

Central hub: the liver integrates the use of fuels (glucose, FAs, AA) by each tissue to keep blood glucose
levels in the optimal range – the brain rules in terms of systemic requirements!

Body mass maintenance is a priority, and the inputs/outputs regulated accordingly during fasting/feeding

Local perturbations at single points in the system can have far-reaching consequences on the equilibrium
of the whole network
Principles of metabolic integration

Coordination: Tissues in our body are connected by the neuro-endocrine system

Division of labor: different organs perform different and often complementary metabolic functions:

Central hub: the liver integrates the use of fuels (glucose, FAs, AA) by each tissue to keep blood glucose
levels in the optimal range – the brain rules in terms of systemic requirements!

Body mass maintenance is a priority, and the inputs/outputs regulated accordingly during fasting/feeding

Local perturbations at single points in the system can have far-reaching consequences on the equilibtrium
of the whole network
The liver
metabolic distribution & coordination centre (right proportions of fuels in the blood)

buffering temporal fluctuations due to feeding/fasting

processing of excess precursors (e.g. detoxification of nitrogen, re-esterification of FFAs)

detoxification of xenobiotics (CYP450 enzymes)

 1) Gluconeogenesis

2) Glucose storage (Glycogen) & release

3) Glucose breakdownn (limited – usually FAs are

the preferred energy source)

4) Acetyl-CoA as the precursor for FAs, TAGs and

NADPH reducing
power
Cholesterol (export to extrahepatic tissues as
VLDL) + Bile acids

5) Glucose as a fuel for NADPH production to

sustain FAS + detoxification of xenobiotics
(CYP450 enzymes)
1) AA for the turnover of liver proteins + plasma proteins

2) AA for extrahepatic tissues

3) other AA derivatives

4) breakdown of excess AA
a) to Pyruvate
b) detoxification of ammonia through Urea

5) AA-derived Pyruvate directly to gluconeogenesis

9) AA-derived Acetyl-CoA as FAS precursor

10) AA-derived TCA intermediates to gluconeogenesis

11) Muscle-derived AA (fasting) + Cori cycle (Exercise)

1) Lipids needed by hepatocytes

2) FAO to spare other fuels (Glucose)

5) Excess Acetyl-CoA (from FAs and from AAs )

used to produce Ketone bodies for the brain (FAs do
not cross the BBB – up to 60% energy during
fasting) and the heart (up to 30% energy)

6) Cytoplasmic Acetyl-CoA (from Glucose?

Glutamine? FAs?) used for cholesterol and bile acid
synthesis + reverse transport

7) free FAs converted back to TAGs (VLDLs)

8) minor part of FFAs in the blood directly (main

source is the WAT)
WAT
- Feeding: Glucose/AA to FAs
conversion, dietary FFAs uptake
(CM, VLDL), lipid storage as TAGs

- FAsting: FFAs release, FFAs re-

esterification (part of basal
thermogenesis - glyceroneogenesis)

- Endocrine functions (Adipokines)

BAT

- TAG storage & usage (together with

glucose when available) for non-
shivering thermogenesis by UCP1 &
Creatine Kinase futile cycles
In humans, the BAT is mainly found in newborns
 2-[18F]-fluoro-2-deocy-GLucose (FDG) PET of an adult

BAT in the collarbone region

WAT tissue can be

converted by
perivertebral regions hormonal and
adrenergic
stimulation into
beige adipocytes
that behave as BAT
(long-term
adaptation to cold)

(+fasting)
Skeletal muscle
adapted to provide maximal supply of ATP over short, intermittend periods

capacity to provide both short-time and prolonged power (including long-term adaptation) thanks to

- Slow-twitch mucle fibers (red muscle)

lower tension, but fatigue-resistant
FAO as main fuel (rich in mitocondria)
high need for vascularization and oxygenation

- Fast-twitch muscle fibers (white muscle)

greater/faster tension over limited periods
fewer mitos and vascularization
uses ATP faster than it can replace it
can be trained (glycogen storage to support anaerobic glycolysis)
3xATP per Glucose during intense activity
Creatine and Phospho-Creatine undergo
spontaneous degradation in muscles

Creatine is mainly obtained by the diet

(only animal products) or by de novo
synthesis starting from Glycine, Arginine
and Methionine (liver, kidney)

The skeletal muscle takes up circulating

Creatine againts its gradient (this can be
enhanced by continuous exercise)
Creatine and Phospho-Creatine undergo
spontaneous degradation in muscles

Creatine is mainly obtained by the diet

(only animal products) or by de novo
synthesis starting from Glycine, Arginine
and Methionine (liver, kidney)

The skeletal muscle takes up circulating

Creatine againts its gradient (this can be
enhanced by continuous exercise)

Creatinine is excreted by the kidney

Elevated blood levels of Creatinine is

associated with renal failure (usually the
measure is based on glomerular filtration
rate to buffer against interindividual
variations of baseline creatinine levels)
Because of the Cori cycle, we keep breathing
heavily AFTER intense exercise

extra O2 needed in the liver to support increased

OXPHOS
3xATP per Glucose during intense activity

Very high ATP consumption +

Incomplete coupling of the ETC/OXPHOS
= Heat production

Shivering thermogenesis
Heart (cardiac muscle cells)

- continuous activity
- continuous complete aerobic metabolism
- more abundant mitochondria compared to skeletal muscle
- FFAs are the main energy fuel (also Glucose, Ketone bodies)

- Lack of anaerobic capacity & of significant stores makes

cardiomyocytes heavily dependent on O2 supply

- obstruction of blood vessels (atherosclerosis, coronary

thrombosis) induces CM death very shortly
Brain (neurons)
- neurons maily use Glucose (blood) or Lactate (Astrocytes) as fuels
- 90% of ATP derives from OXPHOS
- 20% of the body’s O2 consumption at rest
- no storage = dependance on contonuous blood glucose (and O2) supply

- Astrocytes can also use FFAs + can use aerobic glycolysis to produce Lactate
from WAT FFAs (via liver ketogenesis) – mainly b-hydroxybutyrate

from muscle AAs (via liver gluconeogenesis) is the ultimate resourse

at difference with other cell types,

and in addition to basal
maintenance of plasma membrane
functions, the membrane potential
is constantly wasted in neurons to
evoke action potentials
Principles of metabolic integration

Coordination: Tissues in our body are connected by the neuro-endocrine system

Division of labor: different organs perform different and often complementary metabolic functions:

Central hub: the liver integrates the use of fuels (glucose, FAs, AA) by each tissue to keep blood glucose
levels in the optimal range – the brain rules in terms of systemic requirements!

Body mass maintenance is a priority, and the inputs/outputs regulated accordingly during fasting/feeding

Local perturbations at single points in the system can have far-reaching consequences on the equilibtrium
of the whole network
The many ways cells can communicate with each other
(TAGs, VLDLs)
Fed state
The liver is lipogenic
Pancreatic endocrine
beta-cells monitor Glucose
levels based on their own
energy charge

ATP levels translate into

Insulin secretion by
modulating membrane
potential
Constituively-open
K+ channel
mutations: neonatal
diabetes mellitus

Constituively-closed
K+ channel
mutations: severe
hypoglycemia and
brain damage
Insulin is the ligand for a Receptor Tyrosine Kinase (RTK)

Proximity-induced Phosphorylation-dependent
Trans-phosphorylation recruitment of signalling protein
Insulin controls Glut4 translocation at the plasma membrane (Glucose uptake)
Insulin controls the formation of Phosphatidyl-Inositol-3P (PIP3)
the concept of second messengers

(PIP-4,5-P2)

(PIP-3,4,5-P3)
Each intracellular membrane compartment can be recognized by its own PIP code
 GSK3

Multiple
targets
 GSK3

Multiple Glycogen storage

targets

Protein synthesis
FOXO
Glycolysis (liver) FAS
FAO (liver) Autophagy
Gluconeogenesis
mTOR coordinates
metabolism to maximize
cell growth
AMPK

AMPK Fasting

TAG deposition (WAT)

mTOR is at the centre
of one of the two known
AA-sensing
mechanisms

AA scarcity = risk of stalling ribosomes during protein synthesis

inefficient and energetically expensive

better preventing initation of translation

the mTORC complex senses AA scarcity

mTOR phosphorylates and activates:

- the translation initiation factor 4 inhibitor eIF4BP1
- the ribosomal protein S6 kinase
- autophagy mediators
mTOR is at the centre
of one of the two known
loading of tRNAs (protein
AA-sensing synthesis) depending on AA
mechanisms abundance

AA scarcity = risk of stalling ribosomes during protein synthesis

inefficient and energetically expensive

better preventing initation of translation

the GCN2 (general control nonderepressible protein 2) protein recognizes any uncharged tRNA

GCN2 then phosphorylates and inactivates the translation initiation factor 2 alpha (eIF2a)
↓ PFK-2 (F-2,6-BP)

↑ PEP
Fasting state
The liver is gluconeogenic
PROLONGED fasting state

Liver non-
essential
proteins
Glucagon is an agonist of G-Protein-Coupled Receptor signaling

Adenylate
Cyclase

the second messenger is cyclic AMP

Glycogen Glycogen
Phosphorylase Synthase
Inactive PKA

AC PDE
G-Protein-Coupled Receptor signaling can also regulate other pathways

the second messengers are

- membrane DAG
- soluble IP3
- Ca2+
+ H2O
breakdown of Lyso-PL

breakdown of PC to DAG
Epineprhine beta-adrenergic stimulation: similar but different from Glucagon

changes in
peripheral vs.
central perfusion
Principles of metabolic integration

Coordination: Tissues in our body are connected by the neuro-endocrine system

Division of labor: different organs perform different and often complementary metabolic functions:

Central hub: the liver integrates the use of fuels (glucose, FAs, AA) by each tissue to keep blood glucose
levels in the optimal range – the brain rules in terms of systemic requirements!

Body mass maintenance is a priority, and the inputs/outputs regulated accordingly during fasting/feeding

Local perturbations at single points in the system can have far-reaching consequences on the equilibrium
of the whole network
The set-point model for
constant mass maintenance
(body mass homeostasis)

postulated by many years

first molecular hint in 1994

Leptin is the first discovered

Adipokine
 ob/ob spontaneous mouse mutants OB/OB = wt Leptin locus

unrestrained appetite
elevated plasma cortisol (stress)
defective thermoregulation
lack of reproductive behavior
insulin-resistance (tissues became non-responsive to insulin)
 Leptin receptor

Direct action in the CNS on appetite

Additional sympathetic effects:

increased blood pressure
increased heart rate
ANOREXIGENIC OREXIGENIC
(appetite suppressing) Neuropeptide Y (appetite stimulating)
 Adiponectin

Muscle
higher uptake of blood FFAs
higher rates of FAO
Insulin action on other organs glucose oxidation
Liver
lower FAS and gluconeogenesis
Liver and Muscle glucose oxidation
metabolism
Adiponectin (GPCRs)
 Adiponectin (GPCRs)

whole organism energy

status sensing and
regulation

monitoring of individual
cell nutrient status
 Satiety signals
AMPK is regulated in Feeding
hypothalamic cells behavior

by multiple hormonal Basal energy

signals expenditure

Fat tissue depleted

Empty stomach

Fat tissue is full

general effects on metabolic pathways

general metabolic effects on peripheral tissues

 Satiety signals
Ghrelin is secreted by stomach cells Feeding
to signal «empty stomach» behavior

acts via GPCR Basal energy

expenditure
stimulates appetite in a short time
scale

Fat tissue depleted

Empty stomach

Fat tissue is full

Endocannabinoids increase appetite and
heighten the sensory response to sweet
and fatty food – elevate mood!

act via GPCR

Food
Chewing

Reduced motor activity Intestinal release of

Reduced thermogenesis Endocannabinoids
attachment of an Acyl
to the head group
G-Protein-Coupled Receptor signaling can also regulate ion channels
Endocannabinoids increase appetite and
heighten the sensory response to sweet
and fatty food – elevate mood!

act via GPCR

Food
Chewing
Cannabis indica

Reduced motor activity Intestinal release of

Reduced thermogenesis Endocannabinoids
G-Protein-Coupled Receptor signaling can also regulate ion channels
The sense of smell

Each Olfactory cell expresses

only ONE among hundreds of
Odorant Receptor genes
Principles of metabolic integration

Coordination: Tissues in our body are connected by the neuro-endocrine system

Division of labor: different organs perform different and often complementary metabolic functions:

Central hub: the liver integrates the use of fuels (glucose, FAs, AA) by each tissue to keep blood glucose
levels in the optimal range – the brain rules in terms of systemic requirements!

Body mass maintenance is a priority, and the inputs/outputs regulated accordingly during fasting/feeding

Local perturbations at single points in the system can have far-reaching consequences on the equilibrium
of the whole network
The chief of metabolic diseases: Diabetes Mellitus
Inability to take up glucose efficiently
High levels of blood glucose
Elimination of glucose via the urine (requires high volume of water)
Excessive thirst

Cardiovascular disease
Kidney failure
Blindness
Neuropathy

Type 1: inhability to produce Insulin (autoimmune destruction of pancreas beta-cells)

Type 2: inhability of peripheral tissues to respond to Insulin («Insulin resistance»), often associated to obesity
Diabetes diagnosis:
elevated levels of Glycated Hemoglobin

HbA1c acts as a long-term «memory»

of average blood glucose levels
Diabetes diagnosis: Diabetes diagnosis:
elevated levels of Glycated Hemoglobin Glucose Tolerance Test
(after fasting)

HbA1c acts as a long-term «memory»

of average blood glucose levels
The chief of metabolic diseases: Diabetes Mellitus
Inability to take up glucose efficiently
High levels of blood glucose
Elimination of glucose via the urine (requires high volume of water)
Excessive thirst

Incomplete FAO in the liver

Excess production of ketone bodies (ketosis)
Ketonemia (potentially leading to ketoacidosis)
Ketonuria
The chief of metabolic diseases: Diabetes Mellitus
Inability to take up glucose efficiently
High levels of blood glucose
Elimination of glucose via the urine (requires high volume of water)
Excessive thirst

Incomplete FAO in the liver

Excess production of ketone bodies (ketosis)
Ketonemia (potentially leading to ketoacidosis)
Ketonuria

FA become the main fuel

FAO oxidation in the liver exceeds the ability of the ETC to use NADH
NADH inhibits the TCA cycle
Acetyl-Coa is coverted into ketone bodies
 Irreverisble reactions = regulatory sites
remember?

DG0’ = -33.5 kJ/mol

accumulation of mitochondrial [NADH]
mitochondrial NADH used up
availability of substrates DG0’ = -35.6 kJ/mol
Acetyl-coA
elevated energy charge [ATP]/[ADP]

retroactive inhibition by
(cis-aconitate)
accumulation of products
NADH

DG0’ = -33.6 kJ/mol

ATP
The chief of metabolic diseases: Diabetes Mellitus
Inability to take up glucose efficiently
High levels of blood glucose
Elimination of glucose via the urine (requires high volume of water)
Excessive thirst

Cardiovascular disease
Kidney failure
Blindness
Neuropathy Untreated 3mo Insulin
treatment
(Banting 1921)
Type 1: inhability to produce Insulin (autoimmune destruction of pancreas betal-cells)

Type 2: inhability of peripheral tissues to respond to Insulin («Insulin resistance»), often associated to obesity
The chief of metabolic diseases: Diabetes Mellitus
Inability to take up glucose efficiently
High levels of blood glucose
Elimination of glucose via the urine (requires high volume of water)
Excessive thirst

Cardiovascular disease
Kidney failure
Blindness
Neuropathy

Type 1: inhability to produce Insulin (autoimmune destruction of pancreas betal-cells)

Type 2: inhability of peripheral tissues to respond to Insulin («Insulin resistance»), often associated to obesity
- beta-cells initially compensate but eventually fail to provide enough Insulin
- obesity / hypertesion / high blood TAG (metabolic synrdome)
- abnormal clotting / inflammation
The «lipid toxicity» hypothesis for Type 2 Diabetes onset
The incretin effect: Glucose passing through the intestine has a better ability to stimulate Insulin secretion
GLP1 is secreted by the GLP1 agonists have been
intestine and remains in the modified to be stable for 100
plasma for minutes hours – weekly injections

no clevage by the DPP4 peptidase

binding to albumin
reduced renal excretion
GLP1 agonists decrease glucose blood levels in Type 2 Diabetes patients
GLP1 agonists decrease body weight in Type 2 Diabetes patients
side effects of
over-dosage:
vomiting
GPCRs
The PPAR family of transcription
factors: regulation of transcription
by Fatty Acids
PPAR peroxisome proliferator-activated
receptors

part of the family of Nuclear Receptors

(whose activation can be drive directly within
the nucleus by a soluble molecule)

activated by FFAs or FA derivatives

dimerize with RXR to form a heterodimeric

transcription factor

- control over genes involved in fat and

carbohydrate metabolism
- differentiation of adipocytes
- lipid storage in WAT
The SREBP1-2 (Serum Response Element Binding Proteins) of transcription factors:
the transcriptional regulation of Cholesterol homeostasis (by ER cholesterol content)
The LXR (Liver X Receptor a and b) transcription factors: regulation of transcription
by Oxysterols

SREBP1c
 Promotion of
Inhibition of
Cholesterol efflux
Cholesterol synthesis

Promotion of
FA synthesis
Cholesterol
excretion as bile
acids Inhibition of
Cholesterol uptake
Reverse (Idol = inducible
Cholesterol degrader of LDLR)
Transport

Promotion of
Cholesterol efflux

Inhibition of
Cholesterol uptake
Glucose sensing by the ChREBP (Carbohydrate Response Element Binding Protein )Transcription factors
The microbiota also play
important roles:
- modification of
metabolites
- production of bioactive
moelcules