Publication # 33
Nutrient Sensing and Metabolic
Disturbances
Pennington Biomedical Research Center
Division of Education

Potential Causes of the Metabolic
Syndrome & Insulin Resistance
 Ectopic fat/Impaired fat oxidation
 Intrinsic defects in substrate
oxidation/mitochondrial biogenesis
 “Locking” fat in the fat cell/lipolysis
 Adipose tissue as an endocrine tissue
 Nutrient/energy sensors
Smith, S. Metabolic Syndrome Targets. Curre nt Drug Ta rg e t.
2004:3;431-439. Pennington Biomedical Research Center

Ectopic Fat/Impaired Fat Oxidation
 Defect in fat oxidation may be a precursor to obesity
and the metabolic syndrome.
 Early studies demonstrated that the “pre-obese”
individuals have increased carbohydrate oxidation
and impaired fat oxidation.
 This increase in carbohydrate oxidation leads to storage
of lipid energy as fat leading to obesity and the
metabolic syndrome.
 Intervention causing an increase in fat oxidation should
improve the clinical features of metabolic syndrome.

Intrinsic Defects in Substrate Oxidation/Mitochondrial
Biogenesis
Mitochondrial Biogenesis
 Several recent studies have demonstrated that
mitochondrial biogenesis and mitochondrial
function are impaired in aging, diabetes, and in
individuals with insulin resistance.
 These defects show a reduction in the number,
location and morphology of mitochondria and
are strongly associated with insulin resistance.
 In skeletal muscles, exercise is an effective
strategy to increase mitochondrial number.

Intrinsic Defects in Substrate Oxidation/Mitochondrial
Biogenesis
Mitochondrial Biogenesis
 Exercise also switches fiber type from glycolytic to oxidative.
 Modest physical activity has been shown to reduce the common
phenotypes of the metabolic syndrome, i.e. triglycerides
decrease, insulin action improves, and waist circumference
decreases.
 Therefore, exercise looks to be an effective method in reducing
the effects of metabolic syndrome.

Intrinsic Defects in Substrate Oxidation/Mitochondrial
Biogenesis
Lipid Metabolism
 Lipid is stored in two main compartments:
 Adipose tissue
 Intracellular compartments in peripheral tissues
(skeletal muscle, liver)
 The presence of lipid in the adipose tissue is
important for providing fuel during overnight
fasting and starvation.
 Excess lipid delivery to skeletal muscle and liver Adipose tissue
during periods of energy excess leads to an
accumulation of lipid in the muscle.
 This accumulation of lipid in the liver and muscle
is associated with insulin resistance.

Intrinsic Defects in Substrate Oxidation/Mitochondrial
Biogenesis
Lipid Metabolism
 Although these intracellular stores may not be the
cause of the insulin resistance, they are good markers
of underlying cellular defects such as: activation of
PKC, and increases in ceramides or long chain CoA’s.
 Efforts to increase lipid flux into oxidation
(and hence away from the generation of “toxic”
intermediates) in skeletal muscle and the liver
are likely to decrease signaling through these
aforementioned pathways.
 PPAR-α and ß are two examples of nuclear
transcription factors that should produce beneficial
effects on insulin action by increasing fat oxidation.

PPARα
 PPAR-α and ß
 Peroxisome proliferator-activated receptor (PPARα) is a ligand activated
transcription factor that plays a key role in the regulation of genes involved in
carbohydrate, lipid, and lipoprotein metabolism.
 PPARα is highly expressed in tissues with high mitochondrial and peroxisomal
β-oxidation activities, such as liver, heart, kidney, and skeletal muscle (2-5).
 In humans, treatment with PPARα agonists, i.e. fibrates, results in decreased
Plasma levels of triglycerides and increased plasma HDL cholesterol levels.

Locking Fat in the Fat Cells/Lipolysis
 Obesity is associated with increases in whole body
lipid turnover and elevated free fatty acid (FFA)
concentrations in the blood.
 One way that PPARγ agonists improve the lipid and
insulin phenotype of the metabolic syndrome is by
sequestering lipid within the triglyceride droplet in
adipose tissue.
 It is believed that this will protect the skeletal
muscle, liver, and beta cells (from the pancreas)
from excess lipid supply.
 Some of the evidence supporting PPARγ agonists
effectiveness include the observation of:
 Decreased free fatty acids (FFA) in the blood
 Increased insulin stimulated lipid storage

Locking Fat in the Fat Cells/Lipolysis
 Of the available PPARγ agonists, it is still not
fully understood how pioglitazone, but not
rosiglitazone, lowers triglycerides.
 With the development of “cleaner” PPARγ
agonists, antagonists which act specifically on
one area of the body, a better understanding
of whether or not activation of lipid storage
(sequestration) is an effective therapeutic
strategy should be able to be determined.

“Locking” Fat in the Fat Cell/Lipolysis
Lipolytic Pathways
 During exercise, both circulating catecholamines and lipolysis
increases.
 Other hormones and growth factors increase during
exercise as well, including brain natriuretic peptide.
 It has been recently demonstrated that natriuretic peptides
are potent lipolytic agents which support exercise mediated
lipolysis through activating cGMP mediated lipolysis
in adipose tissue.
 This pathway seems to provide a potential avenue
to augment lipolysis.
 However, if this lipolysis is not balanced by increased
uptake and oxidation by muscle and liver, the peripheral
effects (lipotoxicity) could be deadly.

“Locking” Fat in the Fat Cell/Lipolysis
Lipolytic Pathways
 If these hormones and growth factors do increase
fatty acid utilization similar to catecholamines,
then either the ANP/BNP receptor or the
cGMP/PDE system might have therapeutic
relevance in the metabolic syndrome.
 Further research in animal models is unlikely, since
the adipocyte cGMP system is primate specific and
not present in rodents.

Adipose Tissue as an Endocrine Organ
Adipocytokines
 With the recognition of the adipocyte as an
endocrine organ and the realization that the
adipocyte plays a critical role in the
metabolic syndrome, the discovery of
several “adipocytokines” came about.
 Adipocytokines influence peripheral
metabolism and regulate CNS function.
 Adiponectin is an adipocyte derived hormone
also known as ACRP 30.

Adipose Tissue as an Endocrine Organ
Adipocytokines
 Recent evidence suggests that Adiponectin is an important target for
metabolic syndrome for several reasons:
1. Receptors for Adiponectin are all in the right places: liver, skeletal muscle, beta cells,
and the brain.
2. Plasma concentrations of adiponectin are decreased in obesity and insulin resistance
states making replacement therapy possible.
3. Adiponectin is an activator of the AMPK cellular energy sensor and AMPK plays a key
role in the regulation of fat oxidation, mitochondrial biogenesis, glucose uptake, and
other cellular functions.

Adipose Tissue as an Endocrine Organ
Adipocytokines
 Another adipocytokine, known as Resistin or FIZZ3, has been suggested as
a therapeutic target in the metabolic syndrome.
 Resistin blocks adipocyte differentation in vitro and might contribute to
the metabolic syndrome by increasing ectopic fat accumulation in
peripheral tissues.
 However, at the Endocrine society’s 86 th Annual Meeting, it was concluded
that because there are only modest relationships between resistin and the
metabolic syndrome phenotype, resistin is actually a less desirable
therapeutic target.

Nutrient Sensors
Overview
 Energy and nutrient sensors effect how cells
ultimately respond to energy excess.
 In general, systems that detect energy excess
will shunt energy into storage and dissipate
energy by increasing energy expenditure and
consuming ATP.
 In contrast, systems sensing energy deficits will
increase fuel utilization in order to increase ATP
production, decreasing carbohydrate oxidation in
an effort to preserve glycogen stores.
 Some of these pathways will be examined in more
detail because of:
 Their potential to either attenuate or
intensify the features of metabolic syndrome

Nutrient Sensors
AMPK
 AMPK is an energy sensor which can activate or
inactivate a variety of cellular systems in order to
restore the ATP versus AMP balance within a cell.
 When AMP levels rise, AMPK is activated.
 This leads to a series of cellular events that serve to
increase fat oxidation.
 Long-term activation of AMPK may have other effects
that are undesirable such as: a.) decreased protein
synthesis and b.) increases in food intake.
 These concerns contrast with animal studies that
clearly demonstrate that activation of AMPK improves
the negative effects of the metabolic syndrome.

Nutrient Sensors
CHREBP/X-5-P/PP2A
 In the liver, carbohydrate excess leads to de novo synthesis of lipids
from carbohydrate
 In humans, de novo lipogenesis contributes to overall fat balance.
 It was thought that insulin and glucagon were primary regulators of this system
 Recent discoveries have illustrated the hexose monophosphate shunt pathways
involvement.
 Inhibition of PP2A is a therapeutic target to decrease lipid synthesis of
triglycerides and increase fat oxidation in the liver.

CHREBP/X-5-P/PP2A Pathway
Overview
1.Carbohydrate flux
increasing intracellular 3. This causes
Xyulose-5-phosphate dephosphorylation of
concentrations 2. Leads to the the 3 subunits of PP2A
activation of Protein
phosphatasePP2A
4. Leads to the
5. Decreased fatty acid oxidation activation of
occurs via CREBP’s regulation over carbohydrate response
fructose 2,6 bisophoshate levels element binding protein
(CREBP)

Nutrient Sensors
Glucosamine/GFAT
 The Glucosamine/Glucosamine Fructose Amido-Transferase (GFAT) pathway is
another cellular sensor of energy excess believed to lead to insulin resistance.
 Increased carbohydrate flux into muscle cells leads to the formation of
UDP-glucosamine via conversion by the enzyme GFAT.
 Although the mechanism is unclear, increased glucosamine inhibits insulin action,
which is an undesirable affect for any individual.
 The contribution that this pathway might play in the metabolic syndrome in vivo
is still uncertain, as specific inhibitors have not been described.

Nutrient Sensors
Long Chain AcylCoA’s/Ceramides
 Increases in fatty acid flux lead to increases in the intracellular concentrations
of Long chain AcylCoA’s and other intracellular molecules such as ceramides.
 Evidence shows that these molecules drive insulin secretion and
peripheral insulin resistance.
 These pathways are difficult to use as candidates for the treatment of
metabolic syndrome, since there is an absence of any specific downstream
molecular targets.

Other Potential Therapeutic Targets
1. Inhibition of myostatin.
Myostatin is a TGF-like growth factor that suppresses skeletal muscle protein
synthesis/accumulation. In myostatin knock out animals, huge skeletal muscle mass
and decreased adipose tissue have been observed. This is presumably due to
“repartitioning” energy into muscle, decreasing lipid synthesis in adipose tissue, and/or
increasing basal energy expenditure.
2. Inhibition of GSK-3.
Glycogen synthase kinase 3 (GSK-3) is upregulated in insulin resistance and diabetes.
GSK-3 inhibitors actually mimic insulin, leading to reduced insulin levels and improved
glycemic control in preclinical models. It is currently unknown as to whether or not this
approach will reduce the other features of metabolic syndrome.
3. Inhibition of ACC.
Acetyl-CoA Carboxylase (ACC) catalyzes the carboxylation of acetyl CoA to form
malonylCoA. MalonylCoA is a potent inhibitor of CPT-1 mediated fatty acid entry into
mitochondria for oxidation. It is believed that by inhibiting ACC, this will allow for
increased fat oxidation.

Other Potential Therapeutic Targets
4. Administration of anti-inflammatory salicylates.
There is some evidence that treatment with salicylates will improve insulin
action and the metabolic syndrome. One downside observed with this
treatment is that the pathways inhibited are necessary for the normal
immune response to infectious agents. Therefore, an adverse effect of this
treatment may be increased infections.
5. Inactivation of the glucocorticoid receptor in adipose tissue.
Systemic cortisol excess, known as Cushing’s syndrome, has long been
known to increase visceral abdominal fat and lead to the development of
diabetes and features of the metabolic syndrome. Cortisol has potent
effects on adipocyte function leading to the differentiation of adipocytic
precursors and lipid storage. These effects are mediated via the nuclear
hormone receptor for cortisol: the glucocorticoid receptor. Therefore,
inactivation of the glucocorticoid receptor is currently believed to be a
rational target.

Division of Education
Heli J. Roy, PhD, RD
Shanna Lundy, BS
Division of Education
Phillip Brantley, PhD, Director
Pennington Biomedical Research Center
Steven Heymsfield, MD, Executive Director
Edited : October 2009

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References
 Smith S. Metabolic syndrome targets. Current Drug Targets. 2004;3: 431-439.
 Mayo Clinic: Metabolic syndrome. Available at: http://www.mayoclinic.com .
 The American Heart Association: Metabolic Syndrome. Available at:
http://www.americanheart.org