Nutrient Sensing and Metabolic Disturbances

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Nutrient Sensing and Metabolic Disturbances

• Pennington Biomedical Research Center
• Division of Education

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Potential Causes of the Metabolic Syndrome
Insulin Resistance

• Ectopic fat/Impaired fat oxidation
• Intrinsic defects in substrate oxidation/mitochond
  rial biogenesis
• Locking fat in the fat cell/lipolysis
• Adipose tissue as an endocrine tissue
• Nutrient/energy sensors

Smith, S. Metabolic Syndrome Targets. Current
Drug Target. 20043431-439. Pennington
Biomedical Research Center
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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.

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Intrinsic Defects in Substrate Oxidation/Mitochond
rial 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.

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Intrinsic Defects in Substrate Oxidation/Mitochond
rial 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.

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Intrinsic Defects in Substrate Oxidation/Mitochond
rial BiogenesisLipid 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 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.

Adipose tissue
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Intrinsic Defects in Substrate Oxidation/Mitochond
rial BiogenesisLipid 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 CoAs.
• 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-a and ß are two examples of nuclear
  transcription factors that should produce
  beneficial effects on insulin action by
  increasing fat oxidation.

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PPARa

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

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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 PPAR? 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 PPAR? agonists
  effectiveness include the observation of
• Decreased free fatty acids (FFA) in the blood
• Increased insulin stimulated lipid storage

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Locking Fat in the Fat Cells/Lipolysis

• Of the available PPAR? agonists, it is still not
  fully understood how pioglitazone, but not
  rosiglitazone, lowers triglycerides.
• With the development of cleaner PPAR? 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.

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Locking Fat in the Fat Cell/LipolysisLipolytic
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.

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Locking Fat in the Fat Cell/LipolysisLipolytic
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.

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Adipose Tissue as an Endocrine OrganAdipocytokine
s

• 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.

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Adipose Tissue as an Endocrine OrganAdipocytokine
s

• Recent evidence suggests that Adiponectin is an
  important target for metabolic syndrome for
  several reasons
• Receptors for Adiponectin are all in the right
  places liver, skeletal muscle, beta cells, and
  the brain.
• Plasma concentrations of adiponectin are
  decreased in obesity and insulin resistance
  states making replacement therapy possible.
• 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.

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Adipose Tissue as an Endocrine OrganAdipocytokine
s

• 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 societys 86th 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.

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Nutrient SensorsOverview

• 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

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Nutrient SensorsAMPK

• 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.

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Nutrient SensorsCHREBP/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.

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CHREBP/X-5-P/PP2A PathwayOverview

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

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Nutrient SensorsLong Chain AcylCoAs/Ceramides

• Increases in fatty acid flux lead to increases in
  the intracellular concentrations of Long chain
  AcylCoAs 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.

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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.

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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
  Cushings 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.

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Heli J. Roy, PhD, RDShanna Lundy, BSBeth
KalickiDivision of EducationPhillip Brantley,
PhD, DirectorPennington Biomedical Research
CenterClaude Bouchard, PhD, Executive Director

• Division of Education

Edited October 2009
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About Our Company

• The Pennington Biomedical Research Center is a
  world-renowned nutrition research center.
•  
• Mission
• To promote healthier lives through research and
  education in nutrition and preventive medicine.
•  
• The Pennington Center has several research areas,
  including
•  
• Clinical Obesity Research
• Experimental Obesity
• Functional Foods
• Health and Performance Enhancement
• Nutrition and Chronic Diseases
• Nutrition and the Brain
• Dementia, Alzheimers and healthy aging
• Diet, exercise, weight loss and weight loss
  maintenance
•  
• The research fostered in these areas can have a
  profound impact on healthy living and on the
  prevention of common chronic diseases, such as
  heart disease, cancer, diabetes, hypertension and
  osteoporosis.
•  
• The Division of Education provides education and
  information to the scientific community and the
  public about research findings, training programs
  and research areas, and coordinates educational
  events for the public on various health issues.

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References

• Smith S. Metabolic syndrome targets. Current Drug
  Targets. 20043 431-439.
• Mayo Clinic Metabolic syndrome. Available at
  http//www.mayoclinic.com .
  Accessed September 20, 2005.
• The American Heart Association Metabolic
  Syndrome. Available at http//www.americanheart.o
  rg . Accessed September 20, 2005.