SlideShare une entreprise Scribd logo
1  sur  28
Télécharger pour lire hors ligne
ECTOPIC FAT:
AN IMPORTANT FEATURE OF INTRA-
  ABDOMINAL OBESITY IN TYPE 2
          DIABETES
         Marja-Riitta Taskinen, MD, PhD
    Professor of Medicine, Division of Cardiology
            Helsinki University Hospital
                  Helsinki, Finland
What Is Ectopic Fat Accumulation?
                                 and/
       Caloric intake             or    Energy expenditure



                  Positive energy balance                  Lipid overflow into liver,
                                                         pancreas, muscle and heart




                                             FFA
     Inflamed
     adipose
     tissue

                     Imbalance between loading and export of lipids results
                             in ectopic fat accumulation at organs

                                                                          FFA: free fatty acids
Source: www.myhealthywaist.org
Why Is the Fatty Liver Dangerous for Cardiovascular Health Risk?

                                     Glucose
                                                       VLDL
                                                                            HDL
                                                                                            ALT
                                  The fatty liver :
                                  overproduction of
                                  cardiometabolic
                                                                             Fibrinogen
                                  risk factors
        Obesity                                          CRP
 Genetic predisposition
    Fat in the diet?                          PAI-1
       Fructose?
                                        FVII

                                                         ALT: alanine aminotransferase
                                                         CRP: C-reactive protein
                                                         FVII: factor VII
                                                         PAI-1: plasminogen activator inhibitor-1
 Source: www.myhealthywaist.org
Determination of Liver Fat Content Using Magnetic Resonance
          Spectroscopy
                                       Water peak




                                 Liver fat 6%                     Liver fat 28%




          Triglyceride peak



                                                Reproduced by permission of the American Diabetes Association. Copyright© 2000
                                                    American Diabetes Association. From Ryysy L et al. Diabetes 2000;49:749-58

Source: www.myhealthywaist.org
Regulation of Lipid Metabolism in the Liver



Free fatty
                                  De novo
acid flux                          lipogenesis
                                  Fatty acid
                                   oxidation
Dietary                           VLDL assembly
fatty acids



                                                   VLDL
                                                   secretion

Source: www.myhealthywaist.org
The Atherogenic Lipoprotein Triad


Lifestyle                                          Insulin resistance
                                                   Type 2 diabetes
                                        Large      FCH subjects
                                                   Low HDL subjects
                                        VLDL
Genes




                             Small,
                             dense    Increased                   HDL
                             LDL      CAD Risk

                                                  CAD: coronary artery disease
                                                  FCH: familial combined hyperlipidemia
  Source: www.myhealthywaist.org
Relationship Between VLDL1 Production Rate and Plasma
          VLDL1 Triglyceride (TG) Pools


                       VLDL1 TG production   600
                           (mg/kg/day)                 r=0.62, p<0.001

                                             400


                                             200


                                              0
                                                   0       10      20          30           40          50          60

                                                                VLDL1 TG pool (mg/kg)



              VLDL1 TG production rate is the predictor for VLDL1 TG pool size


                                                                        Adapted from Adiels M et al. Arterioscler Thromb Vasc Biol 2005;25:1697-703

Source: www.myhealthywaist.org
VLDL1 Triglyceride (TG) Production Is Linked With Detrimental
                                               Changes of LDL Size and HDL Cholesterol
VLDL1 TG production (mg/kg/day)




                                                                                                     VLDL1 TG production (mg/kg/day)
                                  600                                                                                                  600
                                                                             r=-0.56, p<0.005                                                                                    r=-0.64, p<0.001
                                  500                                                                                                  500

                                  400                                                                                                  400

                                  300                                                                                                  300

                                  200                                                                                                  200

                                  100                                                                                                  100

                                      0                                                                                                 0
                                          22     23       24       25   26   27    28   29      30                                       0.7          0.9       1.1        1.3        1.5        1.7

                                                                   LDL size (nm)                                                                          HDL cholesterol (mmol/l)




                                                                                                                                             Adapted from Adiels M et al. Diabetologia 2006;49:755-65

                                  Source: www.myhealthywaist.org
Relationship Between VLDL1 Triglyceride (TG) Production and
          Liver Fat Assessed Using Proton Spectroscopy



                                        600
                  VLDL1 TG production

                                                  r=0.58, p<0.01
                      (mg/kg/day)



                                        400


                                        200


                                         0
                                              0          5          10       15              20              25
                                                                   Liver fat (%)

              Liver fat content is the driving force for VLDL-TG overproduction

                                                                                   Adapted from Adiels M et al. Diabetologia 2006;49:755-65

Source: www.myhealthywaist.org
Defective Regulation of VLDL Metabolism by Insulin in Type 2
              Diabetic Patients
                                                                                  1000
                                                                                             VLDL1 apo B production
               FFA                    Oxidation




                                                                              mg/day
                                                  De novo lipogenesis
                                                                                       500          -51%
                              FA
Remnants                               TG
                                                                                        0
                    CE                                                                         Controls             Type 2
                                                                                                                    diabetes
Degradation
                          MTP                                                    VLDL1
                                                                        LPL
                                                           VLDL2                                       Apo B: apolipoprotein B
                    Apo B                                                                              CE: cholesteryl ester
                                                                                              LPL
                                                          LPL      VLDL2                               FA: fatty acid
                                                                                                       FFA: free fatty acids
                                              IDL          HL                                          HL: hepatic lipase
  Insulin fails to                                                                                    LPL: lipoprotein lipase
  suppress VLDL1 apo                                    IDL                                            MTP: microsomal triglyceride
  B production.                      LDL
                                             HL                                                              transfer protein
                                                                                                       TG: triglycerides
  Accumulation of
  VLDL1 particles.                          LDL

                                                    Small, dense                                Adapted from Malmströn R et al.
                                                    LDL                         Arterioscler Thromb Vasc Biol 1997;17:1454-64

    Source: www.myhealthywaist.org
Characteristics of the Subjects

                                                 Low liver fat                  High liver fat
                                                   (n=10)                          (n=10)

Body mass index (kg/m2)               26.0  2.9                                  28.4         3.6
Subcutaneous fat (cm3)               2150  730                                  2420          520
Intra-abdominal (visceral) fat (cm3) 1600  880                                  2480          860*
Liver fat (%)                          2.1  1.5                                  11.4         4.5***
M value (mg/kg/min)                    6.4  1.8                                   4.0         2.1*
Fasting triglycerides (mmol/l)         1.4  0.5                                   2.0         0.8
HDL cholesterol (mmol/l)               1.4  0.2                                   1.1         0.3**
LDL size (nm)                         26.6  0.8                                  25.3         1.1**

* p<0.05           ** p<0.01       *** p<0.001


                                                        Adapted from Adiels M et al. Diabetologia 2007;50:2356-65

  Source: www.myhealthywaist.org
High Liver Fat: Lack of VLDL1 Suppression in Response to Insulin


                                                       VLDL1 triglyceride production rate
                       % of total VLDL at baseline

                                                     100
                                                                        61%, p<0.01                     Low liver fat <5.5%
                                                     75                                                  High liver fat >5.5%


                                                     50


                                                     25


                                                       0
                                                           0    200       400        600
                                                                Time (minutes)


                                                                                 Adapted from Adiels M et al. Diabetologia 2007;50:2356-65

Source: www.myhealthywaist.org
Normal Production and Suppression of VLDL1 Particles
          in Normal Healthy Subjects by Insulin

Low liver fat                                  Insulin             Apo B: apolipoprotein B
                                                                   MTP: microsomal triglyceride transfer protein
                                                                   TG: triglycerides




                                          TG

                                    MTP

                                                                                           VLDL1
                                 Apo B
                                                         VLDL2
                                                                      VLDL2




                                                         Adapted from Adiels M et al. Diabetologia 2007;50:2356-65

Source: www.myhealthywaist.org
Overproduction and Dysregulation of VLDL1 Particles in Type 2
           Diabetes

 High liver fat                        Insulin
                                                                                Apo B: apolipoprotein B
                                                                                TG: triglycerides




                                  TG




                                                                                  VLDL1
                         Apo B
                                                 VLDL2

                                                             VLDL2


High liver fat is linked with hepatic insulin resistance and
overproduction of large VLDL particles

                                                     Adapted from Adiels M et al. Diabetologia 2007;50:2356-65

 Source: www.myhealthywaist.org
Why People With a Big Waist do not all Have Dyslipidemia?




                                            Metabolic
                                           syndrome?




                                                                                 Elevated VLDL1
                                                                                  concentrations


                         Insulin resistance?            Insulin resistance
   Normal                                                                             The
    lipid                                                                         atherogenic
   profile                  Intra-abdominal             Intra-abdominal              triad
                            (visceral) obesity          (visceral) obesity
                                                                             Low HDL        Small, dense
                                                                                            LDL particles



Source: www.myhealthywaist.org
Sources of Fatty Acids for Liver and VLDL Triglycerides (TG)

                                 FFA
                                               1
                                 POOL

                                                   STORAGE?
                                              FA
                         CM               2                                β-ox
                                     TG
                                                                          4
                                 2             LIVER
                                                 TG

                                 DNL          Apo B
                                                               5              VLDL               Apo B: apolipoprotein B
                                      3                                        TG                -ox: -oxidation
             GLUCOSE
                                                                                                 CM: chylomicron

                INSULIN                                                                          DNL: de novo lipogenesis
                                                                                                 FA: fatty acids
                                                                                                 FFA: free fatty acids


                                                    Adapted from Adiels M et al. Arterioscler Thromb Vasc Biol 2008;28:1225-36

Source: www.myhealthywaist.org
Whole-Body Palmitate Rate of Appearance in Obese Subjects
              Without and With Nonalcoholic Fatty Liver Disease (NAFLD)

                    Palmitate rate of appearence                                           *
                                                                                                                  Normal IHTG
                                                                                                                  NAFLD
                           (µmol/minute)




                                                                 n=14                   n=14


                                                   Liver fat (%) 3.4    0.4         22.7        2.0
                                                   BMI (kg/m2) 35.3     1.3         36.8        1.2
*Significantly different from the normal IHGT group, p<0.05                                                IHTG: intrahepatic triglycerides


                  The rate of the release of fatty acids from adipose tissue is increased
                  in obese subjects with NAFLD

                                                                              Adapted from Fabbrini E et al. Gastroenterology 2008;134:424-31

    Source: www.myhealthywaist.org
VLDL Triglyceride (TG) Secretion Rate Is Increased in Obese
           Subjects With Nonalcoholic Fatty Liver Disease (NAFLD)

                                  30
                                                                     *                    Systemic plasma FFA
                                  25
                                                                                          Nonsystemic fatty acids
                                                                     *
                  (µmol/minute)

                                  20

                                  15

                                  10

                                  5
                                                                     *
                                  0     Normal IHGT             NAFLD
                                                                                               BMI: body mass index
                        Liver fat (%) 3.4        0.4          22.7       2.0
                        BMI (kg/m2) 35.3         1.3          36.8       1.2                   FFA: free fatty acids
                                                                                               IHTG: intrahepatic triglycerides
*Significantly different from the normal IHGT group, p<0.05

               Fatty acids derived from nonsystemic sources are the major factors
               responsible for the increase in VLDL TG secretion

                                                                Adapted from Fabbrini E et al. Gastroenterology 2008;134:424-31

 Source: www.myhealthywaist.org
Sources of Fatty Acids for Liver Fat and VLDL Triglycerides

 Increased rate of free fatty acid flux from adipose tissue
  results in increased rate of hepatic free fatty acid uptake.

 Intrahepatic de novo lipogenesis is enhanced in subjects
  with nonalcoholic fatty liver disease (NAFLD).

 The production and secretion of large VLDL particles
  correlate with liver fat content.

 Basal hepatic lipid oxidation seems to be unaltered in
  subjects with NAFLD.

           Overproduction of VLDL particles is NOT able to
           adequately compensate for increase of hepatic
           triglyceride production liver fat accumulation
Regulation of DNL by SREBP1-C, ChREBP and LXRs in Liver




                                              ACC: acetyl-CoA carboxylase
                                              ChREBP: carbohydrate-responsive element-binding protein
                                              DGAT: diacylglycerol acyltransferase
                                              DNL: de novo lipogenesis
                                              ELOVL6: long-chain elongase
                                              FAS: fatty acid synthase
                                              GK: glucokinase
                                              GPAT: mitochondrial glycerol 3-phosphate acyltransferase
                                              L-PK: liver-pyruvate kinase
                                              LXR: liver X receptors
                                              SCD1: stearoyl-CoA desaturase
                                              SREBP-1: sterol regulatory element-binding protein 1
                                              TG: triglycerides




                                        Adapted from Postic C and Girard J. J Clin Invest 2008;118:829-38

Source: www.myhealthywaist.org
Mechanisms Leading to Insulin Resistance in the Liver
                                                                                       Akt: protein kinase B
                                                                                       DAG: diacylglycerol
                                                                                       FA: fatty acids

                                                      Acylcarnitine                    LPA: lysophosphatidic acid
                                                                                       mTOR: mammalian target of rapamycin
FA         TG                                                                          NFkB: nuclear factor-kappa B
                                                       Fatty acyl-CoA
                                                                                       PA: phosphatidic acid
                                                                β-oxidation            PKC: protein kinase C
                                                         Acetyl-CoA                    TG: triglycerides
     FA
                                                CO2
                   Fatty acyl-CoA                                                    Ketones
                                              Ceramide
                                                                                   Acylcarnitines
                 G-3-P

                             LPA                                  Akt
                   Fatty
                 acyl-CoA
                                               NFĸB
                                               PKC
                                                                                               ?
                                  PA           mTOR


                                       DAG                       Insulin resistance

                                     Fatty      TG
                                   acyl-CoA


                                                                 Adapted from Fabbrini E et al. Hepatology 2010;51:679-89

 Source: www.myhealthywaist.org
Consequences of Ectopic Fat Accumulation: Insulin Resistance,
          Dyslipidemia, NAFLD and Left Ventricular Dysfunction
                                      FFA                Glucose production                                Glucose
Subcutaneous
     fat
                                                          Oxidation
                                                                                             ChREBP
                                                                                             SREBP-1c
                                 Intra-abdominal    FFA           DNL
                                   (visceral) fat


                                                             TG
                                    FFA             TG
                                                                                                   Insulin
                                                                                      Atherogenic
                                                                   VLDL               dyslipidemia
                                                              CAD: coronary artery disease
         LV dysfunction
                                                              ChREBP-1c: carbohydrate-responsive element-binding protein-1c
         CAD risk factor?               Glucose uptake        DNL: de novo lipogenesis
                                                              FFA: free fatty acids
                                                              NAFLD: nonalcoholic fatty liver disease
                                                              SREBP-1: sterol regulatory element-binding protein 1
                                                              TG: triglycerides

                                                                  Adapted from Fabbrini E et al. Hepatology 2010;51:679-89

Source: www.myhealthywaist.org
Fat in Cardiomyocyte

Low myocardial                                        High myocardial
TG content                                            TG content              CH2

                H2O
                                                               H2O

                                                                                          CH3

                   • Adapted from McGavock JM et al.
                     Circulation 2007; 116: 1170-5 x 50
                                  CH2 + CH3




            6        5        4   3     2     1   0        6    5    4    3   2     1     0
                              ppm                                     ppm
                                                                                    TG: triglycerides


 Source: www.myhealthywaist.org
Cardiac Steatosis – a Component of Ectopic Fat

                                               Lean   Obese   Impaired glucose tolerance        Type 2 diabetes



                                             1.2                                                          *
                  Myocardial triglycerides


                                                                                      *
                                             1.0
                       (fat/water )




                                             0.8

                                             0.6

                                             0.4

                                             0.2

                                             0.0
     Intra-abdominal 54 ± 39                                  120 ± 53*      132 ± 36*          160 ± 65*
  (visceral) fat (cm2)
Hepatic fat (fat/water) 1.1 ± 0.9                             4.3 ± 5.2      8.3 ± 11.1*         8.9 ± 8.8*
                                                                                                                     *p<0.05 vs. lean

                                                                              Adapted from McGavock JM et al. Circulation 2007;116:1170-5

Source: www.myhealthywaist.org
Myocardial Fat and Coronary Heart Disease


 Proton magnetic resonance spectroscopy is technically
  challenging but a powerful research tool.

 Is accumulation of myocardial triglycerides related to diastolic
  dysfunction?
  - More rigorous characterization of diastolic function needed.

 No data available on the relationship between myocardial fat
  and coronary heart disease.

 Determinants of myocardial triglyceride accumulation are
  largely unknown.

 Data on responses of myocardial triglycerides to
  pharmacological interventions are non-existing.
Why Is Ectopic Fat Accumulation a Health Hazard?
                                 and/
       Caloric intake             or    Energy expenditure



                  Positive energy balance                    Lipid overflow into liver,
                                                        pancreas, muscle and epicardium




                                             FFA
     Inflamed
     adipose
     tissue

                    Ectopic fat accumulation results in lipotoxicity at organ levels
                    with deleterious consequences at cardiovascular disease health.

                                                                            FFA: free fatty acids

Source: www.myhealthywaist.org
My Warmest Thanks to my Collaborators


  "Current players"              Gothenburg
  Anne Hiukka                    Martin Adiels
  Eeva Leinonen                  Jan Boren
  Sakari Mänttäri                Sven-Olof Olofsson
  Aino Soro-Paavonen
  Sanni Söderlund                Glasgow
  Jukka Westerbacka              Muriel Caslake
  Hannele Yki-Järvinen           Chris J. Packard
                                 Philip Steward

  "The ladies of the lab"        Imaging team
  Hannele Hilden                 Nina Lundbom
  Virve Naatti                   Jesper Lundbom
  Helinä Perttunen-Nio           Antti Hakkarainen
Ectopic Fat: An Important Feature of Intra-Abdominal Obesity in Type 2 Diabetes

Contenu connexe

Tendances

Diabesity (Diabetes and Obesity)
Diabesity (Diabetes and Obesity)Diabesity (Diabetes and Obesity)
Diabesity (Diabetes and Obesity)simplyweight
 
Diabetes Remission and Prevention
Diabetes Remission and PreventionDiabetes Remission and Prevention
Diabetes Remission and PreventionUsama Ragab
 
Managment of Diabesity (Obesity in diabetes mellitus)
Managment of Diabesity (Obesity in diabetes mellitus) Managment of Diabesity (Obesity in diabetes mellitus)
Managment of Diabesity (Obesity in diabetes mellitus) Tarek Al 3reeny
 
SGLT2 Endocrine CME Grand Rounds Final
SGLT2 Endocrine CME Grand Rounds FinalSGLT2 Endocrine CME Grand Rounds Final
SGLT2 Endocrine CME Grand Rounds FinalShannon DeGrote
 
Medical nutrition therapy_for_diabetes
Medical nutrition therapy_for_diabetesMedical nutrition therapy_for_diabetes
Medical nutrition therapy_for_diabetes9849443728
 
Weight Management in Type 2 Diabetes: 2015
Weight Management in Type 2Diabetes: 2015Weight Management in Type 2Diabetes: 2015
Weight Management in Type 2 Diabetes: 2015drsamianik
 
Basic carbohydrate counting final
Basic carbohydrate counting finalBasic carbohydrate counting final
Basic carbohydrate counting finalHaifaa Abdulsalam
 
Diabetes & obesity
Diabetes & obesityDiabetes & obesity
Diabetes & obesityBJunkin
 
Lifestyle modification in the prevention of type 2 diabetes: The experience w...
Lifestyle modification in the prevention of type 2 diabetes: The experience w...Lifestyle modification in the prevention of type 2 diabetes: The experience w...
Lifestyle modification in the prevention of type 2 diabetes: The experience w...My Healthy Waist
 
Intensification Options after basal Insulin Revisited
Intensification Options after basal Insulin RevisitedIntensification Options after basal Insulin Revisited
Intensification Options after basal Insulin RevisitedUsama Ragab
 
Diabetes and nutritional managemant
Diabetes and nutritional managemantDiabetes and nutritional managemant
Diabetes and nutritional managemantBushra Tariq
 
Nutrition Therapy For CKD: A Case Study Approach
Nutrition Therapy For CKD: A Case Study ApproachNutrition Therapy For CKD: A Case Study Approach
Nutrition Therapy For CKD: A Case Study Approachkiolinski
 

Tendances (20)

Diabetes mellitus by dr shahjada selim
Diabetes mellitus by dr shahjada selimDiabetes mellitus by dr shahjada selim
Diabetes mellitus by dr shahjada selim
 
Diabesity (Diabetes and Obesity)
Diabesity (Diabetes and Obesity)Diabesity (Diabetes and Obesity)
Diabesity (Diabetes and Obesity)
 
Diabetes Remission and Prevention
Diabetes Remission and PreventionDiabetes Remission and Prevention
Diabetes Remission and Prevention
 
NUTRITIONAL CARE PLAN
NUTRITIONAL CARE PLANNUTRITIONAL CARE PLAN
NUTRITIONAL CARE PLAN
 
Managment of Diabesity (Obesity in diabetes mellitus)
Managment of Diabesity (Obesity in diabetes mellitus) Managment of Diabesity (Obesity in diabetes mellitus)
Managment of Diabesity (Obesity in diabetes mellitus)
 
SGLT2 Endocrine CME Grand Rounds Final
SGLT2 Endocrine CME Grand Rounds FinalSGLT2 Endocrine CME Grand Rounds Final
SGLT2 Endocrine CME Grand Rounds Final
 
Medical nutrition therapy_for_diabetes
Medical nutrition therapy_for_diabetesMedical nutrition therapy_for_diabetes
Medical nutrition therapy_for_diabetes
 
Weight Management in Type 2 Diabetes: 2015
Weight Management in Type 2Diabetes: 2015Weight Management in Type 2Diabetes: 2015
Weight Management in Type 2 Diabetes: 2015
 
ACCORD Trial_Review
ACCORD Trial_ReviewACCORD Trial_Review
ACCORD Trial_Review
 
Basic carbohydrate counting final
Basic carbohydrate counting finalBasic carbohydrate counting final
Basic carbohydrate counting final
 
Diabetes & obesity
Diabetes & obesityDiabetes & obesity
Diabetes & obesity
 
Lifestyle modification in the prevention of type 2 diabetes: The experience w...
Lifestyle modification in the prevention of type 2 diabetes: The experience w...Lifestyle modification in the prevention of type 2 diabetes: The experience w...
Lifestyle modification in the prevention of type 2 diabetes: The experience w...
 
Obesity
Obesity Obesity
Obesity
 
Diet in diabetes
Diet in diabetesDiet in diabetes
Diet in diabetes
 
Intensification Options after basal Insulin Revisited
Intensification Options after basal Insulin RevisitedIntensification Options after basal Insulin Revisited
Intensification Options after basal Insulin Revisited
 
Obesity & its management
Obesity  & its management Obesity  & its management
Obesity & its management
 
Diabetes
DiabetesDiabetes
Diabetes
 
Diabetes and nutritional managemant
Diabetes and nutritional managemantDiabetes and nutritional managemant
Diabetes and nutritional managemant
 
facts and myths about diabetes
facts and myths about diabetesfacts and myths about diabetes
facts and myths about diabetes
 
Nutrition Therapy For CKD: A Case Study Approach
Nutrition Therapy For CKD: A Case Study ApproachNutrition Therapy For CKD: A Case Study Approach
Nutrition Therapy For CKD: A Case Study Approach
 

En vedette

Dm &amp; liver
Dm &amp;  liverDm &amp;  liver
Dm &amp; liveralaa wafa
 
Clinical, laboratory and histological associations in clinical, laboratory an...
Clinical, laboratory and histological associations in clinical, laboratory an...Clinical, laboratory and histological associations in clinical, laboratory an...
Clinical, laboratory and histological associations in clinical, laboratory an...Dr. sreeremya S
 
Using nutrigenomics to study ranges and plasticity in homeostasis
Using nutrigenomics to study ranges and plasticity in homeostasisUsing nutrigenomics to study ranges and plasticity in homeostasis
Using nutrigenomics to study ranges and plasticity in homeostasisNorwich Research Park
 
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"Norwich Research Park
 
Ueda2016 diabetes&amp;liver - ashraf talaat
Ueda2016 diabetes&amp;liver - ashraf talaatUeda2016 diabetes&amp;liver - ashraf talaat
Ueda2016 diabetes&amp;liver - ashraf talaatueda2015
 
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...Norwich Research Park
 
Fatty liver disease with Diabetes Mellitus [BANGLADESH]
Fatty liver disease with Diabetes Mellitus [BANGLADESH]Fatty liver disease with Diabetes Mellitus [BANGLADESH]
Fatty liver disease with Diabetes Mellitus [BANGLADESH]drsamianik
 
Non alcoholic fatty liver disease(NAFLD)
Non alcoholic fatty liver disease(NAFLD)Non alcoholic fatty liver disease(NAFLD)
Non alcoholic fatty liver disease(NAFLD)Bhavin Mandowara
 

En vedette (9)

Dm &amp; liver
Dm &amp;  liverDm &amp;  liver
Dm &amp; liver
 
Clinical, laboratory and histological associations in clinical, laboratory an...
Clinical, laboratory and histological associations in clinical, laboratory an...Clinical, laboratory and histological associations in clinical, laboratory an...
Clinical, laboratory and histological associations in clinical, laboratory an...
 
Using nutrigenomics to study ranges and plasticity in homeostasis
Using nutrigenomics to study ranges and plasticity in homeostasisUsing nutrigenomics to study ranges and plasticity in homeostasis
Using nutrigenomics to study ranges and plasticity in homeostasis
 
Diabetes and liver
Diabetes and liverDiabetes and liver
Diabetes and liver
 
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"Nanjing 3 2013 Lecture "Nutrigenomics part 3"
Nanjing 3 2013 Lecture "Nutrigenomics part 3"
 
Ueda2016 diabetes&amp;liver - ashraf talaat
Ueda2016 diabetes&amp;liver - ashraf talaatUeda2016 diabetes&amp;liver - ashraf talaat
Ueda2016 diabetes&amp;liver - ashraf talaat
 
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory s...
 
Fatty liver disease with Diabetes Mellitus [BANGLADESH]
Fatty liver disease with Diabetes Mellitus [BANGLADESH]Fatty liver disease with Diabetes Mellitus [BANGLADESH]
Fatty liver disease with Diabetes Mellitus [BANGLADESH]
 
Non alcoholic fatty liver disease(NAFLD)
Non alcoholic fatty liver disease(NAFLD)Non alcoholic fatty liver disease(NAFLD)
Non alcoholic fatty liver disease(NAFLD)
 

Similaire à Ectopic Fat: An Important Feature of Intra-Abdominal Obesity in Type 2 Diabetes

Dyslipidemia [Compatibility Mode]
Dyslipidemia [Compatibility Mode]Dyslipidemia [Compatibility Mode]
Dyslipidemia [Compatibility Mode]Jimma university
 
Focus on triglycerides
Focus on triglyceridesFocus on triglycerides
Focus on triglyceridesSachin Verma
 
Fat – good or bad registrartraining2012
Fat – good or bad registrartraining2012Fat – good or bad registrartraining2012
Fat – good or bad registrartraining2012PeninsulaEndocrine
 
Atorvastatin & dyslipidemia
Atorvastatin & dyslipidemiaAtorvastatin & dyslipidemia
Atorvastatin & dyslipidemiaMUPEG
 
Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...
Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...
Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...vaibhavyawalkar
 
Metabolismo Intermedio
Metabolismo IntermedioMetabolismo Intermedio
Metabolismo IntermedioDigital Med
 
Lipid Guidelines - Dr. Ajay Kantharia
Lipid Guidelines - Dr. Ajay KanthariaLipid Guidelines - Dr. Ajay Kantharia
Lipid Guidelines - Dr. Ajay KanthariaIndian Health Journal
 
Kindex Final2010v3
Kindex Final2010v3Kindex Final2010v3
Kindex Final2010v3Melz333
 
Role of the dysregulated endocannabinoid system in determining cardiometaboli...
Role of the dysregulated endocannabinoid system in determining cardiometaboli...Role of the dysregulated endocannabinoid system in determining cardiometaboli...
Role of the dysregulated endocannabinoid system in determining cardiometaboli...My Healthy Waist
 
Who want's to be a nutrition genius
Who want's to be a nutrition geniusWho want's to be a nutrition genius
Who want's to be a nutrition geniuskellybolton
 
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...My Healthy Waist
 
Powerpoints Hypolipidemics
Powerpoints HypolipidemicsPowerpoints Hypolipidemics
Powerpoints HypolipidemicsMD Specialclass
 

Similaire à Ectopic Fat: An Important Feature of Intra-Abdominal Obesity in Type 2 Diabetes (20)

Dyslipidemia [Compatibility Mode]
Dyslipidemia [Compatibility Mode]Dyslipidemia [Compatibility Mode]
Dyslipidemia [Compatibility Mode]
 
Focus on triglycerides
Focus on triglyceridesFocus on triglycerides
Focus on triglycerides
 
Fat – good or bad registrartraining2012
Fat – good or bad registrartraining2012Fat – good or bad registrartraining2012
Fat – good or bad registrartraining2012
 
Atorvastatin & dyslipidemia
Atorvastatin & dyslipidemiaAtorvastatin & dyslipidemia
Atorvastatin & dyslipidemia
 
Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...
Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...
Diabetic dyslipidemia and residual risk by Dr. Vaibhav Yawalkar MD DM Cardiol...
 
Biochem 18.01.55(เช้า)
Biochem 18.01.55(เช้า)Biochem 18.01.55(เช้า)
Biochem 18.01.55(เช้า)
 
Metabolismo Intermedio
Metabolismo IntermedioMetabolismo Intermedio
Metabolismo Intermedio
 
Lipo protein metabolism
Lipo protein metabolismLipo protein metabolism
Lipo protein metabolism
 
Lipid Guidelines - Dr. Ajay Kantharia
Lipid Guidelines - Dr. Ajay KanthariaLipid Guidelines - Dr. Ajay Kantharia
Lipid Guidelines - Dr. Ajay Kantharia
 
Kindex Final2010v3
Kindex Final2010v3Kindex Final2010v3
Kindex Final2010v3
 
Diabetic dyslipidemia
Diabetic dyslipidemiaDiabetic dyslipidemia
Diabetic dyslipidemia
 
Fat
FatFat
Fat
 
Hyperlipidemia
HyperlipidemiaHyperlipidemia
Hyperlipidemia
 
Role of the dysregulated endocannabinoid system in determining cardiometaboli...
Role of the dysregulated endocannabinoid system in determining cardiometaboli...Role of the dysregulated endocannabinoid system in determining cardiometaboli...
Role of the dysregulated endocannabinoid system in determining cardiometaboli...
 
Lipid metabolism 2
Lipid metabolism 2 Lipid metabolism 2
Lipid metabolism 2
 
APPROACH TO DIABETES
APPROACH TO DIABETESAPPROACH TO DIABETES
APPROACH TO DIABETES
 
hypolipidemic drugs-AHS Gowtham sap
hypolipidemic drugs-AHS Gowtham sap hypolipidemic drugs-AHS Gowtham sap
hypolipidemic drugs-AHS Gowtham sap
 
Who want's to be a nutrition genius
Who want's to be a nutrition geniusWho want's to be a nutrition genius
Who want's to be a nutrition genius
 
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...
 
Powerpoints Hypolipidemics
Powerpoints HypolipidemicsPowerpoints Hypolipidemics
Powerpoints Hypolipidemics
 

Plus de My Healthy Waist

Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...
Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...
Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...My Healthy Waist
 
Global Sugar-Sweetened Beverage Sale Barometer
Global Sugar-Sweetened Beverage Sale BarometerGlobal Sugar-Sweetened Beverage Sale Barometer
Global Sugar-Sweetened Beverage Sale BarometerMy Healthy Waist
 
Targeting abdominal obesity in diabetology: What can we do about it?
Targeting abdominal obesity in diabetology: What can we do about it?Targeting abdominal obesity in diabetology: What can we do about it?
Targeting abdominal obesity in diabetology: What can we do about it?My Healthy Waist
 
Clinical Management of CVD Risk in Abdominal Obesity and Type 2 Diabetes Targ...
Clinical Management of CVD Risk in Abdominal Obesity and Type 2 DiabetesTarg...Clinical Management of CVD Risk in Abdominal Obesity and Type 2 DiabetesTarg...
Clinical Management of CVD Risk in Abdominal Obesity and Type 2 Diabetes Targ...My Healthy Waist
 
Global dimensions of sugary beverages in programmatic and policy solutions.
Global dimensions of sugary beverages in programmatic and policy solutions.Global dimensions of sugary beverages in programmatic and policy solutions.
Global dimensions of sugary beverages in programmatic and policy solutions.My Healthy Waist
 
Physical Activity in the Management of Abdominal Obesity
Physical Activity in the Management of Abdominal ObesityPhysical Activity in the Management of Abdominal Obesity
Physical Activity in the Management of Abdominal ObesityMy Healthy Waist
 
Managing cardiometabolic risk
Managing cardiometabolic riskManaging cardiometabolic risk
Managing cardiometabolic riskMy Healthy Waist
 
Fatty acid metabolism in humans
Fatty acid metabolism in humansFatty acid metabolism in humans
Fatty acid metabolism in humansMy Healthy Waist
 
Metabolic syndrome and adipose tissue
Metabolic syndrome and adipose tissueMetabolic syndrome and adipose tissue
Metabolic syndrome and adipose tissueMy Healthy Waist
 
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...My Healthy Waist
 
The concept of cardiometabolic risk
The concept of cardiometabolic risk The concept of cardiometabolic risk
The concept of cardiometabolic risk My Healthy Waist
 
Plasma lipid transport - Role of HDL
Plasma lipid transport - Role of HDL Plasma lipid transport - Role of HDL
Plasma lipid transport - Role of HDL My Healthy Waist
 
A simplified view of Victor Dzau´s cardiovascular continuum
A simplified view of Victor Dzau´s cardiovascular continuumA simplified view of Victor Dzau´s cardiovascular continuum
A simplified view of Victor Dzau´s cardiovascular continuumMy Healthy Waist
 
Evaluating cardiometabolic risk
Evaluating cardiometabolic riskEvaluating cardiometabolic risk
Evaluating cardiometabolic riskMy Healthy Waist
 
Raising HDL with drugs - does it work?
Raising HDL with drugs - does it work?Raising HDL with drugs - does it work?
Raising HDL with drugs - does it work?My Healthy Waist
 
Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...
Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...
Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...My Healthy Waist
 
Metabolic syndrome: an Asian perspective
Metabolic syndrome: an Asian perspectiveMetabolic syndrome: an Asian perspective
Metabolic syndrome: an Asian perspectiveMy Healthy Waist
 
Impact of obesity on cardiometabolic risk: Will we lose the battle?
Impact of obesity on cardiometabolic risk: Will we lose the battle?Impact of obesity on cardiometabolic risk: Will we lose the battle?
Impact of obesity on cardiometabolic risk: Will we lose the battle?My Healthy Waist
 

Plus de My Healthy Waist (18)

Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...
Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...
Update on Management of Atherogenic Dyslipidemia of Insulin Resistance, Obesi...
 
Global Sugar-Sweetened Beverage Sale Barometer
Global Sugar-Sweetened Beverage Sale BarometerGlobal Sugar-Sweetened Beverage Sale Barometer
Global Sugar-Sweetened Beverage Sale Barometer
 
Targeting abdominal obesity in diabetology: What can we do about it?
Targeting abdominal obesity in diabetology: What can we do about it?Targeting abdominal obesity in diabetology: What can we do about it?
Targeting abdominal obesity in diabetology: What can we do about it?
 
Clinical Management of CVD Risk in Abdominal Obesity and Type 2 Diabetes Targ...
Clinical Management of CVD Risk in Abdominal Obesity and Type 2 DiabetesTarg...Clinical Management of CVD Risk in Abdominal Obesity and Type 2 DiabetesTarg...
Clinical Management of CVD Risk in Abdominal Obesity and Type 2 Diabetes Targ...
 
Global dimensions of sugary beverages in programmatic and policy solutions.
Global dimensions of sugary beverages in programmatic and policy solutions.Global dimensions of sugary beverages in programmatic and policy solutions.
Global dimensions of sugary beverages in programmatic and policy solutions.
 
Physical Activity in the Management of Abdominal Obesity
Physical Activity in the Management of Abdominal ObesityPhysical Activity in the Management of Abdominal Obesity
Physical Activity in the Management of Abdominal Obesity
 
Managing cardiometabolic risk
Managing cardiometabolic riskManaging cardiometabolic risk
Managing cardiometabolic risk
 
Fatty acid metabolism in humans
Fatty acid metabolism in humansFatty acid metabolism in humans
Fatty acid metabolism in humans
 
Metabolic syndrome and adipose tissue
Metabolic syndrome and adipose tissueMetabolic syndrome and adipose tissue
Metabolic syndrome and adipose tissue
 
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...
 
The concept of cardiometabolic risk
The concept of cardiometabolic risk The concept of cardiometabolic risk
The concept of cardiometabolic risk
 
Plasma lipid transport - Role of HDL
Plasma lipid transport - Role of HDL Plasma lipid transport - Role of HDL
Plasma lipid transport - Role of HDL
 
A simplified view of Victor Dzau´s cardiovascular continuum
A simplified view of Victor Dzau´s cardiovascular continuumA simplified view of Victor Dzau´s cardiovascular continuum
A simplified view of Victor Dzau´s cardiovascular continuum
 
Evaluating cardiometabolic risk
Evaluating cardiometabolic riskEvaluating cardiometabolic risk
Evaluating cardiometabolic risk
 
Raising HDL with drugs - does it work?
Raising HDL with drugs - does it work?Raising HDL with drugs - does it work?
Raising HDL with drugs - does it work?
 
Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...
Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...
Sugar-sweetened beverage consumption in relation to diabetes and cardiovascul...
 
Metabolic syndrome: an Asian perspective
Metabolic syndrome: an Asian perspectiveMetabolic syndrome: an Asian perspective
Metabolic syndrome: an Asian perspective
 
Impact of obesity on cardiometabolic risk: Will we lose the battle?
Impact of obesity on cardiometabolic risk: Will we lose the battle?Impact of obesity on cardiometabolic risk: Will we lose the battle?
Impact of obesity on cardiometabolic risk: Will we lose the battle?
 

Ectopic Fat: An Important Feature of Intra-Abdominal Obesity in Type 2 Diabetes

  • 1. ECTOPIC FAT: AN IMPORTANT FEATURE OF INTRA- ABDOMINAL OBESITY IN TYPE 2 DIABETES Marja-Riitta Taskinen, MD, PhD Professor of Medicine, Division of Cardiology Helsinki University Hospital Helsinki, Finland
  • 2. What Is Ectopic Fat Accumulation? and/ Caloric intake or Energy expenditure Positive energy balance Lipid overflow into liver, pancreas, muscle and heart FFA Inflamed adipose tissue Imbalance between loading and export of lipids results in ectopic fat accumulation at organs FFA: free fatty acids Source: www.myhealthywaist.org
  • 3. Why Is the Fatty Liver Dangerous for Cardiovascular Health Risk? Glucose VLDL HDL ALT The fatty liver : overproduction of cardiometabolic Fibrinogen risk factors  Obesity CRP  Genetic predisposition  Fat in the diet? PAI-1  Fructose? FVII ALT: alanine aminotransferase CRP: C-reactive protein FVII: factor VII PAI-1: plasminogen activator inhibitor-1 Source: www.myhealthywaist.org
  • 4. Determination of Liver Fat Content Using Magnetic Resonance Spectroscopy Water peak Liver fat 6% Liver fat 28% Triglyceride peak Reproduced by permission of the American Diabetes Association. Copyright© 2000 American Diabetes Association. From Ryysy L et al. Diabetes 2000;49:749-58 Source: www.myhealthywaist.org
  • 5. Regulation of Lipid Metabolism in the Liver Free fatty  De novo acid flux lipogenesis  Fatty acid oxidation Dietary  VLDL assembly fatty acids VLDL secretion Source: www.myhealthywaist.org
  • 6. The Atherogenic Lipoprotein Triad Lifestyle  Insulin resistance  Type 2 diabetes Large  FCH subjects  Low HDL subjects VLDL Genes Small, dense Increased HDL LDL CAD Risk CAD: coronary artery disease FCH: familial combined hyperlipidemia Source: www.myhealthywaist.org
  • 7. Relationship Between VLDL1 Production Rate and Plasma VLDL1 Triglyceride (TG) Pools VLDL1 TG production 600 (mg/kg/day) r=0.62, p<0.001 400 200 0 0 10 20 30 40 50 60 VLDL1 TG pool (mg/kg) VLDL1 TG production rate is the predictor for VLDL1 TG pool size Adapted from Adiels M et al. Arterioscler Thromb Vasc Biol 2005;25:1697-703 Source: www.myhealthywaist.org
  • 8. VLDL1 Triglyceride (TG) Production Is Linked With Detrimental Changes of LDL Size and HDL Cholesterol VLDL1 TG production (mg/kg/day) VLDL1 TG production (mg/kg/day) 600 600 r=-0.56, p<0.005 r=-0.64, p<0.001 500 500 400 400 300 300 200 200 100 100 0 0 22 23 24 25 26 27 28 29 30 0.7 0.9 1.1 1.3 1.5 1.7 LDL size (nm) HDL cholesterol (mmol/l) Adapted from Adiels M et al. Diabetologia 2006;49:755-65 Source: www.myhealthywaist.org
  • 9. Relationship Between VLDL1 Triglyceride (TG) Production and Liver Fat Assessed Using Proton Spectroscopy 600 VLDL1 TG production r=0.58, p<0.01 (mg/kg/day) 400 200 0 0 5 10 15 20 25 Liver fat (%) Liver fat content is the driving force for VLDL-TG overproduction Adapted from Adiels M et al. Diabetologia 2006;49:755-65 Source: www.myhealthywaist.org
  • 10. Defective Regulation of VLDL Metabolism by Insulin in Type 2 Diabetic Patients 1000 VLDL1 apo B production FFA Oxidation mg/day De novo lipogenesis 500 -51% FA Remnants TG 0 CE Controls Type 2 diabetes Degradation MTP VLDL1 LPL VLDL2 Apo B: apolipoprotein B Apo B CE: cholesteryl ester LPL LPL VLDL2 FA: fatty acid FFA: free fatty acids IDL HL HL: hepatic lipase  Insulin fails to LPL: lipoprotein lipase suppress VLDL1 apo IDL MTP: microsomal triglyceride B production. LDL HL transfer protein TG: triglycerides  Accumulation of VLDL1 particles. LDL Small, dense Adapted from Malmströn R et al. LDL Arterioscler Thromb Vasc Biol 1997;17:1454-64 Source: www.myhealthywaist.org
  • 11. Characteristics of the Subjects Low liver fat High liver fat (n=10) (n=10) Body mass index (kg/m2) 26.0  2.9 28.4  3.6 Subcutaneous fat (cm3) 2150  730 2420  520 Intra-abdominal (visceral) fat (cm3) 1600  880 2480  860* Liver fat (%) 2.1  1.5 11.4  4.5*** M value (mg/kg/min) 6.4  1.8 4.0  2.1* Fasting triglycerides (mmol/l) 1.4  0.5 2.0  0.8 HDL cholesterol (mmol/l) 1.4  0.2 1.1  0.3** LDL size (nm) 26.6  0.8 25.3  1.1** * p<0.05 ** p<0.01 *** p<0.001 Adapted from Adiels M et al. Diabetologia 2007;50:2356-65 Source: www.myhealthywaist.org
  • 12. High Liver Fat: Lack of VLDL1 Suppression in Response to Insulin VLDL1 triglyceride production rate % of total VLDL at baseline 100  61%, p<0.01 Low liver fat <5.5% 75 High liver fat >5.5% 50 25 0 0 200 400 600 Time (minutes) Adapted from Adiels M et al. Diabetologia 2007;50:2356-65 Source: www.myhealthywaist.org
  • 13. Normal Production and Suppression of VLDL1 Particles in Normal Healthy Subjects by Insulin Low liver fat Insulin Apo B: apolipoprotein B MTP: microsomal triglyceride transfer protein TG: triglycerides TG MTP VLDL1 Apo B VLDL2 VLDL2 Adapted from Adiels M et al. Diabetologia 2007;50:2356-65 Source: www.myhealthywaist.org
  • 14. Overproduction and Dysregulation of VLDL1 Particles in Type 2 Diabetes High liver fat Insulin Apo B: apolipoprotein B TG: triglycerides TG VLDL1 Apo B VLDL2 VLDL2 High liver fat is linked with hepatic insulin resistance and overproduction of large VLDL particles Adapted from Adiels M et al. Diabetologia 2007;50:2356-65 Source: www.myhealthywaist.org
  • 15. Why People With a Big Waist do not all Have Dyslipidemia? Metabolic syndrome? Elevated VLDL1 concentrations Insulin resistance? Insulin resistance Normal The lipid atherogenic profile Intra-abdominal Intra-abdominal triad (visceral) obesity (visceral) obesity Low HDL Small, dense LDL particles Source: www.myhealthywaist.org
  • 16. Sources of Fatty Acids for Liver and VLDL Triglycerides (TG) FFA 1 POOL STORAGE? FA CM 2 β-ox TG 4 2 LIVER TG DNL Apo B 5 VLDL Apo B: apolipoprotein B 3 TG -ox: -oxidation GLUCOSE CM: chylomicron INSULIN DNL: de novo lipogenesis FA: fatty acids FFA: free fatty acids Adapted from Adiels M et al. Arterioscler Thromb Vasc Biol 2008;28:1225-36 Source: www.myhealthywaist.org
  • 17. Whole-Body Palmitate Rate of Appearance in Obese Subjects Without and With Nonalcoholic Fatty Liver Disease (NAFLD) Palmitate rate of appearence * Normal IHTG NAFLD (µmol/minute) n=14 n=14 Liver fat (%) 3.4 0.4 22.7 2.0 BMI (kg/m2) 35.3 1.3 36.8 1.2 *Significantly different from the normal IHGT group, p<0.05 IHTG: intrahepatic triglycerides The rate of the release of fatty acids from adipose tissue is increased in obese subjects with NAFLD Adapted from Fabbrini E et al. Gastroenterology 2008;134:424-31 Source: www.myhealthywaist.org
  • 18. VLDL Triglyceride (TG) Secretion Rate Is Increased in Obese Subjects With Nonalcoholic Fatty Liver Disease (NAFLD) 30 * Systemic plasma FFA 25 Nonsystemic fatty acids * (µmol/minute) 20 15 10 5 * 0 Normal IHGT NAFLD BMI: body mass index Liver fat (%) 3.4 0.4 22.7 2.0 BMI (kg/m2) 35.3 1.3 36.8 1.2 FFA: free fatty acids IHTG: intrahepatic triglycerides *Significantly different from the normal IHGT group, p<0.05 Fatty acids derived from nonsystemic sources are the major factors responsible for the increase in VLDL TG secretion Adapted from Fabbrini E et al. Gastroenterology 2008;134:424-31 Source: www.myhealthywaist.org
  • 19. Sources of Fatty Acids for Liver Fat and VLDL Triglycerides  Increased rate of free fatty acid flux from adipose tissue results in increased rate of hepatic free fatty acid uptake.  Intrahepatic de novo lipogenesis is enhanced in subjects with nonalcoholic fatty liver disease (NAFLD).  The production and secretion of large VLDL particles correlate with liver fat content.  Basal hepatic lipid oxidation seems to be unaltered in subjects with NAFLD. Overproduction of VLDL particles is NOT able to adequately compensate for increase of hepatic triglyceride production liver fat accumulation
  • 20. Regulation of DNL by SREBP1-C, ChREBP and LXRs in Liver ACC: acetyl-CoA carboxylase ChREBP: carbohydrate-responsive element-binding protein DGAT: diacylglycerol acyltransferase DNL: de novo lipogenesis ELOVL6: long-chain elongase FAS: fatty acid synthase GK: glucokinase GPAT: mitochondrial glycerol 3-phosphate acyltransferase L-PK: liver-pyruvate kinase LXR: liver X receptors SCD1: stearoyl-CoA desaturase SREBP-1: sterol regulatory element-binding protein 1 TG: triglycerides Adapted from Postic C and Girard J. J Clin Invest 2008;118:829-38 Source: www.myhealthywaist.org
  • 21. Mechanisms Leading to Insulin Resistance in the Liver Akt: protein kinase B DAG: diacylglycerol FA: fatty acids Acylcarnitine LPA: lysophosphatidic acid mTOR: mammalian target of rapamycin FA TG NFkB: nuclear factor-kappa B Fatty acyl-CoA PA: phosphatidic acid β-oxidation PKC: protein kinase C Acetyl-CoA TG: triglycerides FA CO2 Fatty acyl-CoA Ketones Ceramide Acylcarnitines G-3-P LPA Akt Fatty acyl-CoA NFĸB PKC ? PA mTOR DAG Insulin resistance Fatty TG acyl-CoA Adapted from Fabbrini E et al. Hepatology 2010;51:679-89 Source: www.myhealthywaist.org
  • 22. Consequences of Ectopic Fat Accumulation: Insulin Resistance, Dyslipidemia, NAFLD and Left Ventricular Dysfunction FFA Glucose production Glucose Subcutaneous fat Oxidation ChREBP SREBP-1c Intra-abdominal FFA DNL (visceral) fat TG FFA TG Insulin Atherogenic VLDL dyslipidemia CAD: coronary artery disease LV dysfunction ChREBP-1c: carbohydrate-responsive element-binding protein-1c CAD risk factor? Glucose uptake DNL: de novo lipogenesis FFA: free fatty acids NAFLD: nonalcoholic fatty liver disease SREBP-1: sterol regulatory element-binding protein 1 TG: triglycerides Adapted from Fabbrini E et al. Hepatology 2010;51:679-89 Source: www.myhealthywaist.org
  • 23. Fat in Cardiomyocyte Low myocardial High myocardial TG content TG content CH2 H2O H2O CH3 • Adapted from McGavock JM et al. Circulation 2007; 116: 1170-5 x 50 CH2 + CH3 6 5 4 3 2 1 0 6 5 4 3 2 1 0 ppm ppm TG: triglycerides Source: www.myhealthywaist.org
  • 24. Cardiac Steatosis – a Component of Ectopic Fat Lean Obese Impaired glucose tolerance Type 2 diabetes 1.2 * Myocardial triglycerides * 1.0 (fat/water ) 0.8 0.6 0.4 0.2 0.0 Intra-abdominal 54 ± 39 120 ± 53* 132 ± 36* 160 ± 65* (visceral) fat (cm2) Hepatic fat (fat/water) 1.1 ± 0.9 4.3 ± 5.2 8.3 ± 11.1* 8.9 ± 8.8* *p<0.05 vs. lean Adapted from McGavock JM et al. Circulation 2007;116:1170-5 Source: www.myhealthywaist.org
  • 25. Myocardial Fat and Coronary Heart Disease  Proton magnetic resonance spectroscopy is technically challenging but a powerful research tool.  Is accumulation of myocardial triglycerides related to diastolic dysfunction? - More rigorous characterization of diastolic function needed.  No data available on the relationship between myocardial fat and coronary heart disease.  Determinants of myocardial triglyceride accumulation are largely unknown.  Data on responses of myocardial triglycerides to pharmacological interventions are non-existing.
  • 26. Why Is Ectopic Fat Accumulation a Health Hazard? and/ Caloric intake or Energy expenditure Positive energy balance Lipid overflow into liver, pancreas, muscle and epicardium FFA Inflamed adipose tissue Ectopic fat accumulation results in lipotoxicity at organ levels with deleterious consequences at cardiovascular disease health. FFA: free fatty acids Source: www.myhealthywaist.org
  • 27. My Warmest Thanks to my Collaborators "Current players" Gothenburg Anne Hiukka Martin Adiels Eeva Leinonen Jan Boren Sakari Mänttäri Sven-Olof Olofsson Aino Soro-Paavonen Sanni Söderlund Glasgow Jukka Westerbacka Muriel Caslake Hannele Yki-Järvinen Chris J. Packard Philip Steward "The ladies of the lab" Imaging team Hannele Hilden Nina Lundbom Virve Naatti Jesper Lundbom Helinä Perttunen-Nio Antti Hakkarainen