metabolically normal and abnormal obesity and effect of weight (fat) loss
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Metabolically Normal and Abnormal Obesity and Effect of Weight (Fat) LossSamuel Klein, MD
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Coronary Heart Disease
Insulin resistance-cell failure Β(Diabetes)
Nonalcoholic fatty liver disease
Atherogenic Dyslipidemia
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Wildman, R. P. et al. Arch Intern Med 2008;168:1617
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Pathogenesis of Obesity-related Metabolic Dysfunction
FFA
FFA
VLDL
TGCO2
Visceralfat
Subcutaneousfat
Glucose production
Glucose uptake
FFAHDL
Adipokines
CETP
CHO
1
TG
3
4
Microbiome
2
2
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Korenblat et al. Gastroenterology 87:3023, 2008
r = -0.62P <0.001
Intrahepatic fat (%)
Liver (Hepatic Insulin Sensitivity Index)
10
15
20
5
0 5 10 15 20 25 30 35 40 45 50
Muscle (% increase in glucose uptake)500
400
300
200
100
0
r = -0.61P <0.001
0 5 10 15 20 25 30 35 40
80
70
45
50
60
Adipose tissue (% suppression of palmitate Ra)
Intrahepatic fat (%)
r = -0.53P <0.00175
65
55
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Insulin Sensitivity is Determined by Intrahepatic Triglyceride (IHTG) Content, not Visceral Adipose Tissue (VAT) Volume
Hepatic Insulin Sensitivity Index
Insulin-mediated stimulation of glucose Rd (%)
Matched on VAT Matched on IHTG
0
0.4
0.8
*
400
0
100
200 *300
Normal
IHTG
High
IHTG
Low
VAT
High
VAT
0
0.4
0.8
400
0
100
200
300
1335±1781290±238Visceral fat (cm3)25.3±3.5 3.7±0.5Liver fat (%)
36±136±2BMI (kg/m2)
1474±317744±104
3.4±0.6 3.7±0.7
36±235±2
Fabbrini E et al. PNAS 106:15430, 2009.
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02/05/15 RiverMend Health, LLC 9Wing R, et al. Diabetes Care. 2011;34:1481
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Obese normal OGT
Obese diabetes
Before
After
Before After
Waist circumference
108±5 94±3* 119±4 107±3*
Systolic BP 119±5 124±4 132±4 137±6
Diastolic BP 70±3 65±4 73±3 68±4
Plasma glucose
89 ±1 90±2 121±15 123±15
Plasma insulin
11±3 9±2 15±2 14±3
Triglycerides
151±28 121±21 162±19 173±24
Total cholesterol
189±12 174±13 160±9 157±10
LDL cholesterol
113±9 110±11 82±7 80±11
HDL cholesterol
45±8 41±9 44 ±3 43±3
Klein S et al. N Engl J Med 350:2549 2004
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Energy Intake
EnergyExpenditure
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Metabolically-normal and Metabolically-abnormal Obesity
Adipose Tissue: 1) FFA Trafficking (delivery, uptake, disposition) 2) CHO Metabolism & Lipogenesis 3) Proliferation & Expansion 4) Immune System Function 5) Adipokines
MNO protected from adverse metabolic effects of weight gain Metabolic abnormalities reversible with negative energy balance
Multi-organ Insulin Resistance -cell Dysfunctionβ
Increased VLDL-TG Secretion & Atherogenic Dyslipidemia
GI Tract: Microbiome, enterokines