Metabolically Normal and Abnormal Obesity and Effect of Weight (Fat) LossSamuel Klein, MD

02/05/15 RiverMend Health, LLC 2

Coronary Heart Disease

Insulin resistance-cell failure Β(Diabetes)

Nonalcoholic fatty liver disease

Atherogenic Dyslipidemia

RiverMend Health, LLC 3

Wildman, R. P. et al. Arch Intern Med 2008;168:1617

02/05/15 RiverMend Health, LLC 4

02/05/15 RiverMend Health, LLC 5

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

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

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.

02/05/15 RiverMend Health, LLC 9Wing R, et al. Diabetes Care. 2011;34:1481

02/05/15 RiverMend Health, LLC 10

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

Energy Intake

EnergyExpenditure

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