Mohamed Kamar

Professor Of Diabetes And Endocrinology

Faculty Of Medicine

Zagazig University

Aswan February 2012

ECTOPIC FAT

FAT AROUND THE BODYIS IT ALL THE SAME?

FAT AROUND THE BODY

• Physiological role of fat----------

The Good

• Too much fat in fat tissue---------

The Bad

• Fat in non-fat tissue-----------------

The Ugly

PHYSIOLOGIC ROLE OF FAT: TRIGLYCERIDE

• Energy dense macromoloecules: 9 kcal/g

• Stored without water

• A 72 kg person has 12 kg fat =110,000 kcal= 60 days (vs 1 day from glycogen)

• 12 kg fat = 126 kg glycogen

• Triglycerides are stored in specialized fat cells (adipocytes)

• The adipose tissue is not just a fat depot

PHYSIOLOGIC ROLES OF FAT: TRIGLYCERIDE

AdiposeAdiposeTissueTissue Unknown Unknown

FactorsFactorsAgouti proteinAgouti protein

RetinolRetinol

PAI-1PAI-1

LeptinLeptinASPASP

AngiotensinAngiotensin

ANG-IIANG-II

AdiponectinAdiponectin

AdipsinAdipsin

ResistinResistin

Bone Morphogenic ProteinBone Morphogenic Protein

IGF-1IGF-1IGFBPIGFBP

TNF-TNF- Interleukins InterleukinsTGF TGF FGFFGFEGFEGF

Fatty AcidsFatty AcidsLysophospholipidLysophospholipidLactateLactateAdenosineAdenosineProstaglandinsProstaglandinsGlutamineGlutamine

EstrogenEstrogen

PHYSIOLOGIC ROLES OF FAT: TRIGLYCERIDE

TOO MUCH FAT IN FAT TISSUE

How much is too much?

TOO MUCH OF A GOOD THING IS BAD

Oral E: A Review Of Endocr Metab Disord 2003

ANDROID (APPLE) VS. GYNOID (PEAR) OBESITY

AATributeTribute

to a to a PioneerPioneer

Jean Vague (1947)

Adapted from Vague J. Presse Med 1947; 30: 339–40

The amount of Visceral fat determines the risk of developing T2DM and

CVD

TOO MUCH FAT IN FAT TISSUE

• Functional consequences of regional differences

Large viscreal adipocytes:

• Enhanced secretion of FFA

• Lower capavity to stiore fat

• Altered adipokine secretion (leptin, adipnvectin, resistin, viscefatin)

• Inflammation (TNFIL6)

12

Wellen K and Hotamisligil G. J Clin Invest 2003; 112:1785Wellen K and Hotamisligil G. J Clin Invest 2003; 112:1785

Too Much Fat In Fat Tissue

Adipose tissue (AT) expansion during weight gain leads to recruitment of macrophages through local hypoxia. These localize around dead adipocytes and secrete inflammaiory cytokines

THE UGLY

FAT IN NON-FAT TISSUE

LIPOTOXICITY

• LIVER Non-alcoholic steatohepatitis

• MUSCLE

• Skeletal (insulin resistance, major impact because the muscle is the major site of insulin stimulated glucose disposal)

• Cardiac muscle cardiomyopathy

• Pancreatic beta cells defective insulin secretion

Florence (Italy),September 30 and October 1, 2005

15

NAFLD and NASH

Pure fatty liver

HCC

Fibrosis + necroinflammation

CirrhosisNAFLD

NASHNASHNASHNASH

No fatNo fatNo fatNo fat

Time

25-30% of US adults

10%

30%

AASLD Single Topic Conference, Hepatology 2003

Florence (Italy),September 30 and October 1, 2005

16

NAFLD - steatosis

Florence (Italy),September 30 and October 1, 2005

17

NAFLD - steatonecrosis

DIAGNOSIS OF NAFLD & NASH• Clinical findings

• Few clinical symptoms (upper right quadrant discomfort)

• Requires a high degree of clinical suspicion

• Laboratory

• May be associated with elevation of liver transaminases (ALT>AST)

• May NOT be associated with an elevation of ALT/AST

• Imaging

• U/S: ( echogenicity) 65-80% sensitivity for NAFLD

• Magnetic imaging streptoscopy

• Gold standard

• Very precise and reproducible measure of liver fat

• Restricted to research setting

• Liver biopsy: only way to make a diagnosis of NASH

19

Glucose disposal in NAFLDGlucose disposal in NAFLD

Sanyal et al. Gastroenterology 2001

5

10

15

CONT NAFLD NASH

Glu

cose

infu

sio

n ra

te(m

g kg

-1

min

-1)

CONT NAFLD NASH

10 mU kg -1 min -1 40 mU kg -1 min -1

Fat in the liver is inversely related to

insulin sensitivity

LIFESTYLE INTERVENTION THERAPIES FOR NASH

• Lifestyle intervention/weight loss

• Reduce ALT, steatosis, less well proven for on necroinflammation, fibrosis

• Need better standardization, RCTs

• Briatric surgery

• Shown in long-term trials to decrease diabetes and CVD

• In short-term studies, surgery improves histological parameters in NASH

• Need better long-term RCTs

• Not effective

• Not effective

• Effective (PIVENS)

• Overall not effective

• Overall not effective

• Moderate efficacy

• Moderate efficacy

• Moderate efficacy

• Moderate efficacy

• Effective

• Ursodeoxycholic acid

• Pentoxyphilline

• Antioxidanta (vit E)

• Orlistat

• Lipid lowering agents (statins fibratem, omega-3 FA)

• Glucose lowerin agents

• Metformin

• Intensive insulin therapy (NAFLD)

• Exenatide added to insulin (NAFLD)

• Rosiglitazone

• Pioglitazone

PHARMACOLOGICAL INTERVENTIONS FOR NASH

Intervention Outcome

Adapted from Cusi K, Current Opinion Endo,diabetes, Obesity, 2009

EFFECT OF VTAMIN E, PIOGLITAZONE OR PLACEBO IN PATIENTS WITH NASH

• PIVENS, NEJM, 2010. (247 non DM patients divided in 3 gps)

• Primary endpoint reached in

• 43% on vit E (p<0.01)

• 34% with PIO, 30 mg/d (<0.04)

• 18% with PBO

• Resolution NASH PIO 47%, vit E, 36%

• Similar response for low dose PIO and vitamin E

LIPOTOXICITY: SKELETAL MUSCLEHyperinsulinemic-euglycemic clamp and intramyocellular lipid content

Morino K et al J Clin Invest 2004

Mitochondria

IMC Lipid

ECTOPIC FAT INFILTRATION

Muscle triglyceride: obesity, insulin resistance trained athletes

31

Ectopic lipid storage and insulin resistance

IMCL (% H2O)

0

8

12

16

0.60

4

r = - 0.692p < 0.002

0.84 1.08 1.32 1.56 1.80

Insu

lin s

ensi

tivity

(m

g·kg

-1·m

in-1)

Muscle M. tibialis ant.

M. soleus

IMCL

IMCL

Anderwald et al. Diabetes 2002; 51:3025

0

2

4

6

8

10

0 10 20 30 40

Insu

lin s

ensi

tivity

(m

g·kg

-1·m

in-1)

HCL (% H2O)

r = - 0.598p < 0.04

H2O

HCL

5 4 3 2 1 0 ppm

Liver

Krssak et al. Diabetologia 1999; 42:113

ExtensorType IIa,b FastGlycolytic

FlexorType ISlow Oxidative

32

MUSCLE FAT AND INSULIN RESISTANCESUMMARY

• Muscle lipids correlate variably with insulin resistance (IR) depending on nutritional and excercise status.

• Increased availability of free fatty acids inhibits insulin signalling by activating PKC/NFB and serine phosphorylation of IRS-1. Consequently, FFA decrease glucose transport and induce IR.

• Impaired lipid oxidation is required to raise intracellular availability of FFA and IMCL in obesity.

• Reduced mitochondrial function is tightly associated with IR. Defective muscle ATP synthesis might be responsible for hereditary IR or result from increased availability of FFA in acquired (nutritional/obesity induced) forms of IR.

LIPOTOXICITY: CARDIAC MUSCLE

Zhou Y-T et al Proc National Acad Science 2000

LIPOTOXICITY: CARDIAC MUSCLE

EXCESS FAT IN THE PANCREATIC ISLETS

LIPOTOXICITY: PACREATIC BETA CELL

Unger RH Biochimie 2005

The Zucker diabetic fatty rat

LIPOTOXICITY: PANCREATIC BETA CELL

Unger et al PNAS 1999

Role Of Pancreatic Fat In Beta Cell Dysfunction And Diabetes

Ildiko Lingvay: Lipids in and out of context OP Stockholm 2010

LIPOTOXICITY: MECHANISMS

•The hallmark of lipotoxicity is the accumulation of fat in non-fat tissue

•But is fat the cause, or merely a marker?

THE PUZZLE OF TRAINED ATHLETES

• Triglycerides accumulate in the muscle tissue of highly physically trained athletes, who demonstrate enhanced insulin sensitivity.

• It has been suggested that muscle triglyceride may not have adverse metabolic consequences in muscle that has the capacity for efficient lipid utilization

GLUCOLIPOTOXICITY• Either hyperglycemia alone or elevated circulating FFAs alone should not

be so detrimental to a cell

• When glucose levels alone are high, glucose is oxidized, and when FFAs alone are high, then they are oxidized instead of glucose.

• FFAs are elevated during fasting, but are not toxic to cells under this low glucose condition.

• When both glucose and FFA levels are high, FFA esters (FACoAs) are high, and cannot be oxidized because glucose-derived malonyl-CoA is also elevated.

• Excess Malonyl-CoA results from excessive glucose metabolism in hyperglycemic hyperinsulinemic diabetic patients

• (Malonyl Co A -->FA synthesis & FA oxidation)

Increased cellular levels of malonyl-CoA and FACoA as a common mechanism causing glucolipotoxicity in various tissues in obesity-associated type 2 diabetes.

Prentki M et al. Diabetes 2002;51:S405-S413

Copyright © 2011 American Diabetes Association, Inc.

LIPOTOXICITY: MECHANISMS

• Triglyceride accumulation is a marker of fat overload

• The “lipotoxic” molecules are not the triglycerides themselves but metabolites derived from fat, e.g., diglycerides, ceramide, etc…

LIPOTOXICITY :MECHANISMS

Glucose oxidation

Malonyl Co A

-oxidation

LC FA-CoA

TG

DAG CERAMIDE

PKC PKB NFB ROS NOS

Lipotoxicity

47

Relationship between decrease in plasma FFA concentration and increase in acute insulin response following acipimox treatment

Paolisso et al. Diabetologia 1998; 41:1127

10 20 30 4020

30

40

50

60r = 0.64p<0.001

De

cre

ase

in p

las

ma

FF

A c

on

c. (

%)

Increase in acute insulin response (%)

LIPOTOXICITY IS IT TREATABLE?

DPP – DIABETES PREVENTION PROGRAM

• 3234 in 25 clinical centers with • BMI >24 (>22 in Asians)• IGT: FPG 95-125 mg/dl or 2HPPG 140-199 mg/dl Randomized to:

• Standard lifestyle + metformin• Standard lifestyle + placebo• Intensive Lifestyle Intervention: 7% weight reduction and 150 min

of exercise/wk• Primary outcome: progression to DM on annual OGTT or

semiannual FPG 126 mg/dl or 2HPPG200 mg/dl

The DPP Research Group. NEJM 2002; 346: 393–403

0 1 2 3 4

0

10

20

30

40

Years from randomizationYears from randomization

Cu

mu

lativ

e in

cid

enc

e (

%)

Cu

mu

lativ

e in

cid

enc

e (

%)

Placebo (n=1082)Placebo (n=1082)Metformin (n=1073, p<0.001 vs. PlaceboMetformin (n=1073, p<0.001 vs. Placebo))Lifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. PlaceboLifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. Placebo))

Incidence of diabetesIncidence of diabetes

Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle

The DPP Research Group. NEJM 2002; 346: 393–403

LIPOTOXICITY IS IT TREATABLE?

• Tuomelehto NEJM, 2001

• FINNISH DIABETES PRVENTION STUDY GROUP

• 522 subjects with IGT randomized to a control group and an intervention group with 5% weight loss and 30 minutes of exercise daily

• Risk of diabetes reduced by 58%

A CENTRAL ROLE FOR AMP KINASE

• Highly sensitive metabolic sensor

• Ubiquitously expressed

• Modulates the activity of numerous proteins and metabolic pathways

LIPOTOXICITY IS IT TREATABLE?

Exercise Leptin Adiponectin TZD Metformin

AMPK

Malonyl CoA LC CoA FA oxidation FA esterifiication Ceramidesynthesis

Lipolysis

Glucose transport

NFB Oxidative stress

Adapted from Rudermam and Pentki, Nature Reviews, Drug Discovery, 2004

CONCLUSION I

• Fat is good but too much of a good thing is bad

• Too much fat in fat tissue is bad especially in visceral adipose depots

• Lipotoxicity affects many tissues

• Skeletal muscle insulin resistance

• Cardiac muscle cardiomyopathy

• Liver NASH and insulin resistance

• Pancreatic beta cell defective insulin secretion ( in the presence of concomitant hyperglycemia)

CONCLUSION II

• Ectopic accumulation of fat is a marker but probably not a mechanism of lipotoxicity

• Non-oxidative lipid metabolites affect a number of signaling pathways and tissue function that underlie the mechanisms of lipotoxicity

• Shifting lipid metabolism toward oxidation may represent a viable therapeutic option

• AMPK plays a central role in metabolic sensing and is an attractive therapeutic target

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