Fatty Acid Metabolism in Humans

Source: International Chair on Cardiometabolic Riskwww.cardiometabolic-risk.org

Fatty Acid Metabolism in Humans

Michael Jensen, MDDivision of Endocrinology and Metabolism

Department of Internal Medicine Mayo Clinic and Foundation, Rochester, MN, USA

Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org

Overview

Adipose function in humans

Free fatty acids (FFA) and health

Regulation of FFA metabolism

FFA in different types of obesity


Fat and Lean Interactions

Lean Body Mass

Adiposetissue


Body Fat in Humans

0

20

40

60%

bo

dy

fat

Leanmen

Leanwomen

Obesemen

Obesewomen

Adapted from Nielsen S et al. J Clin Invest 2004; 113: 1582-8


SQ: subcutaneous

Regional Body Fat in Humans: Where Is It?

0

20

40

60 visceral lower body lower body SQ%

of

fat

in r

egio

n

Lean men Lean women



SQ: subcutaneous

Regional Body Fat in Humans: Where Is It?

0

20

40

60 visceral lower body lower body SQ

% o

f fa

t in

reg

ion

Obese men

Lower body obese women

Upper body obese women




Virtually all fatty acids originate from dietary

triglyceride fatty acids.

Long-term storage site is adipose tissue.

Regulated release of fatty acids as free fatty

acids provides the majority of lipid fuel for

postabsorptive adults.



Oxidation100 gm

TG fatty acids

Chylomicron TG100 gm

FFA

Direct Oxidation CO2 + H2O(20-70 gm)

Adipose tissue(30-80 gm)

FFA: free fatty acidsTG: triglycerides


Adipose Physiology

Insulin

Adipocyte

Triglycerides

FFA

Glycerol

FFA: free fatty acids


Adipose Physiology

Insulin

Adipocyte

Triglycerides

FFA

Glycerol



Adipose Physiology

Growth hormonecatecholamines

Adipocyte

Triglycerides

FFA

Glycerol



Adipose Physiology

Adipocyte

Triglycerides

FFA

Glycerol

Growth hormonecatecholamines



Energy Expenditure, Sex, and Free Fatty Acids (FFA)

What drives the release of FFA in the postabsorptive state?

What is “normal” FFA release? How does FFA release differ in men and

women, lean and obese? Does body fat distribution relate to basal

lipolysis? Do circulating hormone levels relate to basal

lipolysis?


Energy Expenditure, Sex, and Free Fatty Acids (FFA)

50 healthy research volunteers:• 50% women (all premenopausal)

• 50% obese

Body composition: • DEXA (fat and fat-free mass)

• CT abdomen for visceral and subcutaneous fat

• Fat cell size (abdomen & gluteal)

Isoenergetic diet in GCRC x 2 weeksDEXA: dual energy x-ray absorptiometryCT: computed tomography


Experimental Design

Basal studies last 4 mornings of the study:

Palmitate flux = lipolysis (mol/min -

[U13C]palmitate)

Resting energy expenditure (indirect

calorimetry)


0

50

100

150

1000 1200 1400 1600 1800 2000 2200 2400

kcal/day

Pa

lmit

ate

re

lea

se

(m

ol/m

in)

Resting Energy Expenditure vs. Free Fatty Acid Flux

Women

Men



Intra-abdominal (Visceral) Fat Area vs. Residual Palmitate Flux

00

50

-50

300

Intra-abdominal fat area (cm2)

r=0.45p<0.05

Men

00

50

-50

300

Women

Intra-abdominal fat area (cm2)

(m

ol/m

in)

Resid

ual p

almitate release



Summary

Basal free fatty acid (FFA) release (lipolysis) is strongly related to resting energy expenditure.

Women have higher FFA release rates than men at comparable resting energy expenditure and comparable FFA concentrations.

This sex-based difference can only be due to increased non-oxidative FFA clearance in women.

Basal FFA release is partially modulated by body fat and catecholamine availability.


Relationship Between Body Composition and Physiological Consequences

Body fat distribution and free fatty acids (FFA)

Adipose tissue FFA release Effects of excess FFA on health


Body Fat Distribution and Free Fatty Acids (FFA)

Normal FFA High FFA


Intra-abdominal (Visceral) Fat and Upper Body Obesity

Subcutaneous fat

Intra-abdominal fat


FFA

Upper Body / Intra-abdominal (Visceral) Obesity and Insulin Resistance

Insulin resistance

Glucose release

Constriction Relaxation

Insulin secretion

Muscle Vasculature

Liver Pancreas

Upper body /Intra-abdominal obesity

Insulin resistance


Body Fat Distribution and Free Fatty Acids (FFA)

Upper body obesity is associated with adverse metabolic consequences.

Upper body obesity is associated with high basal and postprandial FFA.

Intra-abdominal (visceral) fat most strongly correlated with metabolic abnormalities.

Do the excess FFAs come from intra-abdominal fat?


Regional Adipose Tissue Model

Intra-abdominal (visceral) fat

Lower body subcutaneous fat

Upper body subcutaneous fat


0

50

100

150splanchnic

upper body fat

mo

l/m

i nm

ol/

min

Splanchnic Contribution to Basal Upper Body Adipose Tissue Free Fatty Acid Release

*

Adapted from Martin ML and Jensen M. J Clin Invest 1991; 88: 609-13

Lean women

Lower body obese women

Upper body obese women


Regional Free Fatty Acid Release During Meal Ingestion

0

200

400

600Basal Meal

Upper body obese Lower body obese

0

200

400

600Basal Meal

*

mo

l/min

Nonsplanchnicupper body

LegSplanchnic Nonsplanchnicupper body

LegSplanchnic

* p<0.05 vs. basal values

Adapted from Guo Z et al. Diabetes 1999; 48: 1586-93

**

*


Regional Free Fatty Acid Release in Obese Nondiabetics and Obese Type 2 Diabetics

0

20

40

60

80

100

Nonsplanchnic upper bodySplanchnicLeg

Adapted from Basu A et al. Am J Physiol 2001; 280: E1000-6

Per

cen

t o

f to

tal

Nondiabetic Diabetic


-20%

-10%

0%

10%

20%

30%

40%

50%

0 100 200 300 400

Intra-abdominal (visceral) fat area (cm2)

% H

epa

tic F

FA

de

live

ry

fro

m in

tra

-ab

dom

ina

l fa

t

Hepatic Free Fatty Acid (FFA) Delivery

Women

Men



Summary

Upper body subcutaneous fat accounted for the majority of systemic free fatty acid (FFA) release.

Intra-abdominal (visceral) fat mass correlated with but was not the source of most systemic FFA release.

Intra-abdominal fat mass predicts greater delivery of FFA to the liver from intra-abdominal lipolysis.


Summary

A greater portion of free fatty acid (FFA) appearance derives from leg and splanchnic adipose tissue in obese than lean men and women.

Nevertheless, the majority of systemic FFAs originate from upper body subcutaneous fat in obese men and women.

Intra-abdominal (visceral) fat correlates positively with the proportion of hepatic FFA delivery from intra-abdominal fat in both men and women.


Conclusions

In both men and women, greater amounts of intra-abdominal (visceral) fat result in a greater proportion of hepatic free fatty acid (FFA) delivery originating from intra-abdominal adipose tissue lipolysis in the overnight postabsorptive state.

This implies that arterial FFA concentrations will underestimate hepatic FFA delivery systematically and progressively with greater degrees of intra-abdominal adiposity.


Free Fatty Acids (FFA) and Pancreas

Insulin resistance FFA

• Long-term damage to beta cells• Decreased insulin secretion

Short-term stimulation of insulin secretion

Pancreas

Adipose tissue


Free Fatty Acids (FFA) and Dyslipidemia

Liver

VLDL-TG

HDL cholesterol

Apo B100 synthesis and secretion


Adipose tissue

TG: triglycerides


Free Fatty Acids (FFA) and Glucose Production


Adipose tissue

Liver

Glucose release


Skeletalmusclecells

Free Fatty Acids (FFA) and Muscle

Intra-muscular

TG

Insulin resistance

Glucose uptake

Muscle


Adipose tissue

TG: triglycerides


Free Fatty Acids (FFA) and Hypertension

Relaxation – decreased nitric oxide generation

Vasculature

Constriction –greater response to alpha-adrenergic stimuli


Adipose tissue


Summary

Upper body obesity is associated with high free fatty acids (FFA) due to excess release from upper body subcutaneous fat.

High FFA can result in:– insulin resistance in muscle and liver VLDL TG insulin secretion (?diabetes)– vascular abnormalities


Conclusion

Therapies that correct abnormal adipose tissue free fatty acid release may improve the metabolic abnormalities seen in upper body obesity even if weight loss is not successful.


Adipose Tissue as Endocrine Cells

Angiotensinogen

Resistin

Retinol binding

protein-4Visfatin

Interleukin-6

Tumor necrosis factor-

Adiponectin

Leptin


Conclusions

Fat is a dynamic and varied tissue. Regional differences in adipose biology

affect health. The causes of differences in body fat

distribution are unknown. The relative contributions of high free fatty

acids and adipokines to adverse health is unknown.


www.cardiometabolic-risk.org

Fatty Acid Metabolism in Humans

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