Protein metabolism in obesity: effects of body fat distribution and hyperinsulinemia on leucine turnover13 Michael

D Jensen

ABSTRACT

and

Morey

To examine

whether

ferences in body fat distribution of protein metabolism, leucine groups

ofage-matched

obese (Non

(UB Ob)

condition amounts

carbon

Ob women

premenopausal

flux

than

was

insulin-clamp Ob

women.

(P

(2.96

Ob

We

but that

increased proteolysis and are impaired in upper-body

ings could of obesity.

Am J C/in Nuir

KEY

implications

WORDS

bution,

min, suppressed was

leucine,

and

in the

(UB

LB

LB

is

that insulin’s antiproobesity. These find-

obesity,

present Ob)

(Non

its

result tance

fat distri-

and

in upper-body

obesity

differences free

the metabolic abnormalities Upper-body obesity is more

in effective

fatty

acid

differences body

(FFA)

include

obesity

extraction

than

(4),

obesity

adipose-tissue turnover

greater most

(4) and

in lower-body have

peripheral likely

different

are also

associated

with

however,

fiber type (9) are known Treatment ofobesity in loss

of lean

tissue.

a result

of reduced

proportions

written

to achieve

varies widely to differences

metabolism. frequently

between in protein

to

leucine kinetics and euglycemic to

determine

were hy-

whether

and

effects

in different

whether

and with

for

illnesses

daily

were

and the

for total

30-36

insulin types

none

that and

of

were

and

2 wk before

10 had 10 had

healthy, pre-

women. waist-hip

WHRs

cir< 0.76.

as minimum

waist

and

with the subject in a standing None of the subjects had acute taking

All subjects’

study

20

kg/rn2]

premenopausal

measured

metabolism.

before

from

(BMI)

such

> 0.85,

circumferences feet together (15).

protein

2 mo

selected

(WHRs)

hip girths hip

obtained

index

10 nonobese

were

ratios

for age and

insulin

of protein

nitrogen

into

is considered

obesity

was

mass

and

women

maximum position

hydrate

in upper-

(8), and

or protein breakdown. The provision ofadequate in these diets may limit protein breakdown (12), 172

by Other

(type

Waist

consent [body

women

obese

to affect

each

medications weights

consumed

the study.

had

known been

> 200

Subjects

were

stable

g carbomatched

LBM.

Methods II) [l-’3CjLeucine

(5, 6). It is not known in human obesity

to influence protein with hypocaloric diets ability

noted. hepatic

availability

with

methods

obese

or chronic

specific

of fast-twitch

in regulation

(7), FFA

The

the course of such diets 1 1) and is likely related

been

hyperinsulinemia

differences

insulin

(1). Resispronounced

as measured

also

and slow-twitch (type I) muscle-fiber types whether differences in body fat distribution tabolism;

accomlikely to

(2), and

lipolysis,

(3),

compared

appearance

Subjects

cumference

to be an impor-

and hypertension effects are more

women

obesity.

The

in hyperlipidemia, diabetes, to insulin’s glucoregulatory

whether

leucine

wished

antiproteolytic

of

in upper-body-obese

proteolysis (14), postabsorptive We

the selection

conditions

in moderate

normal

Subjects

Introduction

tant variable in predicting panying human obesity.

postabsorptive

is altered

retains

Ob)

facmass

treatment

body

demonstrated

(LB

antipro-

to determine

is altered

Because

conditions.

proteolysis

its full

(1 3). Delineating oflean body

performed

Ob) women.

perinsulinemic

retains

might facilitate programs.

were

be a marker ofwhole-body measured under overnight

menopausal been

deprivation conservation

metabolism

under

Informed,

has

insulin

caloric improved

or lower-body-obese

moderately

fat distribution

secretion;

studies

ofprotein

nonobese

insulin

Body

during predict

the circulation

Ob

obesity

for future studies ofand 199 1;53: 172-6.

Proteolysis,

The regulation

respectively; during the

moderate

of insulin

(LBM) under such conditions appropriate weight-reduction

physiologic that basal Ob

stimulation

teolytic activity tors that could

vs 3. 14 ± 0.16

-

women

conclude

associated with teolytic actions have

dif-

upper-body-

in UB ± 0.08

kg lean body mass carbon flux was not in UB

and

10 nonobese postabsorptive

oflow showed

0.05)


98%

pure,

me-

muscleI From the Endocrine Research Pediatrics, Mayo Clinic, Rochester, 2 Supported by US Public Health

results

balance

individuals synthesis carbohydrate most likely

Am J C/in Nuir

in (10, and/ via

DK 26989, 3 Address Mayo Clinic, Received Accepted

1991:53:172-6.

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Printed

Unit, Departments of Medicine and MN. Service grants DK 40484, DK 38092,

and RR 585 and the Mayo Foundation. reprint requests to MD Jensen, Endocrine Research 200 First Street SW, Rochester, MN 55905. February 13, 1990. for publication April 18, 1990. in USA.

© 1991 American

Society

for Clinical

Unit,

Nutrition

LEUCINE

BASAL

INSULIN

150-

PLASMA

METABOLISM

CLAMP

of 50% maintain

LEUCINE

the entire

study.

A variable

rate

on the first study

day.

Two

failed to return for the insulin-clamp Blood was sampled before starting each

study

to serve ± SE

50

NOfl

A-A

Ob

#{149}-LB

Ob

E1C1LEUCINE

.L

day

assayed

as background

at 10-mm

intervals

each

day

study

for enrichment

for that from

and

in determining

maintain

euglycemia.

as basal

-

2.5

from and

subsequently concentrations

i

I

1

130

140

150

120

130

140

were

150

nearly

and

Blood

samples

1030

(minutes

for plasma

99 mole % enriched, and the L-isomer. The isotope-infusion rate was determined by multiplying the concentration of leucine in by the isotopic The isotope was

for intravenous pyrogen

Plasma

leucine

and

glucagon

( 19),

measured

by standard

centrations

and

were

the amount

the

first

values

ofdextrose

study

day

obtained

are

during

Board.

Each

tritiated

water

space

an overnight a dorsal hand in a heated An forearm

to

second

clamp. minutes

referred study

day

to are

Plasma hormone 120- 1 50 for each

constant

from

minutes

insulin-clamp-study

days

120 to 1 50 on both

the basal

1 and 2); therefore,

steady-

(Figs

to exist. Plasma use of standard

primary equations

INSULIN PLASMA

pool (23)

CLAMP

KIC

30.

subject and/or

of [l-’3C]leucine subjects returned they 0.2

Plasma

con-

glucose

analyzer

Mayo

underwent body

were

Clinic

LBM

potassium

#{176}C) box infusion and

kept

Institutional

determination counting

for sampling catheter

patent

was

mU

LBM’

UB Ob

.-.

LB Ob I

3.0

I

I

I

l1CIKIC

(2 1) before -e--’----

in a coninfusion

0) a primed (-36 zmo1/ . kg LBM’ - min) infusion

insulin .

min’

=:4=i

2.0

of arterialized placed

(mm

intravenous - kg

NonOb

0-b

by

by controlled

was begun and continued 3 d later and were studied received

SE

1

to the Mayo Clinic General Clinical before the first study. In the morning

(50-55 vein

10

(Yellow

fast, a 19-gauge butterfly needle was inserted vein in a retrograde fashion and a hand was

18-gauge

± A-A

OH).

by the

of0.9% saline (20 rnL/h). At 0800 kg LBM) continuous (‘6.2 gmol

and

en-

concentrations

concentrations

a glucose

Springs,

approved

the studies and was admitted Research Center the evening

bolus

on

and

to be infused

subsequently the

referred to as insulin were constant during

by gas chromatogra(17), C peptide (18),

(20)

with

Yellow

Review

ion except

1 50)

to be sterile

(KIC)

hormone

determined was

tralateral

was determined

were determined (16). Plasma insulin

Instruments,

(22).

and

radioimmunoassay.

protocol

blood

obtained

1 20-

and the infusion rate in 9 g saline/L in prepa-

a-ketoisocaproate

growth

This

placed

enrichment dissolved

infusion

% enrichment spectroscopy

after into

were

KIC

free.

and mole phy-mass

Springs

on

and

concentrations

BASAL

and

infusions

of leucine

to

state conditions were assumed leucine flux was calculated by

FIG I . Plasma leucine concentrations and mole percent enrichment (MPE) under basal and insulin-clamp conditions in upper-body-obese (UB Ob), lower-body-obese (LB Ob), and nonobese (Non Ob) women.

ration

women

study day; therefore, average values were determined for each subject and used to calculate the group mean and standard error (SEM). Plasma leucine and KJC concentrations and enrichments MINUTES

the infusate (mL/min).

nonobese

day.

1000

analyzed

to assist

Values

:-$

120

and

ofthe

study. the isotope

Calculations

k-

LU

0

infusion study to at the val-

richment ofleucine and KIC as well as plasma glucose and hormone concentrations. In addition, plasma glucose concentrations were measured at 10-mm intervals throughout the second study

.

A.

intravenous

Ob

0-otiS

0

5.0

173

dextrose was administered during the second each subject’s plasma glucose concentration

ues observed

42

100

OBESITY

throughout

:

A---

IN

through 1030. The in an identical fash(0. 14 mU/kg constant

LBM

infusion)

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/1/172/4691224 by guest on 22 February 2018

I .0

120

I 130

I

I

I

I

I

140

150

120

130

140

I

150

MINUTES

FIG 2. Plasma a-ketoisocaproate basal and insulin clamp conditions body-obese (LB Ob), and nonobese

(KIC) concentrations in upper-body-obese (Non Ob) women.

and MPE under (UB Ob), lower-

174

JENSEN

TABLE Subject

AND

HAYMOND

I characteristics4

two-tailed used

Height (cm) Weight(kg) Age(y) Body mass index (kg/m2)

Lean body mass (kg) Serum triglycerides (mmol/L) Waist-hip ratio Fasting plasma glucose (mmol/L)

bridge,

UBOb

LBOb

NonOb

159 ± 1 82±2 36±2

165 ± 3 88±3 39±2

164 ± 2 59±2 36±2

32.6

± 0.7

43.4

±

1. I

The

BMIs

33.2

± 0.5

21.8

± 0.6

± I .7

42.8

± 1.1

women.

0.88 0.72

± 0.10

0.57 0.73

± 0.06

and

± 0.01

concentrations. women were

5.2±0.1

5.2 ±0.1

4 . ± SEM: n = 10 for each group. UB Ob, Ob, lower-body obese: Non Ob, nonobese women. ference ratios were not random variables between not, therefore, subject to statistical analysis; the and body mass index values between groups. t Significantly different from LB Ob and Non of variance and nonpaired I test).

Non

Significantly

different

and nonpaired

0.001


0.05 vs UB Ob

E is

enrichment

study

which

present

leucine

day among

and

the same

WHRs

of LB Ob women.

in the habitual

EL is the

Statistical

on the same

similar

ofNon

in plasma growth found. As assessed

i)

studies),

is the

The those

53 ±

The

are expressed the values

EK,c

than

women

among the groups, and the women their diet during the course of these

as zrnol/min,

in these

and

of was

EKIC

expressed

(eg, 99%

with

had

Serum triglyceride greater (P < 0.001)

than

the -

Cam-

and C peptide (Table 2) concentrations were different (P < 0.001) among all three groups, with Non Ob women having

1)

_______

=

was

Corp.

insulin

of variance

as an indicator of pool model) (24).

i( kg LBM

isons

(analysis

LB Ob

did not differ

Non Ob women. During plasma glucose concentrations

(analysis

isotopes by using the plasma enrichment [l)3C]leucine; total leucine carbon flux

Leucine

where

0.001

database

Products

to be greater

obesity

Ob women.

proportion

I test).

adapted for stable the infused tracer determined intracellular

Non Ob, P

from