International Textbook of Obesity - part 4 ppt

Exercise and Macronutrient Balance Angelo Tremblay and Jean-Pierre Despre´s Laval University, Ste-Foy, Quebec, Canada INTRODUCTION Reduced physical activity represents one of the most si

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mass Therefore, a mitochondria protein—the

un-coupling protein (UCP), found in the mitochondria

in the brown adipose tissue—is of great interest in

this respect

Brown adipose tissues have many mitochondria

The energy released in the brown fat cells is to a

lesser degree than in other cells used for active

phosphorylation of ADP to ATP and more for

thermogenesis Recently, proteins which have

struc-tures very like the UCP ones in brown adipose

tissue have also been found in muscle tissue

Al-though there are many questions to be answered

regarding the presence of the UCP-like protein in

the muscle (exact function, regulation etc.), it can be

speculated that this protein might explain why only

about half of the oxygen used in metabolism in the

muscles is used for active phosphorylation of ADP

at rest (4) The consequence could be that some part

of the energy taken in is not stored in the body, if the

energy released in the metabolism is not used for

mechanical events in the muscle but only increases

the thermogenesis Of interest in this discussion is

that it has been shown that there are diﬀerences

between overweight and normal-weight individuals

in how this UCP-like protein is expressed in mRNA

(5)

Studies in rats have shown that regular

endur-ance training decreases the mRNA linked to the

UCP in muscles (6) On the other hand, after an

endurance exercise session the activity of UCP is

increased (7), which might explain part of the

in-creased post-exercise oxygen consumption Regular

physical training increases muscle and

mitochon-drial mass and as a consequence presumably also

the amount of UCP Thus, both acute and chronic

exercise is of importance for the BMR and

conse-quently the energy balance in both normal-weight

and overweight individuals

If UCP is downregulated by physical activity

then its activity should increase with physical

inac-tivity, leading to an increased BMR per kilo lean

body mass On the other hand, muscle mass is

reduced as a result of physical inactivity In any

case, when studying changes in body weight, diet

and eating habits and level of physical exercise in

individuals, in groups and also in population

inves-tigations, it is obvious that the energy turnover both

during and after exercise as well as the inﬂuence of

exercise on BMR must be considered Thus, level of

physical exercise is therefore of vital importance in

the discussion of energy balance in humans

Summary

About two-thirds of the energy expenditure over 24hours amounts to the resting energy metabolism.New ﬁndings regarding the uncoupling protein canshed new light on BMR and might to some extentexplain the variations in BMR between individualsand perhaps also changes in BMR with time andageing

ENERGY EXPENDITURE DURING

EXERCISE

Intensity and Duration

One cannot apply strict mathematical principles tobiological systems, but when analysing energy bal-ance for longer periods of time, energy metabolismduring and after exercise must be taken into ac-count It is obvious that both the intensity and theduration are the main determinants of energy ex-penditure during exercise However, many factorsmay modify the energy expenditure for a given rate

of work and the total cost for certain activities Forthis reason it is diﬃcult to give exact ﬁgures for theenergy cost of exercise Therefore the discussion ofenergy expenditure should be based on individualconditions and values given for certain activities orfor groups of subjects are subject to large uncertain-ties

During short-term (a few minutes) hard dynamicmuscular exercise carried out with large musclegroups, the energy metabolism may increase to

10—15 times the BMR in untrained subjects and 25—30 times the BMR in well-trained athletes from

endurance events However, due to muscle fatigueduring heavy exercise the duration of exercise isoften fairly short In such cases the total energyexpenditure is relatively low On the other hand,low-intensity exercise, which may require half ortwo-thirds of the individual’s maximal aerobicpower, can be performed for a very long time even

by an untrained individual In this case total energyturnover can be fairly high

Variations in Energy Expenditure During Submaximal Exercise

Variations in energy expenditure for a given

sub-150 INTERNATIONAL TEXTBOOK OF OBESITY

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Figure 11.2 Energy expenditure (as measured by oxygen

up-take) during walking and running

maximal rate of work are due both to individual

variations in economy of locomotion, such as

diﬀer-ent technique and body mass, and to temporary

interindividual factors, such as changes in core

tem-perature and choice of substrate

Energy expenditure (as evaluated from oxygen

consumption) during walking and running is

illus-trated in Figure 11.2 At low speeds—2—5 km per

hour—walking costs less than running; that is

oxy-gen uptake during walking is less than in running at

the same speed This is true for both energy

expen-diture per minute of exercise and net cost of energy

per kilometre covered However, at speeds greater

than 6 to 8 km per hour running is more eﬀective

than walking in both these aspects The upper panel

of the ﬁgure also shows that the net energy cost forrunning per kilometre is more or less independent

of speed For a normal man with a body mass of 70

to 75 kg the energy expenditure during running isabout 280 to 300 kJ per kilometre independent ofspeed, while walking for the same man may costbetween 150 and 350 kJ per kilometre depending onspeed It must be emphasized that well-trained maleand female racewalkers and long-distance runnershave much lower values for energy expenditureboth per minute and net per kilometre than normal,untrained individuals

Women and children have lower energy cost for agiven speed in walking and running due to theirlower body mass However, energy expenditure cal-culated per kilo body mass is the same for men andwomen whereas children have higher values Theenergy expenditure also increases with body weight.Overweight individuals can have 50% and higherenergy expenditure for a given walking speed For

example, during uphill treadmill walking (4—5 km

per hour, 4° elevation) the oxygen uptake in an

untrained overweight woman with a BMI of 35—40

may be maximal Thus, for a given low walkingspeed the variation in energy expenditure can be up

to 100% in a normal population

The energy expenditure at a given speed variesalso with diﬀerent conditions such as surface, uphilland downhill walking and running, wind resistanceetc People with joint disease, an amputation orother physical handicaps have decreased locomo-tion economy, that is the oxygen uptake for a givensubmaximal rate of work is increased

In some types of exercise in which technique isvery important, such as swimming, the energy ex-penditure at a given speed may vary by more than100% for poor and good swimmers for the sameswimming stroke but also for diﬀerent swimmingstrokes in the same individual On the other hand,the energy expenditure for submaximal cycling isabout the same for well-trained cyclists and as it isfor runners for instance

In high speed activities in which wind resistanceincreases, the energy expenditure increases cur-vilinearly In addition, the style, position and/orequipment can inﬂuence the energy expenditure for

a given speed This is particularly true in cycling butalso for running For example, running behind an-other runner may save up to 6% in energy costbecause of the wind protection

151 ENERGY EXPENDITURE AT REST AND DURING EXERCISE

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Table 11.2 Average energy cost for diﬀerent activities for a

There are situations in which the energy

expendi-ture for a given submaximal rate of work is

in-creased such as in hypothermia due to shivering, in

very cold climates due to resistance of cold, stiﬀ

clothes and when for instance running technique is

impaired for various reasons However, in most

such situations the magnitude of the increased

en-ergy expenditure for a given rate of work is of little

quantitative importance On the other hand, in

many situations the energy expenditure for a given

rate of work does not change There are no major

changes in energy expenditure for a given rate of

work with variations in hot or moderately cold

climate (except for shivering), in moderate altitude

compared to sea-level, in anaemia and most

dis-eases including most types of medication, although

in these conditions the physical performance can be

severely impaired It should also be emphasized

that although the energy expenditure at

submaxi-mal work is not changed, the total energy

expendi-ture may be reduced due to the individual becoming

fatigued earlier

The average energy expenditures for diﬀerent

ac-tivities performed for more than 10—15 minutes by a

man aged 20—30 years are given in Table 11.2 It

must be emphasized that these values are subject to

large interindividual variations, as discussed above

Substrate Use During Exercise and

Physical Training

As stated above, fatty acids and carbohydrates in

combination are used during submaximal exercise

A common question in this discussion of substrate

utilization is: Which is the best way to burn fat

during exercise?

From Figure 11.1 it can be seen that the RQ for

an untrained person (upper part of the shadowed

area) is about 0.85 to 0.88 at exercise intensities

from about 25 to 60% of maximal aerobic power

This means that the fat and carbohydrate

contribu-tion to the energy expenditure is 45 and 55%,

re-spectively From these data the substrate use during

exercise can be calculated

The total fatty acid contribution to the exercise

expenditure is highest at around 60% of maximal

aerobic power, which is a pace that even an

un-trained person can exercise at for some time This

means that for an untrained individual with a

maxi-mal aerobic power of about 3.3 litres per minute,0.50 g of fat is used per minute at this intensity.Suppose that this individual through physical train-ing increases his/her maximal aerobic power by 0.5litres per minute, which is possible in 4 to 5 months

of endurance training Compared to the situationbefore the training period, two observations can bementioned regarding the fat and carbohydrate con-tribution to the energy expenditure Firstly, for agiven submaximal relative but also absolute rate ofwork the RQ is lowered (lower part of the shadowedarea in Figure 11.1) Thus, more fatty acids are usedand the stores of carbohydrate are utilized less.Secondly, the intensity for peak fatty acid contribu-tion to the energy expenditure has increased from60% to about 70% of maximal aerobic power Thismeans that the peak contribution of fatty acids inthis individual has increased due to the trainingeﬀects from 0.50 to 0.75 g per minute In addition,the individual can probably be active for longerperiods of time after the training period and, thus,increase the fatty acid turnover still more For in-stance, if she/he increases the exercise time from 30minutes before to 45 minutes after the training per-iod at the exercise intensity at which she/he canexercise fairly easily, then the fatty acid breakdownincreases from 15 g to 30 g for the exercise period.The increased use of fatty acids at a given rate ofwork and the higher speed of exercise may be ofinterest not only in conditioning exercise such asjogging and cycling but also in the everyday ‘behav-iour’ type of exercise (climbing stairs, walking short

152 INTERNATIONAL TEXTBOOK OF OBESITY

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distances etc.) as part of the energy expenditure in

the discussion of energy balance

Maximal Exercise

Variations in maximal power are due to age, genetic

endowment, body size, physical activity and some

other factors and can partly explain diﬀerences in

total energy expenditure for diﬀerent reasons

Indi-viduals with high maximal aerobic power will more

likely walk distances or climb stairs than use cars

and elevators They can more easily carry loads and

they may in general be more physically active in

normal life In addition, due to increased energy

intake when physically active they also have

in-creased intake of essential nutrients But the total

daily need and turnover for essential nutrients

in-creases less than the increased total daily energy

need and turnover when a person becomes more

physically active Therefore the diﬀerence between

intake and turnover of essential nutrients widens

with increasing levels of physical activity under the

assumption that the individual is in energy balance

while trained and untrained

Total Energy Expenditure

As stated above, duration of exercise may be more

important than intensity for total energy

expendi-ture In Table 11.1 the total energy expenditure is

given for one hour of exercise such as walking in

uneven terrain, cycling or playing a game of tennis,

volleyball or table tennis in a moderate fashion The

intensity of these types of physical activities is on

average about 50 to 60% of maximal aerobic power

when carried out as free-chosen physical activity

The rate of work of 50 to 60% is easily performed

even by an untrained person for one hour The

individual maximal oxygen uptake values for

un-trained men and women at diﬀerent ages and

en-durance athletes are also given in Table 11.1

The table shows that one hour of leisure time

exercise yields an energy expenditure in an

un-trained person which corresponds to about

one-quarter of 24 hour BMR, which is 7 MJ for men and

5—6 MJ for women The importance of these types

of regular physical exercise is illustrated when

dis-cussing body mass changes over time It is not

uncommon that body fat mass in many individualsincreases 2 kg in one year This corresponds to adaily energy imbalance of about 150 kJ Unless netenergy intake is increased this corresponds to anextra 10 minutes of walking per day Furthermore,

in order to maximize the beneﬁcial eﬀects of cal activity on health, and in prevention of diseasesthat are related to physical inactivity, the SurgeonGeneral in the USA has recommended accumulatedlow-intensity physical activity of at least 30 minutesper day (8) Thus, regular low-intensity physicalactivity such as walking and cycling to work two

physi-times 15—20 minutes a day may be a good base for

energy balance, body weight maintenance and goodhealth

Sporting activities can generate quite a large totalenergy expenditure In male elite soccer matchplaythe heart rate is on average some 25 to 30 beats perminute lower than peak heart rate obtained duringmaximal exercise Core temperature after the game

is above 39°C as an average for the players in theteam Blood lactate concentration measured severaltimes during the match varies between 4 and

10 mM Thus, from these ﬁgures it can be calculatedthat the average energy expenditure during thegame amounts to 75 to 80% of maximal aerobicpower For an average male elite player with amaximal oxygen uptake of 4.5 litres per minute thetotal energy expenditure for a whole game includingsome warm-up can be calculated to be about 7.5 MJ(1800 kcal) which is about the same as the BMR for

24 hours Corresponding values for total energyexpenditure for a female elite player are some 20%less (9)

The energy cost of a marathon race (42 km) for a30- to 40-year-old man who performs the race in 4

hours is about 12—15 MJ (3000—3500 kcal)

How-ever, in order to be able to carry out the race in 4hours the training during the preceding 6 monthscan be calculated to be about 400 MJ It is obviousthat regular physical training for sport is of import-ance for energy balance and body weight control

Summary

Energy for physical activity is generated thoughseveral complicated systems of which the aerobicsplitting of fat and glucose is the most importantone For most people physical activity amounts to

153 ENERGY EXPENDITURE AT REST AND DURING EXERCISE

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about 30—40% of the total energy expenditure

during 24 hours The amount of exercise energy

expenditure during 24 hours is dependent on

inten-sity and duration but many other factors can

inﬂu-ence energy expenditure

In the population physical activity can be divided

into four main parts The diﬀerence between them is

often not very clear The lowest one is spontaneous

activity, which is trivial activities such as moving

arms and legs, take small steps etc The energy

needed for this type of activity is fairly small but for

people who seldom sit still or move regularly the

whole day the total amount can reach some volume

The physical stress in most jobs is nowadays

much lower than 20—30 years ago Oﬃce work has

very low energy demands In industrial work

mono-tonous and low energy expenditure physical

exer-cise gives rise to overuse problems On the other

hand, other jobs such as construction work can

reach a daily total average energy expenditure of

12 000—13 000 kJ or more In general, physical

activ-ity in most work places does not add enough

physi-cal activity to the daily physiphysi-cal activity

The next part is the ‘behaviour’ physical exercise,

i.e climbing stairs, walking a few blocks instead of

taking a bus or car, often doing physically active

things inside or outside the home This type of

activity is very important for energy balance Over

the day such activity can easily use 1000 kJ in extra

energy expenditure Of particular importance is the

way that the person travels to work In many

coun-tries it is common to ride a bicycle or walk 15—20

minutes to reach the workplace This type of

physi-cal activity is of utmost importance for good health

and body mass maintenance as well as for weight

reduction in overweight individuals

Physical conditioning can, if carried out on

regu-lar basis, create a daily energy expenditure wellabove 3000 kJ and, thus, well above the level forgood health and body mass maintenance Elite ath-letes often have a daily energy expenditure of

14 000—16 000 kJ (3500—4000 kcal); in some sports it

may be even higher In addition to energy ture during exercise, the eﬀect of regular physicalactivity on resting metabolic rate is of interest.Thus physical activity is very important for bodymass maintenance All its diﬀerent parts must beconsidered when discussing energy balance

expendi-REFERENCES

1 A strand PO, Rodahl K Textbook of Work Physiology New

York: McGraw-Hill, 1986.

2 Speakman JR Doubly-labelled Water: Theory and Practice.

London: Chapman and Hall, 1997.

3 Bandini LG, Schoeller DA, Cyr HN, Dietz WH Validity of reported energy intake in obese and nonobese adolescents.

Am J Clin Nutr 1990; 52: 421—425.

4 Brand MD, Chien LF, Ainshow EK, Rolfe DF, Porter RK.

The causes and functions of mitochondrial proton leak

Bio-chim Biophys Acta 1994; 1187: 132—139.

5 Nordfors L, Hoﬀstedt J, Nyberg B, Tho¨rne A, Arner P,

Schall-ing M, Lo¨nnqvist F Diabetologia 1998; 41: 935—939.

6 Boss O, Samec S, Despplanches D, Mayet MH et al Eﬀect of

endurance training on mRNA expression of uncoupling

pro-teins 1, 2 and 3 in the rat FASEBJ 1998; 12: 335—339.

7 Tonkonogi M, Harris B, Sahlin K Mitochondrial oxidative function in human saponin.skinned muscle ﬁbres: eﬀect of

prolonged exercise J Physiol 1998; 510: 279—286.

8 US Department of Health and Human Services (1996)

Physi-cal Activity and Health A Report of the Surgeon General GA.

Superintendent of Documents PO Box 371954 PA

15250-7954, S/N 017-023-00196-5, USA.

9 Ekblom B (ed.) Handbook of Sports Medicine and Science—

Football (Soccer) Oxford: Blackwell Scientiﬁc Publications,

1994

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Exercise and Macronutrient

Balance

Angelo Tremblay and Jean-Pierre Despre´s

Laval University, Ste-Foy, Quebec, Canada

INTRODUCTION

Reduced physical activity represents one of the

most signiﬁcant changes in lifestyle that has been

observed during the twentieth century.Our

seden-tary lifestyle and the reduced energy requirements

of the majority of our jobs has been a source of

comfort in a business world where eﬃciency and

productivity are sought.The impact of the

transi-tion from a traditransi-tional to a modern lifestyle on daily

energy needs can be estimated by various means.By

using the doubly labelled water technique and

in-direct calorimetry, Singh et al.(1) showed that the

energy cost of living at the peak labor season was as

high as 2.35; resting metabolic rate (RMR) in

Gambian women.When this value is compared to

results usually obtained in women living in

indus-trialized countries, 1.4 to 1.8; RMR (2,3), it can be

estimated that for a given body weight, a modern

lifestyle may have reduced the energy cost of living

by as much as 1 to 4 MJ/day.Accordingly, a recent

analysis by Prentice and Jebb (4) has emphasised

the contribution of sedentariness to the increased

prevalence of overweight in the United Kingdom

Despite these observations, the contribution of

exercise to the prevention and treatment of obesity

is still perceived as trivial by many health

profes-sionals.The perception of many of them was

recent-ly well summarized by Garrow (5) who stated that

exercise is a remarkably ineﬀective means of

achieving weight loss in obese people, mainly cause their exercise tolerance is so low that the level

be-of physical activity that they can sustain makes anegligible contribution to total energy expenditure.When one looks at the currently available litera-ture, it is diﬃcult to disagree with this statement.Indeed, numerous studies have demonstrated thatwhen exercise is used alone to treat obesity, bodyweight loss is generally small (6).In addition, thefurther weight loss generated by adding an exerciseprogram to a reduced-calorie diet is also often small

if not insigniﬁcant (7)

Traditionally, the study of the impact of exercise

on body weight control has focused on its energycost and on the hope that the body energy loss will

be equivalent to the cumulative energy cost of cise sessions.In practical terms, this means for in-stance that if a physical activity program induces anexcess of energy expenditure of 2000 kcal/week, asimilar energy deficit should be expected in theactive obese individual.Recent experimental datashow that such a view is not realistic since it doesnot take into account the compensations in othercomponents of energy balance which may eitherattenuate or amplify the impact of exercise on bodyenergy stores.It thus appears preferable to considerexercise as a stimulus affecting regulatory processeswhich can ultimately affect all the components ofenergy balance instead of only focusing on its en-ergy cost.The objective of this chapter is to

exer-International Textbook of Obesity.Edited by Per Bjo¨rntorp.

International Textbook of Obesity.Edited by Per Bjorntorp.

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Table 12.1 Eﬀects of leptin and insulin (euglycemia) on

summarize recent developments in knowledge

pertaining to the eﬀects of exercise on energy

bal-ance.Clinical implications of these notions are also

addressed

EXERCISE AND MACRONUTRIENT

BALANCE

The maintenance of body weight stability depends

on one’s ability to match energy intake to

expendi-ture.This principle is one of the most accepted

axioms of science and represents the main guideline

for health professionals treating obesity.However,

even if energy balance is a central issue in body

weight control, it does not necessarily imply that

matching energy intake to expenditure is the

pri-mary target of mechanisms involved in the

regula-tion of body energy stores

Flatt (8) reported convincing evidence showing

that energy balance is linked to macronutrient

bal-ance.His research and that of other scientists have

also clearly established that the regulation of the

balance of each macronutrient is not performed

with the same precision.Of particular interest for

obesity research is the fact that fat balance is the

component of the macronutrient balance that is the

most prone to large variations.This is probably

explained by some of the following factors:

∑ The weak potential of dietary fat to promote a

short-term increase in its oxidation (9—11).

∑ The weak potential of high fat foods to favor

satiety without overfeeding (12—15).

∑ The inhibiting eﬀect of the intake of other energy

substrates on fat oxidation (16,17)

∑ The absence of a metabolic pathway other than

lipogenesis to buﬀer a signiﬁcant fraction of an

excess fat input (excess dietary fat intake and/or

fat synthesized from other substrates)

∑ The greater dependence of fat oxidation on

sym-pathoadrenal stimulation (18)

The fact that fat balance appears as the ‘Achilles

tendon’ of the macronutrient balance system is

probably compatible with the importance of

main-taining body homeostasis.Indeed, it is probably less

toxic and damaging for the body to store a large

amount of triglycerides as opposed to an

equi-caloric storage of alcohol and glycogen.However,

in the long run, a large body accumulation of fat

causes metabolic complications which worsenhealth status.For the exercise physiologist, thequestion raised by this argument is whether theexercise stimulus can facilitate the regulation of fatbalance, i.e can favor fat balance without relying onbody fat gain to promote macronutrient balance

REGULATION OF FAT BALANCE: FAT

GAIN OR EXERCISE?

Many years ago, Kennedy (19) proposed a static theory stipulating that variables related toadipose tissue contribute to the long-term control

lipo-of food intake.Accordingly, studies performed der diﬀerent experimental conditions provided evi-dence suggesting that fat cell size (20), plasma gly-cerol (21), fat cell lipolysis (22), and fat oxidation(23) may be related to fat and energy balance and tothe long-term stability of body weight.More recent-

un-ly, the discovery of leptin (24) represented an portant step in the investigation of the role of adi-pose tissue on the regulation of fat and energybalance.As shown in Table 12.1, leptin exerts manyfunctions and its most documented role has been tofavor a negative energy balance or at least to pro-mote the stabilization of body weight in a context ofoverfeeding by reducing food intake (25).This tablealso indicates that variations in plasma insulinwithout changes in glycemia produce effects whichare similar to those of leptin.Since the clearance ofinsulin is modulated by the hepatic exposure to freefatty acid (FFA) flux (26), which itself partly de-pends on fat cell size, it is reasonable to associatechanges in adiposity with the effects of changes ininsulinemia on fat and energy balance

im-To summarize, these observations demonstratethat adipose tissue is not passive when one experi-ences long-term underfeeding or overfeeding.Itrather behaves like an organ actively involved in the

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Table 12.2 Opposite (A) and concordant (B) eﬀects of physical activity and metabolic cardiovascular syndrome related to fat gain

?Additional atherogenic features of the metabolic cardiovascular syndrome (31).

HDL, high density lipoprotein; LDL, low density lipoprotein; SNS, sympathetic nervous system; apoB, apolipoprotein B.

recovery of fat and energy balance and of body

weight stability

Research conducted over the last decades has

shown that exercise can also aﬀect many of the

above referenced variables.It has been

demon-strated that exercise stimulates adipose tissue

lipolysis and that trained individuals are more

sen-sitive to the lipolytic eﬀects of catecholamines

(27,28).Furthermore, Turcotte et al.(29) reported

that for any given plasma FFA concentration,

trained individuals would utilize more fat during

exercise than their untrained controls.With respect

to leptinemia, recent data tend to show that for a

given level of body fat, trained individuals display

reduced plasma leptin levels compared to sedentary

controls (30)

We can therefore suggest from the above

obser-vations that both fat gain and exercise represent

strategies which may contribute to the regulation of

fat and energy balance.However, these results also

indicate that physically active individuals have a

major advantage over sedentary individuals as they

may regulate their fat balance more eﬃciently, i.e

with less substrate gradient and reduced hormone

concentrations.In other words, trained persons are

expected to rely to a lesser extent on variations in

adiposity to maintain fat balance under free-living

conditions.The main corollary of this phenomenon

is depicted in Table 12.2, which reminds us there is

also, unfortunately, a price to be paid in taking

advantage of the regulatory impact of fat gain on fat

and energy metabolism.Indeed, body fat gain,

par-ticularly in the visceral fat compartment, is

asso-ciated with an increase in blood pressure and

plasma glucose and insulin as well as with anatherogenic dyslipidemic plasma proﬁle (32,33).This cluster of atherogenic and diabetogenic meta-bolic abnormalities is seldom formed among non-obese physically active individuals

EXERCISE, FAT BALANCE AND BODY

WEIGHT CONTROL

The evidence summarized above suggests that theexercise-trained individual can maintain a reducedlevel of adiposity because of an increased sensitivityand overall better performance of mechanisms in-volved in the regulation of fat balance.If this benefi-cial adaptation can be reproduced in the obeseindividual undertaking a physical activity program,this response would favor a metabolic context facili-tating body weight loss.Accordingly, recent datademonstrate that the effects of exercise favorablyinfluence components of fat and energy balance

Exercise and Fat Oxidation

Exercise-trained individuals are characterized by anincreased level of fat oxidation despite the fact thattheir adiposity is generally lower than that of un-

trained subjects (34—37).In the post-exercise state,

the increase in fat oxidation is explained by anincrease in resting metabolic rate and/or by an in-creased relative fat content of the substrate mixoxidized.Moreover, evidence suggests that the

157 EXERCISE AND MACRONUTRIENT BALANCE

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Table 12.3 Energy intake, expenditure and balance over 2

days under high or low fat conditions following a moderate intensity exercise session

Post-exercise period

Energy intake (MJ) 25.7 <3.3 32.2 <5.1 Energy expenditure (MJ) 29.9 <7.3 29.1 <6.2

Adapted from Tremblay et al (49).

enhanced fat oxidation characterizing trained

indi-viduals is at least partly explained by acute eﬀects of

exercise (38—40).

The mechanisms underlying the exercise-induced

increase in fat oxidation are not clearly established

but experimental data suggest that it is related to an

increase in sympathetic nervous system activity (35)

that seems to be mediated by beta adrenoreceptors

(36).Other recent data emphasize the possibility

that the impact of exercise on fat utilization is

main-ly determined by a change in gmain-lycogen stores and/or

glucose availability (41,42).This observation is

con-cordant with our recent ﬁnding that when exercise

is immediately followed by a liquid

supplementa-tion compensating for carbohydrate and lipid

oxi-dized during exercise, essentially no change in

post-exercise fat oxidation is found (43)

For the obese individual who displays limitations

in the ability to perform prolonged vigorous

exer-cise, the above ﬁndings open new therapeutic

per-spectives.For instance, they raise the possibility

that combining exercise and food-related

sympath-omimetic agents could produce a substantial

in-crease in fat oxidation.One of these agents is

cap-saicin, which was recently found to signiﬁcantly

increase fat oxidation in the postprandial state (44)

In addition, the possibility that the stimulating

ef-fect of exercise on fat oxidation depends on glucose

availability raises the hypothesis that performing

exercise in the postabsorptive state exerts a greater

enhancing eﬀect on total fat oxidation than an

exer-cise bout performed in the fed state.From a clinical

standpoint, these hypotheses are important since

the ability to burn fat with exercise is a signiﬁcant

correlate of post-exercise energy and fat balance

(45)

Exercise and Fat Intake

Excess dietary fat is known to aﬀect spontaneous

energy intake considerably.In humans tested under

conditions mimicking free-living conditions, the

in-take of high fat foods is associated with a large

increase in daily energy intake (12—15).This is

con-cordant with studies demonstrating a signiﬁcant

positive relationship between habitual dietary fat

intake and adiposity (15,46—48).When the

enhanc-ing eﬀect of a high fat diet on energy intake is

considered in the context of exercise practice, high

fat feeding is expected to inhibit the impact of cise on energy balance.As shown in Table 12.3, wefound that when subjects have free access to high fatfoods after having performed a 60-minute vigorousexercise, they overfeed to a level that does not per-mit exercise to induce a negative energy balance(49).In contrast, a substantial energy deﬁcit isachieved when exercise is followed by free access tolow fat foods.This is in agreement with other re-cently reported data showing that high fat feedingfavors an increase in the post-exercise compensa-tion in energy intake (50)

exer-In another recent study, we examined the impact

of combining exercise and ad libitum intake of low

fat foods on daily energy balance in heavy men (51).These subjects were tested twice in a respiratory

chamber under either a sedentary condition with ad

libitum intake of a mixed diet or an exercise

condi-tion with a low fat diet.As expected, daily energybalance was considerably reduced (1.6 MJ) underthe latter condition.This ﬁnding and the evidencesummarized above suggest that it is of primaryimportance to take into account diet composition

to optimize the daily energy deﬁcit which can beachieved with exercise

Recent studies have been designed to test thehypothesis that exercise per se can modify macro-nutrient preferences.This has been examined by

Verger et al.(52) who reported an increased

prefer-ence for carbohydrate after prolonged exercise.In asubsequent study, these authors did not reproducethis ﬁnding but rather noted an increased prefer-ence for proteins after prolonged exercise (53).An-other recent study performed in our laboratory re-vealed that vigorous exercise in untrained subjectsdid not selectively modify the preference for anymacronutrient (54).On the other hand, Westerterp-

Plantenga et al.(55) obtained results demonstrating

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Table 12.4 Characteristics of individuals maintaining a

weight loss of at least 30 pounds (13.6 kg) for at least one year

Duration of maintenance 5.7 years Relative fat intake 25% of total energy intake Physical activity participation? 11 847 kJ/week

?Including strenuous physical activities.

Adapted from McGuire et al.(57).

that exercise may increase the preference for

carbo-hydrates

In summary, diet composition seems to be an

important determinant of the potential of exercise

to induce an overall negative energy

balance.How-ever, it remains uncertain whether a change in

mac-ronutrient preferences can be spontaneously driven

by exercise or should be the result of a voluntary

change in food selection

CLINICAL IMPLICATIONS

The literature summarized above suggests that

combining exercise and a reduced dietary fat intake

should favor spontaneous body weight loss in obese

individuals.In obese women, this combination was

found to induce a mean decrease in body weight of

16% that was associated with a normalization of

the metabolic risk proﬁle (7).In a more recent study,

we used the exercise—low fat diet combination as a

follow-up of a treatment of obesity consisting of

drug therapy and low calorie diet (56).In this

con-text, exercise and low fat diet accentuated the fat

loss induced by the ﬁrst phase of treatment up to a

mean cumulative weight loss of 14% and 10% of

initial values in men and women, respectively.In

addition, the exercise—low fat diet follow-up was

again associated with a normalization of the

meta-bolic risk proﬁle.As shown in Table 12.4, these

observations are consistent with a recent study

de-monstrating that the regular physical activity and

adherence to a low fat dietary regimen are the main

features of the lifestyle of ex-obese individuals

main-taining a large weight loss on a long-term basis (57)

Even if the combination of exercise and low fat

diet can induce a considerable body energy deﬁcit

under free-living conditions, it is likely that adipose

tissue-related regulatory factors of energy and fat

balance will over time favor the restabilization of

body weight.These factors, which are associated

with resistance to further loss of weight in the

reduc-ed-obese individual, are probably the same ones

that promote the achievement of a new body weight

plateau in the context of overfeeding.Thus, as

dis-cussed above, the decrease in sympathetic nervous

system activity and in plasma FFA, leptin, and

insulin probably contributes to resistance to losing

more fat after having experienced success with

exer-cise and a low fat diet.In this context of increased

vulnerability towards a fattening lifestyle, the obese person obviously must maintain his/her new

ex-exercise—low fat diet lifestyle to prevent further

weight regain

CONCLUSIONS

The combination of exercise and a low fat diet is aneﬀective way to induce a spontaneous negative en-ergy and fat balance.In the context of a weight-reducing program, this represents a strategy thatfocuses on lifestyle changes instead of directly tar-geting caloric restriction.The amount of body fatloss expected under these conditions probably cor-responds to what the body does not need anymore

to regulate macronutrient balance.This model siders adipose tissue as an active organ whose im-pact on energy balance can be at least partly re-placed by a healthy lifestyle characterized byhealthy food habits and regular exercise

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Part IV

Pathogenesis and Types of Obesity

MMMM

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For human and veterinary medicine, the main issue

in adipose tissue biology is obesity and its

asso-ciated metabolic complications So much attention

is devoted to ﬁnding ways of reducing the mass of

adipose tissue and correcting complications such as

hyperglycaemia and hyperlipidaemia, that its

posi-tive contributions to other metabolic functions are

often overlooked This chapter is mainly concerned

with the involvement of adipose tissue in roles other

than as a whole-body energy storage Students of

obesity should be aware of these specialized

func-tions, as they could be jeopardized by

indiscrimi-nate suppression of the growth or metabolism of

adipose tissue, or by its surgical removal It is also

possible that their failure or modiﬁcation

contrib-utes to obesity by emancipating other adipocytes

from their normal controls

The persistent lack of interest in alternative

meta-bolic roles for adipose tissue can be attributed to

ﬁrmly established traditions in techniques and

ma-terials used to study it, as well as to the way in which

theories about its functioning have developed

Early studies of human starvation, mammalian

hi-bernation and bird migration all showed that

adi-pose tissue’s main role is provisioning muscles and

other bulk users of lipid for oxidation as fuel

‘En-ergy balance’ became the byword for all research

into adipose tissue metabolism, and is undoubtedly

still an important concept for many kinds of

investi-gation The discovery of leptin as the mediator of

satiety signals between adipocytes and the brain has

reinforced the notion that adipose tissue is a single,uniform organ that, for its own perverse and per-haps irrelevant reasons, just happens to be disper-sed into many depots widely scattered throughoutthe body

Adipose tissue’s role in storing and releasinglipids for oxidation by muscles and other activetissues became so firmly established that littlethought was given to the possibility that it couldalso supply specific fatty acids for structural orinformational roles, or precursors of protein syn-thesis So, although rat adipose tissue was found tocontain unexpectedly high levels of glutamine morethan 35 years ago (1), its involvement in amino acidmetabolism has only recently been studied in hu-mans (2,3) If adipocytes’ only function is to supplyfuels to the bloodstream, then site-specific differen-ces in the triacylglycerol fatty acid composition ofhuman superficial adipose tissue can only be inter-preted as metabolically trivial and unworthy of fur-ther study (4) The findings that adipocytes asso-ciated with lymph nodes in guinea-pigs containconsistently more polyunsaturated fatty acids thanthose remote from nodes, and that within-depotdifferences persist after major change in composi-tion of dietary lipids, suggest local provisioning ofimmune cells that has nothing to do with serving as

a whole-body energy store (5)

Another problem for the evolution of conceptsabout adipose tissue function is the long-standing

‘habit’ of using murid rodents as animal models ofobesity Young rats are quite lean unless subjected

to surgical, genetic or dietary manipulation, and

International Textbook of Obesity Edited by Per Bjo¨rntorp.

International Textbook of Obesity Edited by Per Bjorntorp.

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only the perirenal, inguinal and gonadal depots

(especially the epididymal in males) provide enough

tissue for most biochemical procedures As

ex-plained below, these depots turn out to be only

minimally involved in non-storage roles The

spec-tacular achievements in the selective ‘knocking out’

of particular genes in mice have reinforced this

habit: this species is so small that only these large

depots contain enough adipose tissue to work with

In all practical biology, what one ﬁnds depends

upon where one looks, as well as upon what is

sought, and concentrating research on the major

depots precludes the chance revelation of features

that might suggest additional or alternative roles

Site-speciﬁc properties of vertebrate tissues have

been most thoroughly studied in the nervous system

and the musculature While the arrangements and

physiological capacities of muscle ﬁbres are easily

explained as adaptations to their roles in the

par-ticular species under investigation, the functional

interpretation of the anatomical location of

special-ized regions of the brain and spinal cord leaves

much to be desired, necessitating chiasmata and

very long spinal and cranial nerves Very thorough

comparative studies starting in the mid-nineteenth

century and encompassing everything from

ag-nathan ﬁsh to modern humans, have explained, and

therefore ‘forgiven’, many of these anomalies as the

products of gradualistic evolutionary change (6)

Common explanations account satisfactorily for

both the tissue’s site-speciﬁc properties and its

ana-tomical location

Unfortunately, all adipocytes look similar under

the microscope with conventional ﬁxation and

staining techniques, and their abundance varies

er-ratically between individuals The lack of easily

rec-ognized internal structure or a ﬁxed relationship to

external ‘landmarks’ undermines conﬁdence in the

reliability of identifying homologous samples even

in clearly delimited adipose depots such as the

mes-entery or popliteal The task was seen as hopeless in

overlapping and irregularly shaped depots such as

inguinal, or superﬁcial abdominal Consequently,

for many years, adipose tissue was believed to ‘have

no anatomy’: its arrangement was regarded as not

amenable to the functional or phylogenetic

inter-pretations that had proved so successful for

charac-terizing the details of the anatomy of nearly all

other tissues Although site-speciﬁc properties are

now widely recognized in humans as well as in

laboratory animals (7,8), we still do not have the

information with which to determine whether pose tissue with certain properties is found in aparticular location because it interacts with adjac-ent tissues, because of its blood supply, or simplybecause the site is convenient for storage (9).Lack of interest in the functional anatomy ofadipose tissue also tended to suppress discussionabout the validity of extrapolating concepts based

adi-on the study of the epididymal depot of rats andmice to the much more widely distributed adiposemass of humans For obvious reasons, the sites fortaking biopsies of human adipose tissue are chosenfor their surgical accessibility, and do not includedepots homologous to those most widely studied inrats As well as these practical considerations, therelative abundance of the major adipose depots inprimates is diﬀerent from that of rodents: in hu-mans, lemurs and monkeys, the epididymal depotsare minimal but these species have substantialquantities of adipose tissue on the inner and outersides of the abdominal wall, with the latter oftenexpanding to form the massive ‘paunch’ depot, butthere is almost none in the homologous sites inrodents (10,11)

Consequently, while many ‘diﬀerences’ betweensample sites have been reported, they are not suﬃ-ciently comprehensive, and the homologies betweendepots are not accurate enough for the data to beintegrated into generalizations from which the bio-logical principles behind the organization can beestablished We should be aiming to develop a syn-thetic theory that accounts for the distribution andanatomical relations of adipose tissue in all mam-mals (12) Such a concept would be a basis foridentifying and interpreting sex and species dif-ferences in the normal arrangement and provide astandard against which deviations could be as-sessed

Although enormous amounts of informationabout ‘fat patterning’ in humans have beenamassed, there is very little corresponding data forwild animals The primary aim of the human studieswas to establish correlations between anatomicalfeatures and metabolic variables as a means of pre-dicting pathological states, rather than to explainthe anatomy in terms of the normal physiology Byconcentrating on humans, scientists made their taskeven more diﬃcult than it really is: modern peopleare not only much fatter than most other mammals,but the distribution of their adipose tissue is compli-cated by sexual and age diﬀerence The tissue’s

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more clear-cut and consistent anatomy in wild

ani-mals more readily suggests hypotheses about the

primary determinants of its distribution But testing

these ideas experimentally requires a large

labora-tory animal that has suﬃcient tissue for

experimen-tal study in at least some of the minor depots

The purpose of this chapter is to show that there

is no reason beyond traditional scepticism why the

organization of adipose tissue cannot be as

explain-able in terms of adaptation to function or

phylo-geny as that of other vertebrate tissues

THE ADIPOSE TISSUE AROUND

LYMPH NODES

Reptiles and amphibians have just a few adipose

depots, mostly in the abdomen or around the tail

This arrangement is clearly practical for tissue

whose sole function is storage because the adipose

tissue can undergo large changes in mass without

aﬀecting the adjacent organs In contrast,

mam-malian adipose tissue is always split into a few large

and numerous small depots scattered over much of

the body In many of the minor depots, including

‘yellow’ bone marrow, the omentum and many

in-termuscular and perivascular sites, adipocytes are

intimately associated with lymphoid tissue (13)

Thorough studies of wild animals (9,12,14) show

that the major depots, such as the perirenal and the

posterior superﬁcial depots, undergo large changes

in mass, like adipose depots in lower vertebrates,

while many of those associated with lymphoid

tis-sue, such as the politeal, do not alter much even in

massive obesity or emaciation The popliteal has

also been extensively studied in humans, because

part of it is clearly visible over the gastrocnemius

muscle of the lower leg Its mass changes only

slight-ly, in spite of large changes in body composition, so

people with bulging thighs may have slim calves

(15) This peculiar and almost universal feature of

mammals remains to be explained convincingly

Most mammalian adipose depots contain one or

more lymph nodes, though the exact number varies

between conspeciﬁc individuals, posing further

ob-stacles to quantitative study Some adipose depots,

such as the mesentery and omentum, have dozens of

lymph nodes embedded in them, but others,

includ-ing the popliteal depot, contain only one or a few,

and they may be concentrated into one corner The

microscopic structure of the adipose tissue

sur-rounding lymph nodes has not been investigated indetail since the work of Suzuki (16): standard his-tological techniques revealed no site-speciﬁc dif-ferences other than adipocyte size, and by the timeimmunocytochemical methods became available,interest in the microscopic anatomy of adipose tis-sue had waned Many such depots are small, itself adisincentive to study, both because those of labora-tory rodents oﬀer very little tissue for experimentalstudy, and because their reduction in humanswould have little impact on obesity

Lymph nodes as major sites of proliferation anddissemination of lymphocytes are a special feature

of mammals: a few similar structures are found incertain birds but they are absent from lower verte-brates They almost always occur embedded in adi-pose tissue, although most anatomical illustrationsand models tend to conceal rather than emphasizethe fact Immunologists habitually begin all his-tological and physiological studies by ‘cleaning’ theadipose tissue off the node (17,18) The fact thatlymph nodes and ducts are embedded in adiposetissue is disregarded in biochemical studies oflymph flow (19) The lymph ducts run through theadipose tissue and divide into numerous finebranches as they approach the node, therebygenerating points of entry over much of its surface,and coming into contact with a large proportion ofthe adipocytes that immediately surround it Theadipose tissue associated with some nodes repre-sents such a tiny fraction of the total that it isdifficult to suppose that it could make a significantcontribution to whole-body lipid supply So why is

it present at all?

The need to swell when fighting infection was,until recently presented as the main, if not the sole,reason for the anatomical association between adi-pose tissue and lymph nodes (17) However,adipocytes embedded in their network of collagenare not very compressible It is difficult to see whyadipose tissue should be preferred as a container forexpandable nodes over a mainly extracellular,genuinely extensible material such as connectivetissue (12) The lymphoid tissue of birds and lowervertebrates also expands when activated, but it isnot closely associated with adipose tissue In manyspecies it could not be, because adipose tissue isconfined to a few centrally located fat bodies, in-stead of, as in mammals, being partitioned intonumerous small depots, where it can be associatedwith lymph nodes

167 THE SPECIFICITY OF ADIPOSE DEPOTS

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Since 1994, we have been exploring an alternative

hypothesis: major lymph nodes occur in association

with adipose tissue because the latter is specialized

to serve as a regulatory and ‘nurse’ tissue A simple

experiment enables the lymphoid cells themselves

to point out which kinds of adipose tissue they

interact with most strongly (20) A standard mixture

of lymphoid cells from the large cervical lymph

nodes was incubated with or without a mitogen for

several days with explants of adipose tissue taken

from near to and away from nodes of various depots

of the same animal The number of new

lym-phocytes formed was estimated from incorporation

of labelled thymidine, and lipolysis by the glycerol

concentration in the incubation medium Mature

guinea-pigs of a large strain were used for this

inves-tigation: there is simply not enough adipose tissue

in the node-containing depots of rats or mice to

supply well-controlled experiments

The presence of adipose tissue always curtails

both spontaneous and mitogen-stimulated

prolifer-ation of lymphocytes, but the extent of inhibition

depends greatly upon the source of the sample In

all the eight depots studied that contain one or

more lymph nodes, but especially the mesentery,

omentum, forearm, popliteal and cervical depots,

the samples taken from near to a lymph node

sup-pressed the formation of new lymphocytes more

strongly than those taken from elsewhere in the

same depot The least eﬀective samples were those

from the perirenal, which in guinea-pigs (and most

other mammals) do not contain any lymph nodes

The same experiments revealed that lymphoid

cells consistently induce more lipolysis in adipose

tissue from near to nodes than in samples from

elsewhere in the same depot, especially in the small

intermuscular popliteal and cervical depots, and the

omentum and mesentery (Figure 13.1)

Co-incuba-tion with lymphoid cells causes lipolysis to rise by

more than threefold in perinodal samples, a greater

increase than is observed when isolated adipocytes

are stimulated with large doses of noradrenaline

Such eﬀects are highly localized: adipose tissue from

1—2 mm around major lymph nodes may respond

twice as much as neighbouring samples from just a

centimetre away Lipolysis from the perirenal is

higher than all the other samples when they are

incubated alone, but the presence of lymphoid cells

stimulates a rise of less than 5%, a negligible

in-crease compared to that observed in explants from

the node-containing depots

The gross anatomy of these nodes and their rounding adipose tissue suggests an explanation forthe strong local interactions The mesenteric nodes,being the ﬁrst to come into contact with materialabsorbed through the gut, are in the front line ofdefence against pathogens invading through the in-testine The omentum also contains a great deal oflymphoid tissue and is believed to remove debrisfrom the abdominal cavity The popliteal lymphnode is the most distal of the lower limb nodes, andlymphoid cells arising from it protect the whole ofthe hindlimb below the knee The cubital lymphnode (in the ‘forearm’ adipose depot) is also located

sur-as ‘the end of the line’, and performs similar tions for the distal part of the forelimb

func-Hands and feet (and paws and hooves) are tinually exposed to abrasion and assaults fromparasites and pathogens, so the nodes that servethem are nearer ‘the front line’ in dealing with local,minor injuries, infections and inﬂammations thanthe more centrally located inguinal and axillary(‘behind arm’) nodes The popliteal depots aresmall, representing less than 5% of the total adiposemass in guinea-pigs and most other mammals (12),but they contain relatively large nodes The pop-liteal ‘space’ contains a little adipose tissue aroundthe node in all eutherian mammals, even in verylean wild animals in which nodeless depots are de-pleted completely, and in seals in which most of theadipose tissue is specialized as superﬁcial blubber.Enclosing these important lymph nodes may betheir main role: they do not enlarge with fattening

con-as much con-as the large superﬁcial and nal depots, and seem to be conserved in starvation(9,10,14,15)

intra-abdomi-Perirenal adipocytes respond satisfactorily to allother known local and blood-borne stimulants oflipolysis, and indeed this depot is often taken as arepresentative of the adipose mass as a whole, but asFigure 13.1 shows, it is atypical as far as interactionswith the lymphocytes and macrophages are con-cerned In guinea-pigs and many other mammals,the perirenal is among the largest of all depots andundergoes extensive changes in size as total fatnesschanges Its lack of interaction with lymphoid cellsmay arise from the fact that it normally contains nolymph nodes, so would be unable to participate inlocal interactions with lymphoid cells, or may sim-ply be a necessary corollary of its role as an energystore for the body as a whole

The other, smaller depots expand and shrink less

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Figure 13.1 Site-specific differences in spontaneous and lymphoid cell-stimulated glycerol release (20) Means<SE of glycerol in the medium after incubation with the mitogen, lipopolysaccharide for 48 h and an explant of adipose tissue Explants were taken from far from (light bars) or near to (dark bars) lymph node(s) (or, in the case of perirenal, a knot of blood vessels) of four superficial (left group of bars), three intra-abdominal (centre) and two intermuscular (right) adipose depots with (shaded bars) or without (striped bars) lymphoid cells All values are means of data from 10 mature adult guinea-pigs

readily because part of their adipose tissue is

con-served for special, local functions Adipocytes

pre-pared from the small quantity of adipose tissue

surrounding lymph nodes are insensitive to fasting:

as Figure 13.2 shows, spontaneous lipolysis in such

adipocytes excised from guinea-pigs after 16—17

hours of food deprivation is much lower than in

those from the perirenal or epididymal depots of the

same animals (21) Somehow, these adipocytes have

not responded to the endocrine conditions of

fast-ing, although as these data show, they are perfectly

capable of large increases in lipolysis The perinodal

adipocytes are more sensitive to noradrenaline

ap-plied alone and in combination with tumour

necro-sis factor- (TNF) or interleukin-6 (IL-6), and their

maximum rate of lipolysis is much higher than that

of the nodeless depots, and signiﬁcantly higher thanthat of adipocytes from elsewhere in node-contain-ing depots

Incubation with mixtures of cytokines andnoradrenaline reveals even larger within-depot dif-ferences in the control of lipolysis Adipocytes takenfrom sites within the same depot as little as 5 mmapart release glycerol at widely diﬀerent rates underthe same conditions (20) Figure 13.3 shows suchdata from the poplineal samples Correspondingsamples from the mesentery and omentum produce

a similar picture High doses of noradrenaline bined with 24 h of incubation with TNF or IL-6stimulated lipolysis, while other combinations ofcytokines suppress the process to below the control

com-values These properties indicate that in the in vivo

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Figure 13.2 Means<SE of spontaneous and noradrenaline-stimulated release of glycerol from adipocytes from near to lymph node(s) (dark bars) and far from lymph node(s) (light bars) on the ﬁrst day of the experiment, without any prior treatment (21) Shaded bars:

popliteal; horizontally striped bars: mesenteric; diagonally striped bars: omental; wavy bars: perirenal; n: 12 guinea-pigs, body mass

1096<35 g, age 16.0<0.2 months, fasted for 16—17 hours Asterisks denote significant differences (Student’s t-test) between pairs of samples from the same depot under the same conditions: *** significantly different at P 0.001; ** significantly different at P0.01;

* signiﬁcantly diﬀerent at P0.05

situation, lymphoid cells could regulate lipolysis in

adipocytes located in the vicinity of their node over

a wide range of values and very precisely

Human subcutaneous adipose tissue

(presum-ably not associated with lymph nodes) releases

small quantities of IL-6 (22), and cytokines from

such sources may somehow be involved in the slow

development of chronic disease (23) But in the short

term, cytokines secreted in and around lymph

nodes that ‘leaked’ into the bloodstream would

have little eﬀect on the large, nodeless depots that

contain the great majority of the body’s lipid stores:

lipolysis in adipocytes from the perirenal and

gonadal depots was unaltered by these mixtures ofcytokines (21)

Noradrenaline also stimulates the smooth muscle

of lymph vessels (24,25) The application of regularelectrical pulses to the lumbar sympathetic gan-glion produced a threefold increase in the flow oflymphocytes out of the popliteal ganglion of a sheep(26) This (and many other) lymph nodes are sup-plied by numerous very fine afferent lymph vesselsthat branch from the main afferent vessel and enterthe node over almost its entire surface (27,28) Suchtiny vessels are permeable to large molecules andeven some kinds of small cells (29) Although the

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Figure 13.3 The effect of pre-incubation with 10 ng/mL IL-4 alone and with 0.5 ng/mL interleukin-6, or 10 ng/mL TNF on spontaneous and noradrenaline-stimulated release of glycerol from adipocytes from near (darker bars) and far from (light bars) lymph nodes in the popliteal depot of the same guinea-pigs as for Figure 13.2 (21) All measurements were made on the second day post mortem Asterisks denote significant differences from the corresponding sample incubated without cytokines: *** significantly different

at P 0.001; ** significantly different at P0.01; * significantly different at P0.05 For clarity, symbols indicating within-depot differences, and those indicating that all the values from ‘near node’ adipocytes are significantly different at P0.001 from those from

the corresponding control samples incubated without cytokines, are not shown Daggers denote significant differences between incubation with two cytokines and the corresponding sample incubated with IL-4 alone: ††† significantly different at P0.001; ††

significantly different at P 0.01; † significantly different at P0.05

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Figure 13.4 Immunoﬂuorescent visualization of receptors for

tumour necrosis factor- on adipocytes around the popliteal depot of a rat The ﬁeld of a view is a little over 1 mm wide (a) Bright-ﬁeld view of a thick section (120 m) through the popliteal adipose depot and the lymph node enclosed therein (bottom right) that has been stained with FITC-labelled antibody to type

II receptors for tumour necrosis factor- All the adipocytes appear similar (b) The same section illuminated with ultraviolet light The antibody binds to cells in the lymph node itself and to adipocytes surrounding it, but those more than 0.5 mm remote from the node remain unstained The blood vessel visible as a nearly horizontal black line in (a) also picks up stain (Courtesy

of H MacQueen (31))

authors of these studies do not mention the adipose

tissue, the consequences of these anatomical

ar-rangements and physiological properties in vivo

would be to bring lymphoid cells and the

adipo-cytes immediately surrounding the node into close

proximity, enabling them to exchange metabolites

The observations on multiple samples taken from

large adult guinea-pigs summarized in Figures

13.1—13.3 highlight the limitations of conclusions

based only on the perirenal or epididymal depots or

on 3T3 adipocyte cell lines, from which no

site-speciﬁc information can be obtained In particular,

they challenge the long-held assumption that all

adipocytes in an anatomically deﬁned depot

re-spond equally to blood-borne and neural stimuli,

and each adipocyte makes a small but equal

contri-bution to the concentration of metabolites in the

blood The data in Figures 13.1 and 13.3 suggest

that a small fraction of the total adipose mass

re-sponds strongly to cytokines, and the rest very little

or not at all In brief, most of the ‘hard work’ of

responding rapidly to the ﬂuctuating state of

lym-phoid cells in a lymph node is performed by a few

adipocytes, while the others, which unfortunately

are the ones most widely studied, respond more

slowly to stronger and more persistent stimuli This

concept should be considered when comparing

levels of blood metabolites with the properties of

samples of adipocytes in vitro Inappropriately

chosen samples can sometimes produce misleading

data (30)

In the popliteal depot of the rat, receptors for

TNF are much more adundant on the adipocytes

that enclose the lymph node in a shell

approximate-ly 1 mm (: 10—15 adipocytes) thick (31) Type II

(p75) receptors are continuously present on

perinodal adipocytes, as well as on many of the

lymphoid cells within it and endothelial cells Type I

(p60) appear on adipocytes surrounding the

pop-liteal lymph node within 30 minutes of a stimulated

immune challenge to the region of the lower leg

drained by this node (Figure 13.4), and on the

homologous adipocytes of the unchallenged leg

within 24 h These receptors cannot be seen on

adipocytes elsewhere in the popliteal lymph node,

although if the signal gets as far as the other leg, it

presumably also reaches the rest of the adipose

depot On a longer time scale, this simulated

im-mune stimulus also increases vascularization of the

activated adipose tissue (32) These observations

indicate that adipocytes around lymph nodes are

equipped to amplify their capacity to respond tolymphoid cells within a few hours of their activa-tion

This concept is conﬁrmed by in vivo studies.

When a single popliteal lymph node is activated bythe long-established procedure of injecting a smallquantity of lipopolysaccharide into the tissues that

it drains, lipolysis in the adipocytes immediatelysurrounding it increases within an hour, and re-mains elevated for at least 9 hours before decliningalmost to baseline (33) Adipocytes thus activatedalso become more sensitive to noradrenaline, a

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synergism that suggests that the adipose tissue

around the lymph nodes may be a forum for

inter-actions between sympathetic stimulants such as

stress and exercise, and immune function These

eﬀects can be ampliﬁed simply by incubating

ex-cised adipose tissue explants in tissue culture

me-dium for 24 h, strongly implicating paracrine and/

or auto-crine interactions in perpetuating the

re-sponse to the immune stimulus after it has been

removed from contact with the activated lymph

node

Cytokines generally seem to act locally in a

para-crine or autopara-crine manner, with only small

quanti-ties reaching all organs via the general circulation

(34) Paracrine interactions between adipocytes are

becoming more widely recognized (35) There

would be good reason for keeping

cytokine-me-diated interactions between adipose tissue and

lym-phoid cells local and transient High levels in the

blood cause severe malfunction of the lungs,

kid-neys and other vital organs, leading to septic shock

syndrome Moderate blood levels of this cytokine

for long periods are associated with abrupt,

sus-tained depletion of adipose tissue lipids and muscle

wasting, leading to cachexia, a common

complica-tion of cancer and chronic bacterial disease, and

possibly at lower concentration to insulin resistance

(30)

To ﬁnd out more about what lymph node

lym-phoid cells might be getting by stimulating lipolysis

in the adipose tissue around them, we compared the

fatty acid composition of triacylglycerols in adipose

tissue from diﬀerent parts of depots that contain

lymph nodes (Figure 13.5) (5) In all those examined,

but especially in the intermuscular, omental and

mesenteric depots, there were fewer saturated fatty

acids, and more polyunsaturates in the

triacyl-glycerols found in the adipose tissue 1—2 mm

around the nodes than elsewhere in the depot

The adipose tissue from around lymph nodes

that in vitro interacts most strongly with lymphoid

cells, and has the largest responses to TNF and the

interleukins, also contains a greater proportion of

the very fatty acids that these cells need for their

proliferation and integrated function, and cannot

make for themselves Selective release and retention

of certain fatty acids has been demonstrated in

adipocytes in vitro (36,37), suggesting how such

site-speciﬁc diﬀerences could arise The processes

meas-ured in Figures 13.2—13.4 suggest some reasons why

they exist: selective, local stimulation of lipolysis

from the adipocytes near the nodes would maximizesupplies of polyunsaturated fatty acids to the ac-tivated lymphoid cells Lipolysis from theseadipocytes is not strongly stimulated by fasting(Figure 13.2), so these local controls determine fattyacid release regardless of fever, anorexia or otherwhole body state that the larger ‘general storage’depots (e.g perirenal, inguinal) readily respond to.These observations are also consistent with the re-ports that lymphocyte function is more stronglymodulated by polyunsaturated fatty acids than by

monounsaturates or saturates both in vitro (38) and

in vivo (39).

While many of the fatty acids so released wereprobably oxidized, some would have been incor-porated into membrane phospholipid and/or serve

as precursors for lipid-based messenger moleculesfor the proliferating lymphocytes The increase inproportion of polyunsaturated fatty acids in ratliver lipids following 10 days of chronic infusion ofTNF has been attributed to changes in liver me-tabolism (40) But such ‘new’ fatty acids couldequally come from triacylglycerols in the adiposetissue around lymph nodes, in which lipolysis isespecially sensitive to this cytokine (21), and poly-unsaturated fatty acids are more abundant (Figure13.5) This concept of local provision of fatty acidsshould be considered for investigations into eﬀects

of diet on lipids in lymphoid tissue (41), and therelationship between dietary lipids, adipocyte com-position and breast cancer (42)

Certain adipose depots also have significant pacity for the synthesis and release of glutamine (3),that activated lymphoid cells use in large quantities(43) Provision of glutamine to support protein syn-thesis in lymphoid cells may be another way inwhich adipose tissue supplies the immune systemduring periods of anorexia and cachexia, when ex-ternal sources are greatly reduced, and competitionwith other tissues such as muscle may be strong.Such site-specific differences in the composition

ca-of the storage lipids came as a surprise—previousinvestigators had assumed that continuous lipolysisand re-esterification of triacylglycerols would even-tually homogenize the entire store The only otherexample of site-specific differences in fatty acidcomposition of triacylglycerols hitherto describedwere the extremities and superficial adipose tissue

of some cold-adapted mammals (12,44) which, though similar in principle, diﬀer in some importantdetails The adaptations of adipose tissue triacyl-

al-173 THE SPECIFICITY OF ADIPOSE DEPOTS

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Figure 13.5 Means<SE of the proportions of saturated FAs, monounsaturated FAs, linoleic acid (18: 2n-6) and -linolenic acid (18: 3n-3) extracted from the triacylglycerols in samples of adipose tisue from six sites in the popliteal depot and four sites in the

intermuscular cervical depot between the neck muscles (5) Popliteal samples 1 and 2 were from as near as possible to the node on the distal and proximal sides; 3 and 4 from the middle of the depot near where the sciatic nerve runs through it towards the gastrocnemius muscle, respectively about 4 mm and 6 mm anterior to the node; sample 5 was from as far as possible from the node going towards the anterior, behind the knee joint; sample 6 was from as far as possible from the node going dorsally Cervical sample 1 was from near the large central node; 2 near the group of smaller nodes near the dorsal edge of the adipose depot; 3 and 4 from opposite sides of the depot,

as far away as possible from lymph nodes n: 17 adult guinea-pigs fed on plain chow Asterisks refer to diﬀerences between the

composition of sample 1 and others from the same depot, assessed using Student’s t-test: *** Signiﬁcantly diﬀerent at P0.001;

** significantly different at P 0.01; * significantly different at P0.05

Trang 24

glycerols to cooler conditions mainly involve

sub-stituting saturated fatty acids with

monounsatu-rates In this case (Figure 13.5), the saturates

de-crease as the relative abundance of the

poly-unsaturates increase, with the proportions of

mono-unsaturates remaining constant

WITHIN-DEPOT SITE-SPECIFIC

PROPERTIES AND OBESITY

These data together clearly show that certain

adipocytes have properties that are minimal or

ab-sent in samples from the standard perirenal or

epi-didymal depots Although indistinguishable in

his-tological appearance from typical adipocytes, those

around major lymph nodes are equipped to

partici-pate in local interactions with lymphoid cells, and

seem to be at least partially exempt from

contribu-ting to whole-body supply during fascontribu-ting Bone

marrow is another site where adipocytes are

con-tiguous with lymphoid cells, and the combination is

known to be capable of functioning like lymph

nodes (45) At least in non-ruminants, these marrow

adipocytes retain their storage lipid, and even the

capacity to accumulate more, during prolonged

starvation when those in the ‘typical’ depots are

almost totally depleted (46) The mammalian

im-mune system seems to have organized its own local

supplies of the polyunsaturated fatty acids (and

per-haps of other metabolites), thereby avoiding the

need for their transportation through the general

circulation, and competition with other tissues

Paracrine interactions between perinodal

adipocytes and lymphoid cells would also allow

ready access to large quantities of fatty acids,

with-out the need for their accumulation inside rapidly

dividing, metabolically active lymphocytes; this

concept recalls that of Unger et al (47) who

suggest-ed that adipocytes protect pancreatic islets (and by

implication other types of cell) from toxic

accumu-lation of triacylglycerols in obesity

Converting adipocytes from fatty acid retention

and controlled secretion to lipid oxidation is being

considered as a therapy for obesity (48) If the

inter-action between lymph nodes and surrounding

adi-pose tissue proves to be an integral part of the

normal immune response, and I ﬁrmly believe that

it is, drastic alteration of the metabolism of these

adipocytes may not be physiologically desirable By

making immune responses slower or less eﬃcient,

such manipulation could make the animal or son more susceptible to infection and perhaps can-cer

per-Nothing is known of how permanent this ized population of cells is, or how it is affected byexpansion of the rest of the adipose tissue There areindications that the lipid composition of the dietaffects the interaction between lymphoid cells andadipocytes In guinea-pigs (5), the capacity of lym-phoid cells to stimulate lipolysis in adipose tissuefrom around lymph nodes is significantly reducedafter small quantities of suet (rich in saturated andmonoenoic fatty acids) were added to the normalchow for several weeks, while spontaneous lipolysisfrom similar explants incubated alone is unaltered(Figure 13.6) The ability of adipose tissue explants

special-to curtail mispecial-togen-stimulated proliferation of phocytes is even more severely impaired (Figure13.7), although the basic pattern of site-specific dif-ferences in triacylglycerol fatty acid compositionremains unchanged In assessing the roles of dietarylipids in immune function (49), the possibility thatadipose tissue is intervening to sequester or releasecertain fatty acids selective cannot be disregarded.Guinea-pigs are grazers, whose natural diet isvery low in fat, and contains mostly unsaturatedfatty acids, so this minor modification of the dietprobably induced a major departure from the nor-mal situation These data suggest that circulatinglipids affect local interactions between adipose tis-sue and lymphoid cells, though the mechanism re-mains unknown A high fat diet or hyperlipidaemiamay impair local immune responses, and reduce thesensitivity of adipocytes to cytokines Such proper-ties could be relevant to known associations be-tween high fat diet, obesity and certain forms ofcancer (42,50,51)

lym-What lessons do these concepts have for thestudy of human obesity? In naturally lean wild ani-mals, depots associated with lymph nodes are notreadily depleted and are relatively massive and con-spicuous The omentum, mesentery and poplitealremain surprisingly small, even in very obese speci-mens, possibly because their specialized functionswould be impaired by too little, or too much,

‘whole-body storage’ In contrast to humans, theadditional adipose tissue in naturally obese speciessuch as polar bears, and subspecies of reindeer andarctic foxes accumulates in the perirenal and insuperﬁcial depots not associated with lymph nodes(9,12,44)

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Figure 13.6 Means<SE of glycerol in the medium after incubation for 48 h of explants of adipose tissue taken from near a lymph node (or, in the case of perirenal, a knot of blood bessels) of four superﬁcial (left group of bars), three intra-abdominal (centre) and two

intermuscular (right) adipose depots of guinea-pigs fed on normal chow (plain bars; n:10 guinea-pigs) or suet-enriched chow (striped

bars; n:7 guinea-pigs), either alone (pale bars) or with lipopolysaccharide-stimulated lymphoid cells (darker bars) (5) Asterisks refer to diﬀerences between measurements from incubations under similar conditions of homologous explants from guinea-pigs on the two

different diets *** Significantly different at P 0.001; ** significantly different at P0.01; * significantly different at P0.05.

Horizontal bracket refers to diﬀerences between homologous explants incubated with or without lymphoid cells NS, not signiﬁcant

The synergism between certain cytokines and the

sympathetic nervous system agonist noradrenaline

(Figure 13.3), and the fact that stimulation of the

perinodal adipose tissue in one popliteal depot

in-duces detectable changes in the mesenteric and

omental adipose tissue (33), suggest that a pathway

by which frequent activation of the immune system

could promote lipolysis in the intra-abdominal

de-pots Repeated activation over many years could

contribute to the development of intra-abdominal

obesity, as does chronic overstimulation of the

hy-pothalamo-pituitary-adrenal endocrine axis (52)

The omentum contains a large amount of

lym-phoid tissue intimately interspersed with adipose

tissue and has a high capacity for glutamine

metab-olism (3) Lipolysis in omental adipocytes is

strong-ly influenced by strong-lymphoid cells (Figures 13.1, 13.2and 13.6), and amino acid metabolism may be aswell Its physiological functions are not firmly es-tablished, but in middle-aged people, especiallymen, living in Europe and the USA the omentum isoften hypertrophied Explanation for this effect,which can lead to metabolic disorders as well asbeing cosmetically unsatisfactory, relate mainly tolipid metabolism and endocrinological abnormali-ties (51) Digby (3) suggested that abnormalities ofamino acid metabolism, perhaps triggered by thehigh protein content of the Western diet and/orexcessive activation of omental lymphoid tissues,may also make an important contribution This

Tiêu đề	International Textbook of Obesity - Part 4 PPT
Trường học	University of Medical Sciences
Chuyên ngành	Obesity and Metabolism
Thể loại	Textbook chapter
Năm xuất bản	2023
Thành phố	Unknown

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Số trang	50
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