Women's higher health risks in the obesogenic environment: a gender nutrition approach to metabolic dimorphism with predictive, preventive, and personalised medicine.

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by  Shapira, Niva

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REVIEW Open Access
Women's higher health risks in the obesogenic
environment: a gender nutrition approach to
metabolic dimorphism with predictive,
preventive, and personalised medicine
Niva Shapira
Abstract
Women's evolution for nurturing and fat accumulation, which historically yielded health and longevity advantages
against scarcity, maynow be counteractedby increasing risksinthe obesogenic environment,recently shown by
narrowing genderhealth gap. Women's differential metabolism/disease risks, i.e. infat accumulation/distribution,
exemplified during puberty/adolescence, suggest gender dimorphismwith obesity outcomes. Women's higher
body fat percentage than men, even with equal body mass index, may be a better risk predictor. Differential
metabolic responses to weight-reduction diets, with women's lower abdominal fat loss, betterresponse to high-
protein vs. high-carbohydrate diets, higher risks with sedentariness vs.exercisebenefits, and tendency toward
delayed manifestationof central obesity, metabolic syndrome, diabetes, cardiovascular disease, and certain cancers
until menopause—but accelerated thereafter—suggesta need for differing metabolic and chronological
perspectives for prevention/intervention. These perspectives,including women's differentialresponses to lifestyle
changes, strongly support further research with a gender nutrition emphasis within predictive, preventive, and
personalized medicine.
Keywords: Women, Gender, Nutrition,Obesity, Metabolic syndrome, Life expectancy, Sexual dimorphism, n-6/n-3
PUFA, Predictive, preventive and personalised medicine (PPPM)
Review processed foods—together defined as an obesogenic envi-
Introduction ronment—haveconferredagreatburdenofoverconsump-
Women's evolution vs. food scarcity, which necessitated tion and obesity (Figure 1), unrelated to nutritional
effective fat accumulation for preparing available energy sufficiency/deficiency[3].Thismaybeespeciallycriticalin
and nutrients for fertility and feeding/caring of offspring, females, giventheir innatetendencytowardfataccumula-
has long translated to a health and longevity advantage. tion and risks from nutrient-exhausting pregnancy/lacta-
However, this may now be counteracted by the ‘obeso- tion, and resultant deficiency disorders [4-6]. This new
genic’environment. metabolic ‘mismatch’ in women could greatly contribute
Pubertal gender dichotomy of girls accumulating fat vs. to the recent decline in the gender gap in life expectancy
boyslosingfatandgrowingmusclesandheight[1,2]illus- (LE) and in healthy LE (HLE), associated with a slowed
tratesanobesity-relatedaspectofgenderdifferentialadap- increase in female LE and HLE compared to males [7-10]
tation to scarcity and women's advantage. However, (Figure 2), that is gradually narrowing the gender gap
extreme changes in the environment, particularly increas- [11,12] resulting from increases in the environmental
ing food availability/accessibility and reduced mobility, as burden on women's health and consequently on the
well as increased calories and reduced nutrient density in healthcaresystem.
Beyondthegeneralperspectivethatthedeclininggender
Correspondence:[email protected] LE gap was associated primarily with changes in smoking
InstituteforNutritionalResearch,RabinMedicalCenter(BeilinsonHospital), andalcoholuse[14],anewperspectiveonwomen'shealth
Office:5KehilatZitomir,TelAviv69405,Israel
©2013Shapira;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
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Figure1Prevalenceofmorbidobesityamongadultsaged16+years:HealthSurveyforEngland1993–2010[13].Theriseofmorbid
obesity(≥40kg/m2)hasbeenledbywomenindeveloped,high-incomecountries,i.e.intheUKwherebetween1993and2010,theprevalence
ofmorbidobesitywasconsistentlyhigheramongwomen(increasingfrom1.5%in1993to3.8%in2010)thanamongmen(increasingfrom0.3%
in1993to1.6%in2010).
should include their specific metabolic risks and differing before the risk manifestation—according to the specific
timetables, i.e. earlier and higher risk of lifelong obesity, timing of physiological events, critical periods, early pro-
differential fat distribution and risk measures, i.e. body gramming,andtheirmetabolicpatterns[15].
massindex(BMI),waistcircumference(WC),anddelayed The present paper shows women's leading role in the
risk manifestation to postmenopausal age, which is asso- obesity epidemic, which could potentially become their
ciated with reduced estrogen protection. Here, predictive, leading lifelong risk factor for disability and mortality.
preventive, personalised nutrition should take a lead— As fewer metabolic studies regarding disease risk have
Figure2Gender-environmentinteractioneffectonobesity,healthrisks,lifeexpectancy(LE),andhealthylifeexpectancy(HLE).
Obesogenic(increasedcaloriesandreducedmobility)conditionsinWesternlifestyles,comparedtohistoricallyrestrictivedietaryconditionsand
highmobility,haveconferredagreatburdenofoverconsumptionandobesity.Women'sinnatetendencytowardfataccumulationandhigher
lifelongbodyfatpercentagecouldmakethemmorevulnerableandhavecontributedtotherecentdeclineinthegendergap
(females-males,years)oflifeexpectancy(LE)andhealthyLE(HLE)years.
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previously been conducted in females, there is a great falling below that of most other industrialised countries,
need for better understanding of women's specific nu- with a ranking of 32nd in the world in 2008 [24], concur-
tritional risks resulting from environmental changes. rent with the highest per capita expenditure on healthcare
Approaching metabolic dimorphism as a major factor in in the world [25]. Obesity was associated with reduced US
gender nutrition is now becoming crucial for designing LE at age 50 years by 1.54 and 1.85 years for women and
andenhancinghealthcarequalityand effectivenessofper- men, respectively, a shortfall (by 42% and 67%) relative to
sonalised medicine [16], as comprehensively described in countries with higher LEs, and a higher (by 25% and 40%)
the recent White Paper of the European Association for effectonLEthaninCanadaandtheUK,thetwocountries
Predictive,PreventiveandPersonalisedMedicine[17]. with the next-highest rates of obesity [26]. Excess US BMI
was responsible for approximately 95 million years of life
Women'sdecliningadvantageinhealthandlife lost (YLL), with women accounting for more than two-
expectancy thirds [27], and their obesity-associated reduction in lon-
Though women still outlive men throughout the world, gevitywashigherthanthatinothercountries[28],possibly
their LE advantage seen in the early twentieth century is because of younger age and higher severity of obesity. Of
now declining, especially in Western countries [11,12]. note, an increase in two BMI units in overweight popula-
For example, in France, previously a gender gap leader tions was estimated to decrease lifespan, i.e. in men by 1
(7.66 years), the LE gap stopped increasing in the 1980s year, comparable to a 10% increase in the prevalence of
and began decreasing in recent years, which was partially smoking[27,29].
attributed to a reduction in cardiovascular disease (CVD) Beyondtheeffectofobesity(BMIof30–34.9kg/m2)on
and lung cancer mortality in men, as found in a few reducingLE,itwasalsoshowntoreducedisability-freeLE
European countries [18]. In Norway during the last 25 [30],i.e.amongmenby2.7years,concurrentwithincreas-
years, the LE increased by ≈6 years in men and only ≈3 ing LE with disability by 2.0 years, compared to changes
years in women, resulting in a 2.5-year reduction in amongwomenby3.6yearsand3.2years,respectively,and
genderLEgap[7].IntheUK,between1990and2002,the overweight (BMI25–29.9)increasedLEwithdisabilityfor
average annual rate of improvement in mortality was women only, by 2.1 years. Women's longest HLE was
≈30% higher in men than in women [8]. Similar trends shown at BMI of 18.5–22.9, men's at 25–29.9 (Figure 3)
had previously been observed in the USA, Sweden, anddecreasedthereafter,togetherwithincreasingLEwith
Englandand Wales, Hungary,Sweden,Australia [19],and disabilities[31].
Canada[20],thoughnotseeninJapan[21].
WhereashealthyLEhasdeclined in women more than Women'sleadintheobesityepidemic
in men, i.e. between 1989 and 2000 by 4.3 years vs. 0.8 Worldwide obesity has more than doubled since the
years,respectively[18],theirunhealthy LEhasincreased, 1980s, and rates continue to push upward throughout
i.e.womenwithheartdiseasehavegreaterLE at50years the world. By 2008, an estimated 1.46 billion adults and
than men, 7.9 vs. 6.7 years, though women's heart 170 million children worldwide were overweight (BMI
diseaseonset tendstobedelayed by≈3.0yearsandheart ≥25 kg/m2) or obese (BMI ≥30), with higher rates in
attacks by 4.4 years compared to men [22]. Similarly, women, though varying widely by country. For example,
HLE in Italian women was reduced by 2 years compared an estimated 18% of women in France are obese, in
to their previous advantage, with resultant equal LE at Greece 26%, in Mexico 35%, andin Saudi Arabia44%; in
age65of≈7years,for bothgenders[9]. contrast, the percentage in both Japan and China was
Agenderhealth-survivalparadoxofwomen'shighermor- 3% [32]. In the USA, with an overall prevalence of 68.3%
bidity rates despite longer LE—as found in Western coun- overweight [28] and 33.9% obesity, women show higher
tries—isalsofoundinSingapore,whereatage65,women's rates than men of severe obesity (BMI ≥35, 17.8% vs.
remaininglifeyieldsmoredisabilities,suchashypertension, 10.7%) and morbid obesity (BMI ≥40, 7.2% vs. 4.2%)
bone/joint problems, walking difficulties, and visual and differencesof78%and71.4%,respectively [33].
functional impairments compared to same-aged men [10]. However, longitudinal trends previously showing
The above and further population studies show that women's increased obesity prevalence—that initially pre-
women's HLE is compromised beyond their declining lon- ceded men's—later slowed, leading to a decline in the
gevity,whichmaynecessitatespecificpreventivestrategies. gender gap, with women's prevalence over the last 12-
year period increasing by only 6.3% vs. men's by 17.1%
Obesity-relateddecreasedlifeexpectancyandincreased (1999–2008)[28].
disability
Manystudieshavedemonstratedthatobeseindividualssuf- Women'sbodyfatpercentagevs.BMIasrisk-predictive
fer an elevated risk of death [23] and that a high level of Though the definition of obesity is uniform for women
obesityiscontributingtoreducedLE,i.e.intheUSA,LEis andmen,womentypicallyhavehigherbodyfatpercentage
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lower fat oxidation, especially postprandially, with more
efficient fat storage [36]; lower resting energy expend-
iture rates [37-39]; higher response to insulin (as shown
in glucose metabolism in both the liver and muscle) and
to an exercise with weight loss diet combination [40];
higher adipose tissue-expanding capacity with long-term
high-fat feeding [41]; and higher leptin levels, associated
with higher inflammatory (C-reactive protein [CRP] and
MetSrisk,thatwere independent ofadiposity[42].
In metabolically obese normal-weight women, there is
a tendency toward greater central fat mass, associated
with reduced insulin sensitivity [43,44], shown even with
normal glucose tolerance [45]. Further, they may have
smaller particlesoflow-densitylipoprotein(LDL);higher
concentrations of oxidised LDL, TNF-alpha, interleukin
(IL)-6, and leptin; and lower plasma adiponectin than
women with normal visceral adiposity [46], all of which
contribute to increased obesity-related disease risk. Such
hidden obesity was found in underactive Western women
andinAsianwomen,whowereobservedtohaveahigher
body fat percentage for each BMI level, potentially asso-
ciated with prominent abdominal obesity, higher intra-
muscular and liver fat content, and predisposition to
insulinresistanceanddiabetesmellitus[47].
According to bodyfat percentage, the prevalence of ‘at
risk’ (preobese or obese) among normal BMI men and
women was 69% and 85%, respectively, suggesting that
screening for adiposity in individuals with a normal
Figure3Lifeexpectancyatage55with/withoutdisabilityin
BMI could further identify those at higher risk for
activitiesofdailyliving(univariateanalysis).Errorbarsrepresent
cardiometabolicdisturbancesandcardiovascularmortality,
95%confidenceintervalsofdisability-freeandtotallifeexpectancy
[31].TheaverageLEat55yearsofageis24.0yearsformenand especially among women, as the false-negative classifica-
28.2yearsforwomen(excludingunderweightindividuals).The tion of BMI was stronger for women than for men [48].
longestdisability-freeLEwasfoundwithaBMIbetween18.5and Together, the above places women at risk for greater
22.9forwomenand25.0and29.9formen.Mildobesity
obesity and sequelae, especially with increasing exposure
(BMI30–34.9)didnotshortentotalLE,butatage55,itshortened
totheglobalobesogenicenvironment.
disability-freelifeto2.9yearsformalesand4.3yearsforfemales
comparedtohighnormalweight(BMI23–24.9).Severelyobesemen
liveanaverageof6.0yearslessfreefromADLdisabilityandwomen Women'searlierandgreaterpredispositiontoobesity
for8.4lessyears.Formen,lownormalweight(BMI18.5-22.9)lowers Women'sobesitytendenciesbeginmuchearlierthanmen's,
bothtotalanddisability-freeLE. already in the womb [49]. Girls aged ≤10 years have 28%
greatertotalfatand30%moresubcutaneousfatthanboys,
and lower fat-free mass (FFM) for the same BMI cut-off with similar amounts of visceral fat [1]. Dimorphism in
point[34].InNHANESIII,women'saveragebodyfatper- totalfatmassandinfattissuedistribution(visceralvs.sub-
centage, at 20–80 years, was higher than men's by 44% cutaneous)progressesfromprepuberty[50],wherebodyfat
(34.9% vs. 24.3%, respectively), despite similar correspon- percentage declines in boys as they gain muscle, but
ding BMIs(26.27vs. 26.83).Thus, women's BMI may not increases in girls [2]; correspondingly, early-maturing boys
accurately reflect but rather may partially mask their ac- arethinner,whereasearly-maturinggirlsarefatter[51],and
tual obesity [34]. This may lead women to a condition of menarcheseemstooccurmostfrequentlywith≥17%body
‘metabolically obese/normal weight’—already at a young fat [52]. Further, adult women's ageof increasing obesityis
age—wherein despite having a normal BMI, they display muchearlierthanmen's,rateshigherat20–39yearsofage
body composition and metabolic characteristics that may by23.7%forBMI≥30and100%forBMI≥35andat40–59
predispose them to development of metabolic syndrome yearsby11.4%and68.1%,respectively[28].
(MetS)[35]. These epidemiological trends and gender differences
Women's tendency toward obesity compared to men's underscore the importance of defining sex-specific char-
is manifested by several metabolic patterns, including acteristics and women's earlier and stricter prevention
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and management of obesity and related risks, such as
MetS, diabetes mellitus, coronary heart disease (CHD),
andcancer [53].
Women'sdelayedriskmanifestation:hormonalschedulevs.
obesitypressure
Estrogenandestrogenreceptors(ER)arewell-knownreg-
ulatorsofseveralaspectsofmetabolism,includingglucose
and lipid metabolism, and impaired estrogen signalling is
associated with the development of metabolic diseases.
Here, ERα seems to play a protective role in insulin and
glucose metabolism, through effects on the liver, adipose
tissue, muscle,and pancreaticβcellsand oncentral regu- Figure4Overviewofinsulinresistanceinducedbyestrogen
lationoffoodintakeandenergyexpenditures.ERβ,onthe deficiency,andsubsequentdisturbancesinmetabolictissues
[54].Asestrogenparticipatesintheregulationofglucose
other hand, has the potential tonegatively influence insu-
homeostasis,estrogendeficiency,likethatseeninpostmenopausal
lin and glucose metabolism by impairment of adipose women,isstronglylinkedtothedevelopmentofinsulinresistance
tissue function, probably through augmented PPARγ sig- andsubsequentimpairmentsmanifestedinthepancreas,liver,and
nalling, and declined expression of GLUT4 in the muscle muscleandadiposetissue,keyorgansinfluencingriskofchronic
metabolicdisease.
[54]. Several epidemiological and prospective studies have
linkedestrogenandtheERtovariousaspectsofmetabolic
disease and to estrogen protection in premenopausal difficultymaintainingbodyweight[59],andtendencyto-
women. ward weight regain following weight loss diets, which is
The onset of menopause dramatically increases the risk highly predictive of later risk [60]. Updated guidelines
for womento develop disease statescoupled tothe MetS, from the American Heart Association note that newer
such as obesity, CVD, and type 2 diabetes. Here, estrogen risk formulas are available to predict 10- and 30-year
deficiencyisstronglylinkedtothedevelopmentofinsulin risks for all CVD events, including CHD, stroke, and
resistanceandsubsequentmanifestationsinvariousmeta- heart failure; for example, the 10-year predicted risk for
bolictissues(Figure4)thatcouldberepairedbyhormone CHD of >20% now includes women aged >60 years with
replacement therapy [54]. For example, estrogen's inverse elevated CRP as candidates for medication intervention,
relationwithenergyintake,asshownwithhormonalshifts even if they do not have heart disease or elevated lipid
during the menstruation/ovulation cycle [52], may par- levels. Other inflammatory/oxidative medical conditions,
tially contribute to young women's ability to control their such as rheumatoid arthritis, systemic lupus, and a his-
weight vs.increasingtendencytowardobesitywithmeno- tory of pre-eclampsia, gestational diabetes, or pregnancy-
pause. Similarly, premenopausal women's capacity for re- induced hypertension, have also been added to the at-risk
moval of very-low-density lipoprotein (VLDL) cholesterol category. Such additional new high-risk criteria for CVD
from the plasma is greater compared to men's and to in women suggest a differential definition of women-
menopausal women's, with resultant rise in the latter's specific recommendations for lifestyle and healthcare
plasmalipoproteinsandassociateddiseaserisk[55]. according to the long-term effectiveness-based paradigm,
However, with increasing obesity levels in young beyond the evidence-based approach to immediate risk
women, MetS and related risks may be manifested earl- measures[61].
ier in this age group, suggesting that weight gain at an
early age predisposes young women to risks as seen with Women-specifichealthylifestyleaspects
menopausal obesity, due to their earlier and higher rates Apart from smoking and/or exposure to environmental
of obesity-related accumulation of metabolic risks than (‘second-hand’) tobacco smoke and alcohol, obesity—
inmen[56]. the suggested leading cause of decreasing gender gap in
LE [14] — is associated with most of women's risk fac-
Women-specificchronologicalperspectivesonhealthrisk tors for MetS and related chronic diseases, i.e. excess
Whereas women were previously considered at high body weight/obesity (BMI ≥25), waist circumference
CVD risk if their 10-year predicted risk of CHD was (WC ≥35 in. or >88 cm), with elevated blood pressure
more than 20%, their cumulative lifetime risk may be (≥120/80 mmHg), dyslipidaemia (LDL cholesterol ≥100
underestimated because of delayed manifestation to mg/dL, high-density lipoprotein (HDL) cholesterol <50
postmenopausal age. This may be related to the peak mg/dL, triglycerides (TG) ≥150 mg/dL, and non-HDL
tendency toward weight gain occurring around 50 years cholesterol ≥130 mg/dL) [61], and dysglycaemia [62].
of age [57], associated with higher rates of gain [58], Long-accepted exacerbating factors remain as they were:
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inadequate physical activity (i.e. <75–150 min/week of preservation, preferential reduction of abdominal vs. sub-
moderate-vigorous exercise with an aerobic element) cutaneous adipose tissue, and improvement in fitness ca-
and dietary factors, including low intake of fruits and pacity compared to diet alone [78]. However, such a
vegetables, whole-grain/high-fibre foods, and n-3 poly- combination, which was further associated with a twofold
unsaturated fatty acid (PUFA; i.e. from n-3 PUFA-rich greaterimprovementininsulinactioncomparedwithdiet
fisha or from supplements), with high intake of saturated alone in men [79], did not show similar effectiveness in
fatty acid (SFA), cholesterol, alcohol, sodium, sugar, and women[80],inwhomexercisealone,evenwithoutcaloric
trans-FA (tFA) [61]. Low socioeconomic/cultural status restrictionand/orweightloss,wasassociatedwithreduced
is another risk factor highly associated with increased totalandabdominalobesityandinsulinresistance[81].
obesity, especially in women—found to be key in a re- Women's fat loss, primarily subcutaneous vs. intra-
cent re-evaluation of the United States Mortality File abdominal in men, yields much smaller improvements
[63]—andin low-andmedium-developed countries[64], in their specific risk factors, such as TG and HDL cho-
requiring specific considerations and economic and cul- lesterol levels,compared tomenlosingthesame amount
tural approaches that are beyond the scope of this of weight/fat, but mostly abdominal [82]. Though WC is
manuscript. known to be positively associated with diabetes in both
Healthy lifestyle in women that was associated with a sexes, increasing WC was more closely associated with
significantly reduced risk of total and ischaemic stroke diabetes in women than in men [83], which may suggest
[65] consisted of no smoking, low BMI (≤22), moderate higher sensitivity of WC as a metabolic measure in
alcohol consumption (4–10.5 drinks per weekb), regular women. The above suggests women's need for specific
exercise (more than four times per week), and a healthy metabolic emphases in obesity management, beyond
diet, incorporating high fibre, folate, and n-3 PUFA, with BMI and weight loss diet per se, vs. their specific risks
generally high PUFA/SFA ratio, and low tFA and gly- and chronological aspects compared to men's achieving
caemic load (GL). Adherence to these lifestyle guidelines better risk reduction already through weight loss and
could dramatically reduce the risk of CHD by approxi- dietary restriction [84].
mately82% [66].Additionally,adherencetotheAmerican
Cancer Society's prevention guidelines—including for Dietarymacronutrientsandmetabolicaspects
BMI, physical activity, diet, and alcohol consumption—
lowered the risk of cancer and all-cause mortality in non- Fats A low-fat/cholesterol diet is routinely recom-
smokers [67]. Further detailed recommendations for pri- mended for individuals with elevated plasma LDL cho-
mary prevention included adjusted intake of meats and lesterol concentrations [85], though the combination of
fattyfoods—especiallysourcesofn-6andn-3PUFA—add- a weight loss diet with exercise was less effective in im-
ing olive oil, selected vegetables, and citrus fruits, and proving lipoprotein levels and LDL size in women than
adequate body fat/lean mass proportions [68]. A dietary in men [86]. A diet low in fat (25% kcal), SFA (7%), and
pattern high in fruit and low-fat dairy and low in white cholesterol (100 mg/day)—consistent with the NCEP
bread, processed meat, margarine, and soft drinks was Step II diet—only partially attenuated the increase in
suggested to help prevent abdominal fat accumulation LDL cholesterol during menopause onset [87]. A diet
[69].TheabovesuggeststhatmajorWesterndiseasesshare low in fat and high in vegetables, fruit, and whole grains
a common metabolic-nutritional basis and thus require in the Women's Health Initiative study showed women
similar preventive measures. However, the alcohol link to to have a smaller decrease in plasma lipoprotein levels,
cancerrisk[70-72]vs.benefitstohearthealthanddiabetes similar decreases in particle sizes of LDL and HDL, but
[73] is a reminder that the specificity of foods and risk greater reductions in postprandial TG levels compared
factors should not be overlooked, especially with regard to to men [85]. As increasing carbohydrate intake may in-
the gender aspect [70,71,74,75]. The Mediterranean diet crease women's risk more than men's [88], a low-fat diet
that has repeatedly demonstrated an advantage against with carbohydrate substitution may not necessarily pro-
Westerndiseasesandwasfurthersuggestedasanutritional vide women with the metabolic protection against
framework for the predictive, preventive, and personalised obesity-related risk that has been shown in men. These
medicine (PPPM) approach [76] can be effectively adapted findings may suggest a need for gender-based dietary
and applied to various metabolic states, including those interventions to improve specific risk factors, with
associatedwithgender-specificrisks. awareness of women's differential response to strategies
thathavesuccessfully been targeted towardmen [89].
Women-specificaspectsofweightmanagement
The general combination of reduced calorie diets and Fatty acids Both essential fatty acids (EFA), linoleic acid
exercise (both aerobic and resistance) [77] was repeatedly (LA; 18:2 n-6) and alpha-linolenic acid (ALA; 18:3 n-3),
confirmed in both sexes to be effective in muscle are known for their lipidemic advantages, i.e. for
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reducing LDL cholesterol and TG. Substitution for SFA the high impact of insulin on their lipid metabolism
with n-6 PUFA has demonstrated an advantage in redu- [38]. Concurrent decreased LDL particle size further
cing LDL/HDL and TC/HDL ratios and TG levels, thus explainsthe link between high dietary carbohydrates and
improving metabolic factors and related effects in both women'sCVD risk[104].
men and women. However, the unsaturated character of While in men replacing SFA with carbohydrate from
PUFA may be associated with greater lipid and LDL oxi- grains, vegetables, legumes, and fruit effectively reduced
dation, especially with inflammation, i.e. facilitated by total and LDL cholesterol blood levels [87], only a mode-
high n-6 proinflammatory eicosanoids, believed to play a rate reduction was observed in women, withlessereffects
key role in chronic diseases and accelerated ageing in onCVD[89].ReplacementofSFAbycarbohydrates,espe-
conditions of a high-n-6 Western diet [90,91]. Essential cially refined sources and ‘added sugars’, increases plasma
PUFA are further converted in the liver to LCPUFA, LA TG and small LDL particles and reduces HDL, which are
into arachidonic acid (20:4 n-6), and ALA into eicosa- of particular concern in the context of the increased
pentaenoic acid (20:5 n-3) and docosahexaenoic acid prevalence of obesity and insulin resistance, all especially
(22:6 n-3). Their conversion varies according to gender criticalforwomen[88].
and age, being highest in young women—especially dur- IntheEPICORstudy,womeninthehighestquartilesof
ing pregnancy [92,93]—compared to males [94,95] and carbohydrateintake,GI,andGLhadasignificantlygreater
declining with age along with levels of the rate-limiting risk of CHD (by about twofold) than those in the lowest
enzymes delta-5- and delta-6-desaturases, more in quartile, whilea lesser associationwas foundin men [88].
women than in men [96]. Desaturase activity is reduced AtwofoldincreasedCHDriskwithhighGL,mostevident
with high SFA intakes [97] and cholesterol [98] and among women with BMI ≥23, was found in follow-up re-
increased with a high-n-3 PUFA and/or MUFA diet [97]. search over a 10-year period (729,472 person-years), but
LA (n-6) and ALA (n-3) share and compete for rate- not among normal-weight women [105]. Dietary GI and
limitingconversionenzymes,emphasizingtheimportance GL were progressively associated with CHD in various
of the n-6/n-3 PUFA ratio for health and sex-related dif- populations [106] and with plasma CRP levels, in general
ferential predisposition. Women's higher production of and in healthy middle-aged women [107], suggesting an
eicosanoids from either dietary n-6 or n-3 PUFA, which explanatorylinkbetweenwomen'sischaemicheartdisease
are pro- and/or anti-inflammation/coagulation/carcino- with overweight and their susceptibility to insulin resis-
genesis, respectively, yields stronger implications for dif- tance[108].
ferential CVD and cancer pathophysiology and clinical
outcomes, corresponding to their dietary PUFA ratios, as Proteins Although energy restriction alone often leads
comparedtomen's. to weight loss, the composition of the lost tissue also
An ‘n-6 Gender Paradox’ hypothesis’ was proposed, matters, and high loss of lean mass could have delete-
based on the Israeli case study of women's higher risk rious metabolic consequences. This is especially critical
with n-6 PUFA vs. men's benefit. Here, women's worse for women with innately low initial FFM, a tendency to-
health ranking vs. men's relative advantage in conditions ward a plateau in weight loss, and for later weight regain
of high dietary n-6 PUFA (10–12% kcal) [99] led to the [56,109]. Moreover, because skeletal muscles play roles
unexpected observation of low national health status, in energy metabolism, their potential loss in the weight
previously defined as the ‘Israeli Paradox’ [100,101]. The reduction process emphasises the need to focus on the
above suggests that with the same diet, at certain high composition of the lost weight for preservation of lean
levels of n-6 PUFA, women's greater transformation to tissue, rather than relating merely to scale weight. Here,
eicosanoids with proinflammatory, carcinogenic, aggre- higher protein, lower carbohydrate, and GI energy-
gatory characteristics may put them at greater risk com- restricted diets have been shown to help offset women's
pared to men, who may benefit due to lower EFA lean mass loss, especially when associated with resist-
transformative capacity. In a recent Danish epidemio- anceexercise[110].
logical study, an n-6 PUFA increase was associated with A high-protein diet was more effective for women,
weight gain and increased WC in women, while the who lost nearly twofold more total and abdominal fat
opposite was shown in men [102], which could further compared with women on the low-protein diet, whereas
support a differential response and high-n-6 risk for in men, there was a lesser difference in fat loss between
women vs.men'sadvantage. diets; in both sexes, a high-protein diet caused greater
total and LDL cholesterol reductions [111,112], with no
Carbohydrates and glycaemic effects High carbohy- effect on blood TG [112]. A high-protein (≥40% kcal)
drate intake may be associated with a disadvantage for diet was also more effective in women with polycystic
the lipid profile, including highTG and VLDL, especially ovary syndrome, yielding a greater reduction in body
in overweight postmenopausal women [103], reflecting weight, body fat, WC, and blood glucose than the
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standard protein (15% kcal) diet after 6 months [113]. A abdominal, and subcutaneous fat; reduced insulin resist-
high-protein diet (1:1 vs. 3:1 carbohydrate/protein ratios) ance (≈32%) inthe exerciseplus diet group, but not with
wassuperiortoalow-fatandhigh-carbohydratediet,with diet alone; and WC closely reflecting the benefits of re-
or without an aerobic/resistance training programme, for ducing abdominal obesity, whereas BMI alone may mask
effective weight loss, nitrogen balance, improved body the positive effects of exercise [81]. The correlation be-
composition, and reduced risk factors for the MetS in tween recreational physical activity and reduction in risk
overweightandobesewomen[114].Ahigh-protein,high- of breast cancer recurrence and mortality, which are
dairy,energy-restricteddietplusexercisecombinationwas known to be associated with increased abdominal obe-
further linked to improved energy-protein balance com- sity, further support the special importance of physical
pared to a lower dairy, higher protein diet, as shown by activitytowomen [120].
greater losses of total and visceral fat, smaller losses of
leanmass,andincreasesinbodystrengthdespiteidentical Conclusions
weight loss [110]. Moreover, during adolescence, higher Findings showing women's differential metabolic respon-
dairy product intake was associated with a lower risk of ses have suggested a gender effect on biochemical-
later adult type 2 diabetes, partially explained by the per- endocrinological patterns, metabolic mechanisms, and
sistence of the consumption pattern through adulthood risk factors, emphasising the importance of more
and results of a cumulative high-protein, high-dairy effect gender-specific prevention strategies. This is especially
[115]. A high-protein, low-carbohydrate diet was also relevant vs. environmental changes and the obesogenic
found to reduce blood glucose, insulin, and lactate levels epidemic, with women's lead in earlier and higher
and to prevent cancer initiation and to slow tumour obesity rates and related disease risk, though with
growth[113]. manifestationmostlydelayedtomenopausalage.
Women's differential metabolic responses compared to
Physicalactivity men throughout the life cycle strongly suggest a need for
Sedentarylife,acharacteristicofthemodernenvironment, gender-specific strategies against obesity and chronic
is a known health risk factor. Moreover, increased sitting diseasessuchas CVD, diabetes, MetS, and cancer, includ-
time was recently found to be an active and independent ing differential metabolic biomarkers and chronological
riskfactor,positivelyassociatedwithfastinginsulin,leptin, patternsacrossthespectrumofdiseases.Thisisespecially
leptin/adiponectin ratio, CRP, and IL-6 in women, more relevant in light of women's unique vulnerability to mod-
thaninmen.Theseassociationsremainedsignificantafter ern environmental pressures, including increased seden-
additional adjustment for total moderate- to vigorous- tary lifestyle, obesity, glycaemic load, dietary n-6/n-3
intensityphysicalactivity[116].Incontrast,physicalactiv- PUFA ratio, and transitional socioeconomic and psycho-
ity was inversely correlated with BMI, insulin levels, CRP, social stresses. Applying men's knowledge to women's
leptin,WC,andbodyfatpercentageinyoungandmiddle- practice may not only yield lower benefits, but may also
aged women, suggesting ‘anti-age’-related increases in the further enable exacerbation of metabolic imbalance, i.e.
above measureswithphysicalactivitythatmaypotentially substitutingdietaryfatwithcarbohydratesand/orrepeated
counteract sedentariness and age effects in women [117]. weight loss diets without considering the preservation
Additionally, non-exercise activity, all activity that is not of women's lean body mass, which may gradually reduce
sleeping, eating, or sports-like exercise, could be a critical their metabolic balance and resistance to Western
component for increasing energy expenditure and meta- diseases,despitegreaterbenefitsformen.Further,thedif-
bolic rate, maintaining FFM, and preventing weight gain, ferentialresponsetohigherprotein/carbohydrateratios,to
obesity,andsedentariness-relatedrisk[81]. lowglycaemicload,aswellastoexercisevs.sedentarylife-
Aswomenoxidise proportionately more lipids andless style should be considered for differential prevention and
carbohydrates and protein compared to men, and as intervention strategies. A differential time perspective is
they do not build muscle glycogen with a carbohydrate also required, considering females' much earlier fat accu-
load but rather more body fat, their exercise-related fat mulationprocess,whichpresetsthemetabolicpatternsfor
loss is critical for improved body composition [116,118]. later increases in obesity risks compared to males. Even a
Exercise-associated increases in lipolysis in abdominal measure considered basic, i.e. BMI, may underestimate
visceral fat and reduction of their related risks, despite a the female obesity state and rather masks fat percentage,
lower response from luteal-femoral adipose tissue, which could better reflect the metabolic obesity state,
explains the higher exercise-related benefit and reduc- which is more closely associated with obesity risk, espe-
tion inwomen'smorbidity and mortality, independent of cially with android type, manifested by abdominal sub-
BMIorweight loss,comparedtomen[119]. cutaneousandvisceralfatandhighWC.
A combined exercise and weight loss diet was asso- AsCVDpreventionsharesrecommendationswiththose
ciated with the greatest reduction in women's total, of cancer as well as other chronic Western diseases,
ShapiraTheEPMAJournal2013,4:1 Page9of12
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eating types of fish with the potential for the highest 14. McCartneyG,MahmoodL,LeylandAH,BattyGD,HuntK:Contributionof
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15. ShapiraN:Agender-specificnutritionalapproachtowomen'shealthcare.
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ALA:Alpha-linolenicacid;BMI:Bodymassindex;CHD:Coronaryheart
predictive,preventiveandpersonalisedmedicine2012:WhitePaperof
disease;CRP:C-reactiveprotein;CVD:Cardiovasculardisease;EFA:Essential
theEuropeanAssociationforPredictive,PreventiveandPersonalised
fattyacid;ER:Estrogenreceptor;FA:Fattyacid;FFM:Fat-freemass;
Medicine.EPMAJ2012,3:14.
GI:Glycaemicindex;GL:Glycaemicload;HDL:High-densitylipoprotein
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femaleadvantage].RevEpidemiolSantePublique2004,52:333–352.
chainpolyunsaturatedfattyacid;LDL:Low-densitylipoproteincholesterol;
19. TrovatoF,LaluNM:Contributionofcause-specificmortalitytochanging
LE:Lifeexpectancy;MetS:mMetabolicsyndrome;MUFA:Monounsaturated
sexdifferencesinlifeexpectancy:sevennationscasestudy.SocBiol
fattyacid;n-:Omega(-3,-6,-9unsaturatedfattyacids);NCEP:National
1998,45:1–20.
CholesterolEducationProject;NHANES:NationalHealthandNutrition
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PUFA:Polyunsaturatedfattyacid;SFA:Saturatedfattyacid;tFA:Trans-fatty lifeexpectancyinCanada,1971–2000.CanRevSociolAnthropol2007,
acid;TG:Triglycerides;TNF:Tumournecrosisfactor;VLDL:Very-low-density 44:101–122.
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