REVIEW

Epigenetic effects of paternal diet on offspring: emphasison obesity

Yuriy Slyvka • Yizhu Zhang • Felicia V. Nowak

Received: 15 January 2014 / Accepted: 5 June 2014

� Springer Science+Business Media New York 2014

Abstract Overnutrition, obesity, and the rise in associ-

ated comorbidities are widely recognized as preventable

challenges to global health. Behavioral, metabolic, and

epigenetic influences that alter the epigenome, when passed

on to offspring, can increase their risk of developing an

altered metabolic profile. This review is focused on the role

of paternal inheritance as demonstrated by clinical, epide-

miological, and experimental models. Development of

additional experimental models that resemble the specific

epigenetic sensitive situations in human studies will be

essential to explore paternally induced trans-generational

effects that are mediated, primarily, by epigenetic effects.

Further elucidation of epigenetic marks will help identify

preventive and therapeutic targets, which in combination

with healthy lifestyle choices, can diminish the growing

tide of obesity, type 2 diabetes, and other related disorders.

Keywords Epigenetic � Metabolic disease � Obesity �Paternal diet � Trans-generational

Introduction

According to recent data, 35.7 % of adults in the United

States are obese [1]. There is no significant difference in

prevalence between men and women at any age. More than

37 million men and almost 41 million women aged 20 and

over are obese in the US alone. In addition, 16.9 % of US

children and adolescents are obese. In 1999–2000, 27.5 %

of men were obese, and by 2009–2010, the prevalence had

increased to 35.5 %. Among women, 33.4 % were obese in

1999–2000 with no significant change in 2009–2010

(35.8 %). The prevalence of obesity among boys increased

from 14.0 % in 1999–2000 to 18.6 % in 2009–2010. There

was no significant change among girls: the prevalence was

13.8 % in 1999–2000 and 15.0 % in 2009–2010 [2]. The

obesity rate of US adults in 1960–1962 was 13.4 %. The

rate tripled over the next 50 years [3]. A similar threefold

increase in the prevalence of overweight and obese chil-

dren and adolescents has been observed over the same time

span. Worldwide, it is reported that there are greater than

155 million overweight and around 40 million obese chil-

dren and adolescents [4]. These increases in obesity in

recent decades have occurred too rapidly to be explained

completely by genomic DNA mutation or selection. This

suggests the involvement of other causes including epige-

netic modifications of gene expression [5], in addition to

and, possibly, as a result of, caloric imbalance imposed by

lifestyle choices that may include high food consumption

and low physical activity. Epigenetic modifications can

occur within the lifespan of numerous individuals within a

population and thus be transmitted immediately to a large

number of offspring in the next generation, unlike genomic

events that spread slowly through a population.

Intergenerational transmission of obesity risk occurs

between parents and children [6] and between grandparents

Y. Slyvka � Y. Zhang � F. V. Nowak (&)

Department of Biomedical Sciences, HCOM, Ohio University,

Athens, OH 45701, USA

e-mail: nowak@ohio.edu

Y. Slyvka � F. V. Nowak

The Diabetes Institute, Ohio University, Athens, OH 45701,

USA

F. V. Nowak

Program in Molecular and Cell Biology, Ohio University,

Athens, OH 45701, USA

123

Endocrine

DOI 10.1007/s12020-014-0328-5

and grandchildren [7]. Based on studies in twins, it has

been established that genetic inheritance contributes to

40–75 % of obesity cases [8, 9]. This includes monogenic,

multigenic, and epigenetic contributions.

Below, we present an overview of epigenetic regulation

and transmission of adaptable markers that may alter

metabolic processes in offspring, with an emphasis on

obesity and paternal inheritance. Related clinical and epi-

demiological studies are summarized, as are experimental

data from animal models.

Epigenetics: definitions and mechanisms

Definitions

Epigenetics is defined as changes in gene expression that

occur without altering the DNA sequence and can be

transmitted through mitosis and/or meiosis [10, 11]. All

cells in the individual organism contain the same DNA

sequence but not all express the same genes or accomplish

the same functions. Epigenetics can be thought of as those

processes that regulate gene expression in a given cell

leading to its cellular transcriptome and phenotype. The

sum of the chemical modifications of the DNA templates in

the organism that lead to changes in gene expression

constitutes the epigenome. Epigenetic modification is a

continual process, and some changes may be reversible.

Epigenetic mechanisms: crafting the epigenome

The main epigenetic mechanisms that are currently known

to regulate gene expression in humans and mammals are

summarized in Table 1 [5, 11–22].

Impact of environment on epigenetic patterns

Specific epigenetic patterns condition the accessibility of

chromatin to transcription factors, facilitating the distinc-

tion between genes that are to be expressed to various

extents and genes that are to be silenced, transiently, or

permanently [23]. These include covalent modification of

histones by phosphorylation, methylation, acetylation, and

ubiquitination. Factors in both the internal and external

environment direct the epigenetic programming of gene

expression. These factors include dietary composition and

caloric intake, physical activity, social stressors, environ-

mental toxicants, medication, hypoxia, inflammation,

aging, metabolic and hormonal disorders, and type and

level of psychosocial interactions [14, 15, 24]. Suscepti-

bility to epigenetic modification increases during certain

critical windows of development which include the pre-

conception period of gametogenesis, pre-implantation

embryo development [25–27], in utero gestation, puberty,

and advanced age [7, 11, 14, 15, 28, 29].

Epigenetic modifications can be heritable

Epigenetic chromatin modifications can be propagated

mitotically or meiotically; the latter results in stable

inheritance of metabolic traits. Although many sperm

chromatin modifications are erased post-fertilization, some

persist into the embryonic stage, supporting the hypothesis

that paternal epigenetic modifications can be transmitted to

subsequent generations. Trans-generational transmission of

epigenetic changes via the paternal line has been shown to

reside in the mature spermatozoa through nuclear siRNAs,

PIWI-interacting RNAs, the pattern of cytosine methyla-

tion of sperm DNA, and acetylation of lysine residues in

nucleohistones and in the chromatin structure [15, 19, 22,

30–33].

Most histones are replaced by protamines at the end of

spermatogenesis with approximately 10 and 1 % histone

retention in human and mouse sperm, respectively. A

majority of transcription factor binding sites are located in

the 1 % of the human genome that comprises the intragenic

and intergenic accessible regions [34]. The retained histone

methylation patterns in sperm are transmitted to offspring,

with high expression of paternal basic housekeeping genes

Table 1 Mechanisms of epigenetic regulation

Mechanism Details and examples

DNA methylation Occurs predominantly in the fifth carbon of

cytosines that are followed by a guanine.

Adenosine can also be methylated

Histone

modifications

These include methylation, acetylation,

ubiquitination and sumoylation of lysine,

phosphorylation of serine and threonine,

and methylation of arginine

DNA-associated

nuclear proteins

These include proteins that are critical

components of chromatin remodeling

complexes, several classes of effector

proteins that facilitate different types of

histone modifications, and insulator

proteins

Genomic imprinting This limits expression of a gene to one of the

two parental alleles

Non-coding RNAs These include microRNAs, picoRNAs, and

long non-coding RNAs, which can bind to

and regulate multiple mRNAs, and possibly

prions

Non-covalent

mechanisms

Examples are physical alterations in

nucleosomal positioning via nucleosome

remodelers or replacement of canonical

histone proteins with specialized histone

variants such as H3.3 and H2A.Z

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in sperm and early embryo, and low expression of genes

that regulate differentiation [35]. Operant mechanisms

identified to date in mammals include distribution of his-

tone H3 variants and retention of specific methylation and

acetylation patterns on histones, especially H3K27me3 and

H3K4me2/3, and H4K12ac [35–37]. Genes bearing high

H3K4me2/3 are significantly enriched in paternal loci

expressed in 4-cell and 8-cell human embryos [32], while

H3K27me3 plays a role in paternal transmission of the

repressed state [35]. Retention of paternal H3K27me3

methylation patterns in early embryos promotes repression

of genes involved in differentiation and helps maintain

totipotency in propagating cells [35]. Of note, the meth-

ylation patterns are highly conserved among fertile men,

but alterations in the methylation status at specific loci for

transcription factors and promoters of genes involved in

embryo development have been observed in infertile men

[38]. When taken together, these data support an effect of

paternal trans-generational transmission of histone-enco-

ded epigenetic information on phenotypic variation in

offspring.

Sperm histones are significantly enriched at the pro-

moters for microRNAs (miRNAs) [32]. MiRNAs can

regulate DNA methyltransferases, histone deacetylases,

and acetyl transferases, enzymes which help regulate DNA

structure and gene transcription [39, 40]. MiRNAs interact

with the 30 UTR of specific target mRNAs to induce their

translational repression, degradation, or deadenylation

[40]. It is known that the circulating miRNA profile of

obese men differs from that of non-obese men, including

miRNAs associated with genes that regulate adipocyte

development and function, as well as markers for acute and

chronic inflammation [41]. As sperm miRNAs have been

shown to respond to diet [19] and can be transmitted to the

developing embryo at fertilization, influencing offspring

phenotype [31], this is another potential epigenetic mech-

anism for effects of paternal high fat diet (HFD).

Diet affects epigenetic marks in sperm

Diet-induced obesity in C57Bl6 mice is associated with

increased reactive oxygen species and DNA damage in

sperm [42], resulting in germline effects including poor

fertilization rates and impaired embryo development and

implantation [42–44]. Binder et al. [45] found embryos of

obese male mice had impaired mitochondrial function and

blastocysts developed with a decreased inner cell

mass:trophectoderm ratio, resulting in decreased rates of

implantation and impaired fetal development. Paternal

HFD has been shown to result in altered expression of

regulatory microRNAs in sperm and global hypomethyla-

tion of sperm DNA [46]. In addition, several studies pro-

vide clear evidence that HFD-induced obesity in C57BL6

male mice results in subfertility in both male and female

offspring for two generations [46–48]. Diminished repro-

ductive and gamete functions are transmitted through the

first generation paternal line to both sexes of the second

generation and via the first generation maternal line to

second-generation males [47]. Interestingly, these effects

can be reversed by paternal dietary fat reduction and

exercise [48–50]. The Tet family proteins, Tet1 and Tet3,

have been shown to play roles in chromatin demethylation

following fertilization in humans and mice, and progeny of

paternal Tet1 knockout mice exhibit developmental

abnormalities, with specific hyper-methylated sites

observed in both sperm and embryos [51, 52]. However,

the complete set of changes in the epigenetic code due to

paternal diet and obesity and the mechanisms for their

reversal remains to be determined.

In humans, increased BMI in males is associated with

decreased blastocyst development and live birth rates after

in vitro fertilization (IVF) [53]. Increased reactive oxygen

species in sperm, increased seminal fluid neopterin, a

marker of reproductive tract macrophage activation,

decreased sperm counts and serum testosterone, and

increased serum estradiol are found in men with BMI

[25 kg m-2 [54]. The impacts of obesity on male fertility,

sperm function, and molecular composition are summa-

rized in an earlier review [55].

Dietary exposure can influence subsequent generations

When considering the scope of environmental effects, it is

necessary to differentiate direct paternal germline effects

(individual, F0 generation) from those that are multigen-

erational, affecting both parent and first generation off-

spring (F0 and F1) or trans-generational. A true paternal

trans-generational effect would be manifested in offspring

from sperm produced in a gonadal environment that has not

been exposed to persistent dietary modification, i.e., F2 and

beyond [18, 30]. This is in contrast to inheritance from the

maternal founder where true trans-generational effects

manifest in the F3 generation [56, 57].

Many studies of the epigenetic effects of obesity have

centered on factors modified in the affected individual

during his personal development [14, 15]. Fewer studies

have focused on transmission of epigenetic changes from

parent to child and possible mechanisms of this, including

formation of metastable epialleles and genomic imprinting.

A majority of reported multigenerational and trans-gener-

ational epigenetic phenomena have been related to mater-

nal transmission, while the paternal epigenome has been

comparatively neglected [5, 30, 31, 58, 59]. The impor-

tance of studying paternal epigenetic effects lies in the fact

that 50 % of autosomal genes are inherited from each

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parent, and expression of the single functional allele of an

imprinted gene that is silenced in one allele, is parent-of-

origin dependent. From this point of view, it is important

and timely to consider the epigenetic effects of paternal

diet, especially the overnutrition that has arisen with cer-

tain modern life styles and may well be having potent

health effects on subsequent generations [5, 60].

Epidemiological and clinical findings

Epidemiological and clinical studies provided the first

evidence of paternal multigenerational and trans-genera-

tional epigenetic effects. Different effects based on age and

sex of offspring and status of fathers were observed.

Grandparental diet is linked to sex-specific phenotype

in offspring

There is compelling evidence that epigenetic marks,

including DNA methylation, vary between tissues, indi-

viduals, and disease conditions in humans. It is likely that

changing circumstances within the individual or over sev-

eral generations can recruit silent alleles back into the

active genome and contribute to the reversibility of adap-

tive or acquired changes. A recent study in obese men

showed changes in circulating microRNAs that target

VEGF, an adipocyte mitogen, that was reversible following

weight loss [41].

Very interesting trans-generational effects were descri-

bed based on tracking three cohorts born in 1890, 1905,

and 1920 in Overkalix parish in Northern Sweden until

death or 1995. Access to food for parents and grandparents

during their slow growth period (SGP) was determined by

referring to historical data on harvests and food prices,

records of local community meetings, and general histori-

cal facts. The age of SGP was defined as 8–10 years for

girls and 9–12 years for boys [7, 61, 62]. When the father

(p = 0.046) was exposed to a famine during his SGP, the

child was protected against cardiovascular causes of death.

Furthermore, if the paternal grandfather lived through a

famine during his SGP, it tended to protect the grandchild

from diabetes (p = 0.09). If the paternal grandfather had

access to a surfeit of food during the SGP, the grandchil-

dren had a fourfold over-risk for death of diabetes mellitus

according to the point estimate (p = 0.01). The authors

concluded a nutrition-linked mechanism through the male

line appeared to influence the risk for cardiovascular and

diabetes mellitus mortality in both genders in subsequent

generations [61].

An association was also established between overall

longevity and food availability during the paternal grand-

father’s SGP [62] whereby increased food availability to

the grandfather decreased survival of the grandchild.

Analysis of the three-generation Overkalix parish data by

sex of the grandchildren shows striking sex-specific effects;

the paternal grandfather’s food supply was only linked to

the mortality risk ratios of grandsons, while paternal

grandmother’s food supply was only associated with the

granddaughters’ mortality risk ratio. The absence of an

association in the reverse paternal grandparent/grandchild

pairings provides an important internal control for paternal-

line social economic confounders, as the presence or

absence of the trans-generational effect involves trans-

mission through the same fathers [7]. Analysis of these

results was not affected by the grandchild’s own childhood

circumstances. Differences in grandparental diet during

other time periods of childhood did not have male-line

trans-generational effects. Effects of paternal diet on off-

spring longevity were also observed. However, these

effects were dependent on offspring childhood circum-

stances. Good food availability for fathers corresponded

with decreased life span in daughters when data were not

adjusted for offspring circumstances, but when adjusted,

the decreased life span was seen only in sons [7].

Paternal and maternal BMI affect BMI of offspring

A study of 127 healthy children (63 girls and 64 boys)

showed BMI at 6–18 months of age is a strong predictor of

BMI at 4 years. Protein intake at 17–18 months and at

4 years, energy intake at 4 years, and the father’s, but not

the mother’s, BMI were independent contributing factors

[63]. A study of the complete birth population in Norway

between 1967 and 1998 identified 67,795 trios of father–

mother–firstborn child. Both maternal and paternal birth

weight correlated positively with offspring birth weight.

There was an almost linear increase in offspring birth

weight as paternal birth weight increases, within categories

of maternal birth weight [64]. However, parental BMI at

the time of conception was not considered. Others have

found that paternal BMI (parental BMIs determined at

28 weeks gestation) had no effect on offspring weight,

length, or BMI at birth but was correlated with offspring

length at 1 year and offspring weight and BMI at 1 year

and 2 years. The authors concluded that paternal BMI has

effects on offspring BMI that are independent but additive

to effects of maternal BMI [65].

Analysis of 9,377 offspring and their parents from the

1958 British Birth Cohort Study indicated both maternal

and paternal BMI positively associated with offspring BMI

at age 11 years and did not diminish at 44–45 years in both

sexes. These associations remained after adjustment for

multiple lifestyle and socioeconomic factors [66]. Exces-

sive gains in paternal BMI in early childhood (7–11 years)

and adulthood (16–33 years) were associated with higher

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BMI and an increased risk of offspring being overweight or

obese [67]. Interestingly, parental obesity may more than

double the risk of adult obesity regardless of offspring

obesity status before the age of 10 [6]. Finally, the com-

bination of increased paternal BMI with diabetes and other

signs of metabolic syndrome further increases risk of BMI

[95th percentile in offspring [68]. These studies did not

consider gender-based assortative effects.

Gender-based differences in obesity inheritance

Very promising results concerning the mechanisms of

paternal epigenetic effects on offspring were obtained from

the newborn epigenetics cohort study [21]. They suggest a

link between increased paternal BMI and hypomethylation

at the imprinted insulin-like growth factor-2 (IGF-2), but

not H19, differentially methylated regions in DNA isolated

from umbilical cord blood leukocytes. A tendency toward

an increase in methylation at these two sites was shown in

newborns of obese mothers, demonstrating a possible

maternal influence on these two paternally inherited alleles.

Transcription of IGF-2 may be affected as a result, leading

to alterations in metabolic homeostasis later in life.

A study based on 226 healthy trios reported assortative

weight gain in mother–daughter and father–son pairs.

Large differences in BMI were found among the daughters

grouped according to mothers’ category of BMI, but not

their sons, and among the sons grouped according to their

fathers’ BMI, but not their daughters. The risks of obesity

at 8 years were ten-fold greater in girls or six-fold greater

in boys if the same-sex parent was obese [69]. In contrast, a

case-controlled study of 10–12 year old children in India

concluded that maternal obesity mainly passes to boys and

paternal obesity to girls [70]. However, several larger

studies failed to confirm any gender-based concordance

between parent and offspring [71–73]. It is not clear if the

disparate results are due to sample size, geographic locale,

genetic background, or other factors. The study by Whi-

taker et al. [73] based on pooled data from 4,432 families

(7,078 children) did show a stronger maternal effect

overall. This study also showed a graded increase in

childhood obesity when both parents had an elevated BMI

and as BMI increased from normal to overweight, then

obese and severely obese.

Longitudinal studies have shown that father’s total and

percentage body fat were predictors of baseline percentage

body fat and changes in body fat of premenarcheal girls

over a 2.7-year period starting at age 7� [74]. Severity of

obesity in both genders at age 15 is correlated strongly with

both paternal and maternal BMI [75], determined when the

child is between 3–18 years of age. Weight and length of

912 European American children from birth to 35 years

and their parental BMI showed that maternal BMI has a

stronger influence on offspring BMI during infancy and

early childhood than paternal BMI [76].

Gender-related effects on offspring epigenome

Chen et al. [77] analyzed the relationship between paternal

BMI and birth weight, ultrasound measurements of fetal

growth and umbilical cord hormone levels including cor-

tisol, aldosterone, renin activity, and fetal glycated serum

protein in a birth cohort of 899 father/mother/child triads.

Paternal BMI correlated significantly with birth weight and

perinatal biparietal diameter, head circumference, abdom-

inal diameter, abdominal circumference, and pectoral

diameter measured in male offspring. There were no sig-

nificant correlations between paternal BMI and these

parameters in female offspring. Cord blood cortisol level

was also associated with paternal BMI in male offspring

only. The authors concluded that a sex-specific trans-gen-

erational effect of paternal BMI on fetal cortisol secretion

may represent a risk factor for cardiovascular disease in

male offspring in later life [77].

Different phenotypic effects of genes inherited from the

paternal versus maternal side, which predispose to Type 1

diabetes mellitus, provide additional evidence of possible

sex-related epigenetic effects. Inheritance of the Class I

insulin (INS) VNTR allele from the father increases the risk

of early onset obesity by a factor of 1.8. Maternal trans-

mission does not have this effect [78]. Analysis of the

transmission of specific INS VNTR alleles in 1,316 families

demonstrated that a non-transmitted Class III allele can

prevent the predisposition to Type 1 diabetes that is usually

conferred by inheritance of the 814 Class I allele. This

effect is observed only with paternal and not with maternal

transmission [79]. In the case of Type 2 diabetes, maternal

transmission of the INS VNTR genotype follows Mendelian

law, but paternal transmission shows a clear excess of

Class III allele [80]. The selective impact of paternal origin

of the INS VNTR in these three metabolic disorders sup-

ports classification of the INS VNTR as imprinted.

Offspring phenotype may differ depending on which

parent is affected. Low birth weight has been shown to

predict later individual development of Type 2 diabetes.

Interestingly, in Pima Indians, low birth weight in offspring

is associated with paternal diabetes, and it also predicts

later development of paternal but not maternal parental

diabetes when neither parent is diabetic at the time of the

child’s birth [81]. Another study of Pima Indians showed

that adult non-diabetic offspring of fathers with early onset

of Type 2 diabetes were leaner and had lower early insulin

secretion than offspring of either mothers with early onset

of Type 2 diabetes or control subjects where neither parent

developed diabetes by age 50 years [82]. These findings

indicate the important role of paternal heritability in body

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composition and b-cell dysfunction and indicate a role for

epigenetic mechanisms in the predisposition to diabetes.

Stability of epigenetic modifications

Clinical and epidemiological studies regarding the relative

contributions of paternal genetics and family environment

to body composition and BMI class of offspring have

provided conflicting and controversial results. However,

several studies of twins reared apart [83] and adopted

children [84, 85] clearly support a significant effect of

heredity. There is a clear relationship between adoptee

weight and BMI of biologic parents, but not BMI of

adoptive parents. The authors conclude that childhood

family environment alone has little to no effect.

Paternal epigenetic contributions to offspring weight

and metabolic profile are complicated by epigenetic marks

that may be modified by maternal pre-pregnancy weight

and perinatal diet. For example, excess weight gain and

hyperglycemia during pregnancy can result in fetal

hyperinsulinemia and increased risk of obesity during

adolescence. Human studies of epigenetic mechanisms are

challenging because of the variety of factors that cannot be

controlled yet influence gene expression.

Challenges of human epigenomics

Human studies are complicated by interpersonal and

environmental factors, extended timeframes in generational

studies, lifestyle and socioeconomic factors, and many

ethical considerations that limit the design and may affect

the results [58]. To avoid these shortcomings, Lecomte

et al. [86] propose that future investigations be designed to

more precisely define human cohorts, assay the epigenetic

state at multiple time points and in multiple tissues in both

parents and offspring, correlate epigenetic changes with

differences in gene transcription and phenotype, and apply

genome-wide studies of epigenetic marks. Ongoing and

future epigenome mapping projects are needed to elucidate

the normal variations in the epigenome [34]. We may also

turn to animal models to understand the mechanisms of

epigenetic modifications as paternal trans-generational

messengers, as there is good evidence to support this

approach based on studies of environmentally induced

maternal inheritance.

Experimental findings

Inherited traits may be epigenomic

Variation in coat color in isogenic fox and mice is among the

first described inherited traits demonstrated to be epigenetic

[87, 88]. While the agouti mouse inheritance pattern is

maternal, the fox star gene expression pattern is transmitted

through both maternal and paternal lines. Likewise, both

maternal and paternal trans-generational inheritance have

been described for the epigenetic state of the murine AxinFu

allele. Hypomethylation in the LTR/intron 6 region of this

allele results in a kinked tail phenotype [89]. Experimental

manipulations of male rodents have also been found to result

in metabolic changes in subsequent generations. These

include neonatal thyroidectomy, alloxan-induced diabetes,

treatment with cyclophosphamide, chromium(III) or meth-

adone, and preconception fasting.

More recently, low paternal dietary folate has been

shown to alter the sperm epigenome and gene expression in

offspring, possibly via differences in histone or DNA

methylation [90].

Effects of perinatal nutrition on metabolism in offspring

Preconception fasting of male mice for 24 h resulted in

consistent decreases in serum glucose in male and female

offspring compared with those of controls at 10 weeks of

age. When fathers were fasted multiple times additional

effects were observed. Corticosterone and IGF-1 levels

were lower in male offspring, and IGF-1 was higher in

female offspring [91].

Maternal perinatal nutritional status has also been

reported to result in metabolic changes that persist across

at least two generations of offspring via the paternal

lineage [57, 92, 93]. The first experimental evidence for

trans-generational transmission of impaired glucose tol-

erance and reduced birth weight through paternal lineage

was demonstrated with in utero 50 % maternal caloric

restriction from day 12.5 until delivery in ICR mice [93].

Male offspring from calorically restricted mice exhibited

reduced birth weight with impaired glucose tolerance due

to b-cell dysfunction. These traits were transmitted to the

next generation of offspring via the paternal line alone

(low birth weight) or maternal line x paternal line com-

bined (impaired glucose tolerance) [93]. Interestingly,

hyperinsulinemia, impaired insulin sensitivity, and

increased visceral fat emerged only in the 2nd generation

when both parents were undernourished in utero. As

discussed above, trans-generational effects of maternal

diet are best supported by findings that are carried into the

F3 generation, and more studies of this type are needed.

Fewer reports are currently available that extend the

observation of phenotypic changes in response to maternal

diet on to the F3 generation. Maternal HFD affects female

grand-offspring body size in mice [57], and maternal pro-

tein restriction results in gender-specific alterations in

glucose metabolism in F3 rats [56].

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Obesity may be determined before conception

Koza et al. [95] demonstrated that differences in mRNA

expression of genes that regulate metabolism may be pro-

grammed pre- or peri-conceptually. Only a subset of male

C57Bl6/J mice fed a HFD (45–58 % kcal fat), approxi-

mately 2/3, becomes obese [94, 95]. This appears to be due

to a mechanism that causes a permanent change in energy

metabolism, possibly due to differences in adipocyte

expression of several imprinted genes and predates con-

sumption of the HFD. Maternal high-fat diet exposure in

C57BL/6:129 hybrid mice resulted in an increase in body

length and reduced insulin sensitivity that persisted across

two generations and was transmitted via both maternal and

paternal lineages [92]. The greatest effect was seen in the

second generation when both parents had high-fat fed

dams. Increased body weight and length occurred in F3

offspring as well, but these traits were transmitted only

through the paternal lineage and only to female offspring.

PCR analysis of an array of paternally expressed imprinted

genes in liver of these female offspring showed greater

than 50 % fluctuation in expression of five growth related

genes, Magel2, Peg12, Peg10, Ins1, and Rasgrf1 [57].

Yazbek et al. [96] provided additional evidence for

paternal trans-generational epigenetic effects on body

weight and food intake, using a 58 % fat diet. They focused

on the obesity-resistant 6C2d congenic strain which carries

the Obrq2aA/J allele on an otherwise C57BL/6J back-

ground. Various crosses between 6C2d and C57BL/6J

showed that the Obrq2aA/J allele in the paternal or grand-

paternal generation was sufficient to inhibit diet-induced

obesity and reduce food intake in the normally obesity-

susceptible, high food intake C57BL/6J strain. The phe-

notype was subsequently transmitted, in the absence of the

Obrq2aA/J allele, through the paternal but not the maternal

lineage to the male offspring with equal strength for at least

two generations. Eliminating social interaction between the

father and both his offspring and the pregnant dam did not

significantly affect food intake levels, demonstrating that

transmission, in this case, is biological, possibly involving

retained histone modifications in the sperm genome [32],

and not socio-environmental.

Consumption of a HFD (41 % fat) for 10 weeks, from

age 4–14 weeks, by male Sprague–Dawley rats pro-

grammed b-cell dysfunction in their female but not male

offspring on regular chow [97]. HFD in rat fathers induced

increased body weight, adiposity, impaired glucose toler-

ance, and insulin secretion. Female offspring had an early

onset of impaired insulin secretion and glucose intolerance,

despite being maintained on normal chow and having

normal adiposity. The authors detected altered expression

of 61 pancreatic islet genes in functionally enriched path-

ways involved in cation and ATP binding, cytoskeleton and

intracellular transport, calcium signaling, MAPK, Wnt, and

Jak-Stat signaling, apoptosis, and the cell cycle. Hypome-

thylation of the interleukin 13 receptor alpha-2 gene,

which showed the highest fold difference in expression (a

1.76 fold increase) was demonstrated in pancreatic islets of

female offspring from HFD fed fathers. This provides

important confirmation of an epigenetic mechanism for

effects of paternal dietary composition on offspring

phenotype.

Paternal diet effects on offspring have also been studied

with male C57BL/6 mice fed a low-protein diet (11 %

rather than 20 % protein, with remaining mass made up

with sucrose) [19]. Low-protein diet offspring of both

genders exhibited elevated hepatic expression of 445 genes

involved in DNA replication and in lipid and cholesterol

biosynthesis, as well as decreased hepatic cholesterol,

when compared to offspring of control diet males. Epige-

nomic profiling of offspring livers revealed widespread

modest changes in CpG methylation depending on paternal

diet, including methylation of a putative enhancer for the

key lipid regulator PPARa. Of note is that the gene

expression profile of genes that change in offspring is not

the same as the genes induced in the parental generation by

the different dietary protocols. Differential expression of a

number of proliferation related hepatic microRNAs was

also observed in offspring from the two diet groups, with

up-regulation of miR-21, let-7, miR-199, and miR-98, and

down-regulation of miR-210 in the low-protein diet

offspring.

More recently, the effects of HFD-induced paternal

obesity on the metabolic health of offspring have also been

studied in mice. Male C57BL/6 mice (F0) were fed a HFD

for 10 weeks to induce obesity without overt diabetes. The

F1 female offspring were obese and insulin resistant. Male

F1 offspring were insulin resistant and hyperleptinemic but

not obese. Altered phenotypes were further transmitted to

the F2 generation. Female, but not male, F2 offspring of F1

males exhibited increased adiposity and decreased insulin

sensitivity. In contrast, male F2 offspring of F1 females

showed increased adiposity and decreased glucose toler-

ance. Female offspring from this group showed only

impaired insulin sensitivity. These differences support the

concept of transmission of impaired metabolic health to

subsequent generations on the basis of paternal environ-

mental variables and physiology [46].

When the effects of neonatal overnutrition were exam-

ined in the ICR-CD1 mouse strain, multiple metabolic

derangements were transmitted to the F1 and F2 offspring

via the paternal line [98]. Neonatal overnutrition was

modeled by adjusting litter size to 8 pups per dam (F0

control), or 4 pups per dam (F0 overnutrition). Overnutri-

tioned males demonstrated accelerated postnatal growth

that persisted until adulthood, hypertriglyceridemia, fed

Endocrine

123

and fasting hyperinsulinemia, fasting hyperglycemia, glu-

cose intolerance and insulin resistance. Offspring (F1)

derived from mating overnutritioned F0 fathers with

external control group mothers also demonstrated fasting

hyperglycemia, moderate glucose intolerance, hyperinsu-

linemia, hypertriglyceridemia, and insulin resistance at

4 months of age. Only mild fasting hyperglycemia and

impaired glucose tolerance transferred to the next genera-

tion (F2) through the paternal line. Neither F1 nor F2 off-

spring of overfed fathers exhibited increased body weight,

and F1 males displayed a seemingly paradoxical reduction

in epididymal fat mass. The fact that the metabolic dys-

regulation is greatly reduced in second-generation off-

spring argues strongly for an epigenetic modification of

gene expression rather than a change in DNA sequence as

the latter would be expected to remain stable across gen-

erations [23].

Recent studies in mice compared offspring obtained by

in vitro versus in vivo fertilization using sperm from

calorically restricted males showed differences in offspring

phenotype. Although this raises the possibility that some

effects of paternal diet are due to maternal exposure to the

males during mating [99] and are still transmitted through

the maternal line, the results may also reflect changes

introduced by the IVF procedure itself. Finally, diet may

also influence the intestinal flora which, in turn, sends

signals that alter the testicular environment and possibly

the sperm epigenome. Thus, there may be multiple routes

whereby environmental factors experienced by parents

alter the development of offspring.

Conclusions

Parental diet has been shown in epidemiological, clinical,

and experimental arenas to have multiple trans-genera-

tional effects on the metabolic profile of offspring through

at least two generations. Many of these effects are trans-

mitted through the paternal germ line. It can be expected

that the increasing prevalence of diet-induced obesity in

parents affects obesity and related metabolic syndromes in

the children. Therefore, development of experimental

models that resemble the specific epigenetic sensitive sit-

uations in human studies is essential. Maternally induced

trans-generational effects are mediated by a complex

interplay of metabolic, mitochondrial, in utero fetal pro-

gramming, epigenetic, and social factors, whereas pater-

nally induced trans-generational effects can be studied in a

model where they are mediated, primarily, by epigenetic

effects. Further elucidation of epigenetic marks will help

identify preventive and therapeutic targets, which in com-

bination with healthy lifestyle choices, can diminish the

growing tide of obesity, type 2 diabetes, and other related

disorders.

Conflict of interest The authors declare they have no conflict of

interest.

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