Adiposopathy and epigenetics: an introduction to obesity as a transgenerational disease

Abstract

Background:

To examine the contribution of generational epigenetic dysregulation to the inception of obesity and its adiposopathic consequences.

Methods:

Sources for this review included searches of PubMed, Google Scholar, and international government/major association websites using terms including adiposity, adiposopathy, epigenetics, genetics, and obesity.

Results:

Excessive energy storage in adipose tissue often results in fat cell and fat organ dysfunction, which may cause metabolic and fat mass disorders. The adverse clinical manifestations of obesity are not solely due to the amount of body fat (adiposity), but are also dependent on anatomical and functional perturbations (adiposopathy or ‘sick fat’). This review describes extragenetic factors and genetic conditions that promote obesity. It also serves as an introduction to epigenetic dysregulation (i.e., abnormalities in gene expression that occur without alteration in the genetic code itself), which may contribute to obesity and adiposopathic metabolic health outcomes in offspring. Within the epigenetic paradigm, obesity is a transgenerational disease, with weight lost or gained by either parent potentially impacting generational risk for obesity and its complications.

Conclusions:

Epigenetics may be an important contributor to the emergence of obesity and its complications as global epidemics. Although transgenerational epigenetic influences present challenges, they may also present interventional opportunities, via justifying weight management for individuals before, during, and after pregnancy and for future generations.

Keywords: :

• Adiposopathy
• Epigenetics
• Obesity
• Transgenerational

Introduction: obesity as a disease

The Obesity Medicine Association (formerly known as the American Society of Bariatric Physicians) defines obesity as: “A chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences”1. The etiology of the disease of obesity is complex and involves the integration of extragenetic, genetic, and epigenetic pathologies, along with contributing abnormalities of neurobehavioral, medical, environmental, endocrine, and immune factors1.

According to the 2009–2010 National Health and Nutrition Examination Survey (NHANES), overweight and obesity affects approximately 70% of US adults2. Manifestations of excessive body fat may begin early in life. According to 2011–2012 NHANES data3, approximately 8% of infants and toddlers were found to have weight that exceeded the corresponding recumbent length. The same NHANES data also showed that among 2 to 19 year olds and adults aged 20 years or older, 17% and 35%, respectively, were obese. The prevalence of obesity has markedly risen in adults in the United States in the past few decades alone4–6, which is a trend that is not exclusive to the US. The World Health Organization (WHO) reports that globally, obesity has dramatically increased in the last 30 years, with twice as many adults with obesity in 2014 than in 19807. This report indicates that adults with overweight exceeded 1.9 billion in 2014, and among these individuals, more than 600 million were obese. This WHO report also notes that data from 2013 suggests 42 million children aged 5 and under were found to be overweight or obese. Finally, some reports suggest obesity as responsible for approximately 5% of all global deaths, with an economic cost of ∼$2.0 trillion, which is comparable to the worldwide impact of smoking8. In summary, both the disease of obesity and its adiposopathic complications are worldwide epidemics, beginning early in life.

This review briefly examines extragenetic factors and genetic conditions that promote obesity and its complications. This review also serves as an introduction to the potential role of epigenetics in contributing to the emergence of obesity and metabolic diseases. Many clinicians are not only involved in the health management of individuals, but also their families. These clinicians may benefit from a review of general genetic principles not frequently applied in clinical practice, as well as an update on the potential clinical implications of epigenetic research. Understanding the potential generational role of epigenetics in worsening metabolic health may further illustrate the need for clinicians, other health care providers, patients, and their families to all work together to implement treatment strategies for patients with overweight or obesity.

Pathogenic potential of adipose tissue

A central diagnostic criterion for obesity is an abnormal increase in body fat, as determined by a reliable measure1. Table 1 describes anatomical consequences of excessive adiposity9. In general, positive caloric balance with increased energy storage in adipose tissue contributes to adipocyte hypertrophy, as well as an increase in other fat depots, with an increase in visceral adipose tissue (i.e., central adiposity) being a clinical surrogate for global fat dysfunction9. Table 1 also includes the histological and functional changes that lead to adiposopathic endocrine and immunologic abnormalities, which, in turn, contribute to metabolic disease9. Due to the anatomic and functional derangement of adipose tissue with increased body fat, adverse health consequences include both ‘sick fat disease’ (adiposopathy, as shown in Table 1) and ‘fat mass disease’1, with this latter term intended to describe the adverse health consequences predominantly due to an increase in fat mass (e.g., stress on weight bearing joints, immobility, tissue compression, and tissue friction)10. Adverse adiposopathic consequences can occur early in life, as evidenced by the contribution of adipocyte and adipose tissue endocrinopathies, immunopathies, and oxidative stress, which manifest in cardiometabolic disturbances in children (and adults) with obesity11^,12.

Table 1. Obesity as a disease: adiposopathic anatomic, functional, histological, endocrine, and immune changes.

Anatomic changes:

• Adipocyte hypertrophy with variable increases in adipocyte number, as regulated by intracellular proteins:

○ Sterol regulatory element binding protein 1 (SREBP1), which is the human analogue to adipocyte determination and differentiation-dependent factor 1 (ADD1)

○ Peroxisome proliferator activated receptor (PPAR) gamma

○ CCAAT-enhancer-binding proteins (C/EBPs)

• When adipogenesis (proliferation and differentiation) in peripheral subcutaneous adipose tissue (SAT) is inadequate to store excess energy, this may:

○ Further worsen adipocyte hypertrophy of existing adipocytes

○ Contribute to energy overflow with increased circulating free fatty acid blood levels, increasing size of other adipose tissue depots, including:

▪ Visceral adipose tissue (VAT) accumulation

▪ Subcutaneous abdominal adipose tissue accumulation

▪ Pericardiac adipose tissue accumulation

▪ Perivascular adipose tissue accumulation

○ Contribute to energy overflow with increased circulating free fatty acid blood levels, increasing fatty infiltration and lipotoxicity to:

▪ Liver, resulting in nonalcoholic fatty liver disease (NAFLD), with subsets including hepatic steatosis, which may contribute in insulin resistance, and nonalcoholic steatohepatitis (NASH), an inflammatory state that may lead to insulin resistance, fibrosis, and cirrhosis

▪ Muscle, resulting in intramyocellular triglycerides and insulin resistance

▪ Pancreas, resulting in beta cell glycolipotoxicity, macrophage infiltration, and β-cell failure

▪ Heart, resulting in fat accumulation within cardiomyocytes, mitochondrial dysfunction, inflammation, and cardiac dysfunction

▪ Kidney, resulting in renal fat accumulation, immune cell infiltration, increased glomerular capillary wall tension, podocyte stress, focal and segmental glomerulosclerosis, proteinuria, and progressive renal dysfunction

Histological and functional changes:

• Adipocyte and adipose tissue hypoxia because of:

○ Growth of adipose tissue beyond vascular supply

○ Inadequate angiogenesis

○ Impaired blood flow (possibly neurologically mediated)

• Increased adipocyte apoptosis

• Increased reactive oxygen species and oxidative stress

• Extracellular matrix abnormalities

• Intraorganelle dysfunction

○ Mitochondrial stress

○ Endoplasmic reticulum stress

• Changes in adipose tissue neural network and innervations

Adiposopathic endocrinopathies resulting from dysfunctional adipocyte and adipose tissue processes involving:

• Angiogenesis

• Adipogenesis

• Extracellular matrix dissolution and reformation

• Lipogenesis

• Growth factor production

• Glucose metabolism

• Production of factors associated with the renin–angiotensin system

• Lipid metabolism

• Enzyme production

• Hormone production

• Steroid metabolism

• Immune response

• Hemostasis

• Element binding

• Adipose tissue has receptors for traditional peptides and glycoprotein hormones, receptors for nuclear hormones, other nuclear receptors, receptors for cytokines or adipokines with cytokine-like activity, receptors for growth factors, catecholamine receptors, and other receptors

Adiposopathic immunopathies resulting from dysfunctional adipocyte and adipose tissue processes involving:

• Proinflammatory adipose tissue factors

○ Factors with cytokine activity

○ Acute-phase response proteins

○ Proteins of the alternative complement system

○ Chemotactic or chemoattractants for immune cells

○ Eicosanoids and prostaglandins

• Anti-inflammatory adipose tissue factors

Reprinted with permission from Bays H. Central obesity as a clinical marker of adiposopathy; increased visceral adiposity as a surrogate marker for global fat dysfunction. Curr Opin Endocrinol Diabetes Obes 2014;21:345-51 Wolters Kluwer Health©

Introduction to the role of genetics in obesity

Table 2 lists some extragenetic etiologies of the obesity epidemic, which include an increase in energy consumption, decreased physical activity, mental stress and emotional responses, medical conditions, and environmental and cultural factors. These etiologic factors support obesity as a multifactorial disease1, and likely represent the most common causes of population based obesity.

Table 2. Potential non-genetic etiologies of the obesity epidemic1.

Increased energy consumption
• Strong biologic forces that resist weight loss
• Weak biologic forces that resist weight gain
• Hypothalamic dysfunction
○ Injury
○ Trauma
• Mental stress
○ Chronic stress-induced limbic (e.g., hypothalamic) endocrinopathies and immunopathies
○ Chronic stress-induced cerebral endocrinopathies and immunopathies
○ Chronic stress-induced priority replacement of personal, work, or emotional priorities that overtake nutritional and physical activity priorities
• Inadequate education
○ Lack of knowledge of nutritional content and value of foods
○ Lack of uniform disclosure of nutritional and caloric content of purchased foods
• Eating disorders
○ Binge eating disorder
○ Bulimia nervosa
○ Night eating syndrome
Decreased physical activity
• Increase in availability of convenient transportation that does not involve as much physical activity as walking, running, or bicycling
• Increase in longevity, potentially resulting in a greater prevalence of musculoskeletal, neurologic, and/or other health problems that may limit physical activity
• Limitations in mobility due to excessive fat mass
○ Joint and muscle biomechanical impairments
○ Musculoskeletal pain
○ Neuropathy (i.e., nerve compression)
• Work commitments
• Family and other personal responsibilities
• Time preferentially allotted for other entertainments
○ Television
○ Movies
○ Video games
○ Internet
• Disinterest
○ Fatigue
○ ‘Exercise is boring’
• Past failures with exercise
○ Past failures to achieve exercise goals
○ Past failures in observing body changes
○ Past injury with exercise
• Concerns of being seen
○ In workout clothes
○ In gyms surrounded by others more fit
• Don’t like to sweat
○ General appearance
○ Hair
○ Odor
• Lack of:
○ Others (family, friends, co-workers) engaged in physical activity
○ Safe environments
○ Nearby parks or other areas for leisure activity
○ Accessible gym
○ Home or workplace exercise equipment
• Insufficient education on physical activity
○ Benefits
○ Risks
○ Techniques
○ Recommendations
○ Expectations
Emotional responses
• Eating for reasons beyond hunger
○ Reward
○ Facilitate sleep
○ Celebrate happiness
○ Soothe sadness
○ ‘Treat’ stress and anxiety
○ ‘Treat’ boredom
○ ‘Treat’ fatigue
Environment and culture
• Surroundings that enhance food-related senses, which may promote eating behavior
○ Sight of food
○ Smell of food
○ Hearing talk of food or cooking of food
○ Taste of food
○ The above senses may exacerbate the feeling of lack of food (e.g., ‘empty stomach’ or borborygmi)
• Others are eating
• Food is available
• Offers of free food
• Food as a surrogate for love and/or affection
• Highly researched advertisements that promote enhanced desire for foods, especially energy-dense foods
• Perceived obligations to eat
○ Family gatherings
○ Business meetings
○ Clean plate syndrome
Increased caloric balance based upon chronology
• ‘Learned’ hunger before mealtimes
• Set mealtimes, even if the individual has just eaten, and is not hungry
• Special occasions
• Holidays

But beyond extragenetic causes, genetics clearly plays a role in obesity as well. While monogenetic inheritance is not generally thought to be the major contributor to most cases of population-based obesity, the proportion of severe cases of obesity caused by isolated gene abnormalities are unknown. In genomewide association studies (GWASs), the strongest genetic signal for body mass index is located in the FTO locus, wherein polymorphic differences in noncoding nucleotide sequences may change the basic function of human adipocytes from energy storage to energy utilization via enhanced thermogenesis13^,14. Furthermore, monogenic diseases that cause severe cases of obesity are described and include leptin and leptin receptor deficiency, SH2B1 mutations, and carboxypeptidase E mutations15–17. Table 3 lists illustrative genetic obesity syndromes experienced by patients, and managed by clinicians, along with their genetic abnormalities16–24.

Table 3. Genetic causes of obesity16^,18–24.*

Genetic syndrome	Clinical presentation	Gene abnormality
Melanocortin 4 receptor deficiency	• Obesity, especially in families • Hyperphagia in early childhood • Increase in bone mineral density – ‘big boned’ • Accelerated linear growth • Reduced sympathetic nervous activity	• Autosomal dominant or recessive • Most common known genetic defect predisposing to obesity • Polymorphism of gene localized to chromosome 18q22
Albright’s hereditary osteodystrophy	• Obesity • Short stature • Rounded face • Skeletal defects: shortened fourth metacarpals and other bones of the hands and feet • Dental hypoplasia • Soft-tissue calcifications/ossifications • Pseudohypoparathyroidism (hypocalcemia, hyperphosphatemia)	• Associated with molecular defect in the gene (GNAS1) which encodes for the alpha subunit of the stimulatory G protein
Prader–Willi syndrome	• Obesity, often hyperphagic • Short stature • Weak muscle tone • Poor growth • Small hands/feet • Delayed development • Underdeveloped genitals (often with infertility) • Behavioral/emotional challenges • Mild to moderate intellectual impairment • Insatiable appetite • Narrow forehead • Almond-shaped eyes • Triangular mouth • Often with fair skin and light colored hair	• Often reported as the most common human genetic "obesity syndrome" • Not inherited • Most cases involve loss of function of a portion of chromosome 15
Bardet–Biedl syndrome	• Obesity • Metabolic abnormalities (e.g., type 2 diabetes mellitus, high blood pressure, dyslipidemia) • Blindness (retinal dystrophy and pigmentary retinopathy) • Anosmia • Hearing loss • Dysmorphic extremities: polydactyly and short or fused fingers and toes • Poor coordination • Dental abnormalities • Intellectual disability • Behavioral/emotional challenges • Hypogonadism (with infertility) • Renal cystic disease; renal insufficiency, which may lead to end-stage renal disease	• Autosomal recessive • Mutations of at least 16 genes (BBS genes) applicable to cilia involved in cell movement, chemical signaling, and sensory input (sight, hearing, and smell)
Cohen syndrome	• Obesity • Developmental delay • Intellectual disability • Small head size • Narrow hands and feet with slender fingers • Weak muscle tone • Retinal dystrophy • Joint hypermobility • Thick hair and eyebrows • Thick eyelashes • ‘Open mouth’ expression with incisoral prominence • Low white blood cell count • Overly friendly behavior	• Typically auto recessive • Mutation of the VPS13B gene (COH1 gene)
Börjeson–Forssman–Lehmann syndrome	• Obesity • Mainly in males • Intellectual disability • Seizure disorders • Large earlobes • Shortened toes • Small genitalia • Gynecomastia	• X-linked disorder • Mutation of the zinc finger gene PHF6 (located on the X chromosome)

*Examples of other genetic conditions associated with obesity include leptin deficiency, leptin receptor deficiency, src homology 2 B adapter protein 1 (SH2B1) mutations, carboxypeptidase E mutations, prohormone convertase-1 deficiency, proopiomelanocortin deficiency, proprotein convertase subtilisin kexin 1/3 deficiency, brain derived neurotrophic factor (BDNF) deficiency, TrkB deficiency, Sim1 deficiency, maternal uniparental disomy of chromosome 14, trisomy 21, fragile X syndrome, Turner's syndrome, Alstrom syndrome, Carpenter syndrome, Macrosomia, Obesity Macrocephaly Ocular abnormalities (MOMO) syndrome, Rubinstein-Taybi syndrome, Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD syndrome), deletions/mutations of various other gene loci17 and polymorphisms of fat mass and obesity associated (FTO) gene located on chromosome 16.

Regarding genetic inheritance applicable to body traits such as obesity, humans have 23 pairs of chromosomes (threadlike structures of nucleic acids and proteins found in the nucleus), with 22 such autosomes numbered 1–22, and another pair of sex chromosomes, for a total of 46 chromosomes25. Within chromosomes are distinct sequencing of nucleotide genes, which code for production of proteins that substantially determine how traits from parents are manifest in offspring. According to Mendelian genetics, genes may exist in alternative allele forms25. Polymorphic genes are those with at least two alleles; multiple allele conditions may have three or more allelic forms (e.g., ABO blood group systems controlled by isohemagglutinin, as in IA, IB, or IO alleles). Two matching alleles are homozygous; two different alleles are heterozygous. In individuals with heterozygous alleles, the allele that is expressed is termed ‘dominant’, while the one that is not expressed is termed ‘recessive’26.

Genetic variations can be due to expression of the dominant allele, and include autosomal dominant diseases such as Huntington’s disease, neurofibromatosis, and achondroplasia, as well as obesogenic conditions such as Albright hereditary osteodystrophy and most cases of melanocortin 4 receptor deficiency16^,25^,27 (Table 3). Genetic variations can also occur with the inheritance of two recessive alleles, which can be clinically manifest by autosomal recessive diseases such as Tay–Sachs disease, cystic fibrosis, and sickle-cell anemia25, as well as some cases of the obesogenic melanocortin 4 receptor deficiency, Bardet–Biedl syndrome, and Cohen syndrome (Table 3). Most inherited diseases are autosomal recessive, which is an important reason why genetic offspring between close relatives is discouraged. Some diseases are due to gene deletion, or mutation of a non-silenced gene, as may occur with the obesogenic Prader–Willi syndrome (Table 3)16.

In addition to disorders due to Mendelian inheritance, another manner in which abnormalities in gene expression can occur is through the activation or inactivation of existing genes via gene regulation28. An example of a non-pathological epigenetic effect is lyonization, wherein one of the two copies of the X chromosome in women is inactivated into an inactive structure termed heterochromatin (i.e., Barr body)28^,29. Once inactivation of the X chromosome takes place, then this X chromosome remains inactive throughout the life of the woman, as well as her offspring28. X chromosome inactivation is an example of an epigenetic effect important for genetic expression within the individual.

Introduction of the role of epigenetics in obesity and its metabolic complications

No evidence yet exists that the rapid worsening of the obesity epidemic is due to the entry of a new, isolated, widespread genetic abnormality that has arisen and increased in prevalence in just the past few decades. So while extragenetic and genetic factors are clearly important (Tables 2 and 3), they may not fully explain the marked increase in prevalence of the obesity epidemic and its adiposopathic consequences. Emerging data suggest epigenetic dysregulation may play a significant role in the generational worsening of the obesity epidemic30.

Parental obesity is a strong predictor of childhood obesity31. The longer a child remains obese, the greater chance that individual will carry obesity into adulthood32. ‘Inheritance’ can be loosely defined as traits passed from parents to offspring. Extragenetic inheritance can result in obesogenic factors being passed from parents to children in the form of cultural or familial habits (Table 2)1. Inherited genetic abnormalities are characterized as abnormalities in deoxyribonucleic acid (DNA) sequencing and gene code additions/deletions16^,17 (Table 3). But beyond extragenetic and genetic inheritance, ‘inherited’ epigenetic dysregulation can also influence the predisposition to obesity and its complications1^,33 (Figure 1).

Figure 1. Multifactorial inheritance factors that may contribute to obesity and its complications.

Epigenetics refers to long-lasting alterations in gene transcription and expression, which result in long-term alterations in cellular/biologic function33^,34, which may include adiposopathic disruption in the adipocyte and adipose tissue physiologic functions listed in Table 1 35–43.

Epigenetic inheritance does not involve alterations in gene sequencing, gene addition, or gene deletion. Rather, epigenetic dysregulation affects gene expression through modifications of: (1) cell differentiation, (2) dosage compensation (e.g., ensuring equal levels of X-linked gene products in males and females in species wherein the sexes differ in the number of X chromosomes), (3) genome structure maintenance, (4) genomic/parental imprinting (with either the mother or father inherited gene active, and the other silenced), and (5) repetitive element repression29.

Examples of gene regulators relative to cell differentiation include DNA methylation and histone modification (e.g., acetylation, methylation, ubiquitylation, phosphorylation, sumoylation, ribosylation, and citrullination). DNA wrapped around eight histones helps form a nucleosome, with a chain of nucleosomes composing chromosomes. Methylation of DNA at promoter regions of genes typically suppresses gene transcription. Histone modification can either promote gene transcription (e.g., acetylation with relaxation of chromatin) or inhibit gene transcription (e.g., methylation with more tightly wrapped chromatin). Through regulation of gene transcription, epigenetic regulation helps guide the differentiation of stem cells to the desired lineage fate.

Dosage compensation occurs when a redundant gene is inactivated, such as inactivation of one X-chromosome in women. Genome structure maintenance involves epigenetic modifications to facilitate DNA damage repair29.

Genomic/parental imprinting occurs when DNA methylation marks (or imprints) which of two genes (from the mother or father) becomes inactive, leaving one gene allele active. While most genes are expressed from both parental chromosomes, a small number of genes are imprinted and expressed in a parent of origin specific manner44. The epigenetically imprinted gene allele is silenced, thus allowing for expression of the allele solely from the other parent. During egg and sperm formation, these epigenetic tags on imprinted genes are typically reset. Prader–Willi syndrome is a multisystemic genetic disorder caused by a maternally imprinted section of chromosome 15 paired with a lack of expression of a paternal section of chromosome 15 (Table 3). Most cases of Prader–Willi syndrome are due to paternal 15q11–q13 gene deletion (∼70% of cases) and maternal uniparental disomy (∼25% of cases). But a small number of cases of Prader–Willi syndrome (<5%) may be due to imprinting defects45, which may occur when the applicable paternal section of chromosome 15 is present, but imprinted due to a failure to erase the silencing maternal imprint during spermatogenesis46.

Repetitive element repression occurs when redundant genetic expression is avoided via epigenetic DNA methylation and histone modification that deactivates one of the repetitive genes, resulting in heterochromatin formation29. Heterochromatin (as opposed to the more loosely coiled, genetically active euchromatin), represents more tightly coiled DNA surrounding histone proteins, which limits messenger ribonucleic acid transcription, thus rendering this portion of the gene more inert.

From a disease state, potential ways in which epigenetics may specifically contribute to obesity include: (1) downstream effectors of environmental signals, which may involve adipogenesis and neural reward pathways; (2) abnormal global epigenetic state driving obesogenic expression patters, as might occur via mutations in epigenetic-modifier genes; (3) facilitating developmental programming, such as through early life exposures to stress, overnutrition during gestation or lactation, and chemical endocrine disrupters; and (4) transgenerational epigenetic inheritance wherein adverse epigenetic consequences of parental obesity may contribute to offspring sharing similar adverse epigenetic consequences29^,47. As before, such adiposopathic consequences of epigenetic effects may involve disruption of any number of adipocyte and adipose tissue physiologic processes otherwise important for human health, as described in Table 1 35–43.

Specific promoters of epigenetic alterations that could potentially contribute to an obesogenic environment include the presence of obesogens (i.e., toxins such as tributyltin, brominated diphenyl ether 47, polycyclic aromatic hydrocarbons, as well as endocrine disrupting chemicals such as excessive estrogens or cortisol exposure in the womb or early life)48^,49; lack of physical activity; and nutritional abnormalities, infection, medications, and other potential environmental factors present at conception, during pregnancy, or even after pregnancy (via post-partum breastfeeding, future pregnancies, etc.)33^,50–52. While adverse epigenetic effects are most often described as deriving from maternal origin, increasingly data support paternal epigenetic effects contributing to adverse effects in offspring as well53. Environmentally induced epigenetic transgenerational inheritance of sperm epimutations may promote genetic mutations54, and toxin and nutritional exposures may result in programming transmissions, or epigenetic inheritance, via either maternal or paternal origin55. In total, this suggests that both parents may share responsibilities in epigenetic transmissions.

Regarding environmental factors, toxins that may contribute to epigenetic dysregulation include endocrine disruptors (e.g., environmental pesticides, exogenous hormones, estrogenic agents [dichlordiphenyltrichloroethane or DDT, high-dose phytoestrogens, polychlorinated biphenyls, dioxins, bisphenol A], androgenic agents [testosterone], anti-estrogenic agents [low-dose phytoestrogens], anti-androgen agents [DDT]). Not only might such toxins have adverse health consequences to the individual, but these epigenetic effects may predispose offspring and future generations to metabolic diseases56–58. Regarding nutrition, epidemiological evidence supports maternal undernutrition during fetal development as increasing the risk of obesity, type 2 diabetes, and cardiovascular disease later in life59. Epigenetically, undernutrition may contribute to obesity via metabolic programming resulting in adipose tissue abnormalities of structure and function (adiposopathy), alterations of appetite regulators in offspring, and mobilization of free fatty acid and ketone formation which may be transported from the mother to the fetus60–62. Conversely, maternal overnutrition during fetal development may also increase the risk of obesity and its complications29^,59. According to the developmental origins of health and disease (DOHaD), maternal obesity during pregnancy is a health hazard to offspring63. Thus, the risk of adiposopathic disease development in an adult may be influenced by his/her perinatal environment50–52, with maternal nutrition affecting epigenetic mechanisms during development in utero, resulting in pathogenic biologic changes maintained through subsequent cell division into adulthood33. Importantly, not only are these epigenetic changes applicable for the first generation offspring, but also may persist for subsequent generations64–66, even in the absence of continued environmental stressors67.

But just as unfavorable epigenetic alterations may increase disease risks, favorable epigenetic changes that occur before conception and during pregnancy may also influence the obesity risk transferred to offspring. Animal studies support that obese and lean mothers have offspring with different metabolic features and different epigenetic markers68. Animal studies also suggest that compared to persistent maternal obesity, periconceptional weight loss can promote epigenomic signaling that maximizes metabolic benefits and minimizes metabolic costs for the next generation69. Human studies also support that dietary restriction in pregnant women with obesity may ablate the programming of obesity70. The caveat here is that excessive weight loss during pregnancy may activate stress axis in offspring (e.g., cortisol secretion), which may have potential impact on offspring glucose tolerance70. Other potential adverse consequences of aggressive weight loss during pregnancy would be undernutrition, which, as noted before, may potentially worsen epigenetic effects and promote offspring obesity and adiposopathic consequences. Thus, rather than implementing a ‘crash diet’ once conception is discovered, a more favorable approach would be to achieve adequate weight loss in mothers with overweight or obesity prior to pregnancy, and ensure the weight loss is stabilized prior to conception. Children born to mothers who have experienced weight loss due to bariatric surgery may have decreased obesity risks and differential methylation patterns compared with their siblings born before the bariatric procedure71.

Overall, inadequately treated pre-conception overweight or obesity may lead to altered genetic signaling, and can thereby affect the health of offspring, including increasing the risk of overweight and/or obesity, as well as other illnesses, including diabetes mellitus, cardiovascular disease, cancer, and hormonal disorders72–74. In women with gestational diabetes mellitus, pregnant women with overweight or obesity may have increased transport of glucose, lipids, fatty acids, and amino acids to the fetus1. The excessive delivery of these nutrients may result in covalent modification of DNA and chromatin, affect stem cell fate, and alter postnatal biologic processes involved in substrate metabolism1^,72^,73^,75. All of these effects may help account for an increased risk of obesity or overweight in offspring, as well as an increased risk for metabolic and other diseases1^,72^,73^,75.

Implications for generational intervention

As noted before, aggressive weight management interventions should optimally occur sooner rather than later, and be focused on preventing obesity and its complications10. For individuals who are already overweight or obese, aggressive weight management is indicated to prevent the onset of a number of adiposopathic and fat mass diseases. If the complications of obesity are already present in patients with overweight or obesity, then aggressive weight management can improve, and sometimes reverse, these conditions1. These are management approaches with potential benefits for the individual. However, comprehensive weight management of both mother and father may have generational offspring health benefits as well (Figure 2). Thus, one might conclude that the optimal prevention of childhood and adult obesity would be aggressive treatment of the parents (and perhaps grandparents) prior to conception.

Figure 2. Dual approach towards improving obesity in individuals and generations.

As noted previously, the prevalence of obesity has risen dramatically in recent decades. Table 3 lists potential genetic etiologies for the rise in obesity prevalence, and Figure 1 describes the interconnectivity of genetic, epigenetic, and extragenetic inherited influences that may contribute to obesity and its complications. While many genetic abnormalities may not be generally preventable, an important first step in managing and potentially mitigating inherited epigenetic and extragenetic contributors is appropriate nutrition and increased physical activity1.

Despite the well documented positive outcomes associated with weight loss among patients with overweight or obesity, effective treatment of obesity as a disease remains a major challenge76–78. Clinicians play a critical role in screening and identifying patients with overweight or obesity, motivating them to take action, and engaging them in safe and effective weight loss treatments, which may include nutritional intervention, increased physical activity, behavior modification, weight management pharmacotherapy, or bariatric surgery1. Given its epidemic nature, obesity would also seem to provide an optimal opportunity for public health initiatives. Unfortunately, thus far, educational efforts, incentives to patients, and incentives to physicians by government agencies for improving patient outcomes79 have not proven successful in reversing the obesity epidemic1^,9^,80–84.

While isolated genetic inheritance resulting in obesity is not yet correctable via correction of the gene abnormalities (although the adverse consequences can sometimes be treated, such as leptin administration to genetically leptin deficient patients), and while public health initiatives addressing extragenetic causes have so far demonstrated limited benefit, the good news is that weight management interventions may not only improve the health of the individual with overweight or obesity, but may also improve the health of future generations (Figure 2). Adopting more favorable lifestyle habits may positively influence the familial/cultural/societal inheritance of extragenetic factors. Similarly, many epigenetic changes are potentially reversible, and thus the potential exists for improved health in offspring. Therefore, if interventions are effectively implemented in a global, life-course approach85, then it is conceivable that the obesity epidemic could undergo improvement as rapid as its onset. At a minimum, the potential for maternal epigenetic effects calls for highly aggressive nutritional and physical activity interventions before, during, and after pregnancy, especially among women with overweight or obesity, to mitigate these effects52.

Conclusions

Obesity is a complex disease and a global epidemic that directly and indirectly contributes to the most common metabolic and biomechanical diseases encountered in the clinical practice of medicine. Epigenetic dysregulation may contribute to the rapid increased prevalence in obesity and its complications. It is possible that aggressive weight management, nutritional intervention, and increased physical activity among parents before, during, and after conception may allow for improvement in the obesity epidemic and its adiposopathic consequences, for now, and for future generations.

Transparency

Declaration of funding

Sponsored focus for this review was funded by L-Marc Research Center. Editorial support for initial drafts was provided by Imprint Publication Science, New York, NY, USA, with funding from Eisai Inc.

Declaration of financial/other relationships

H.B. has disclosed that in the past 12 months his research site has received research grants from Amarin, Amgen, Ardea, Arisaph, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Merck, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, TIMI, VIVUS, and Wpu Pharmaceuticals. H.B. has disclosed that in the past 12 months he has served as a consultant and/or speaker to Alnylam, Amarin, Amgen, Astra Zeneca, Eisai, Eli Lilly, Merck, Novartis, NovoNordisk, Regeneron, Sanofi, and Takeda. W.S. has disclosed that she has served as a consultant for Optifast, and been a committee member of OPMC (Office of Professional Misconduct), expert witness for Bariatric Case Reviews and Medical Director of 3Pound Health, and serves as a speaker for Takeda, Covidien, and Eisai.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.