**About the Editor**

#### **Javier G ´omez-Ambrosi**

Javier Gomez-Ambrosi is a Researcher at the Metabolic Research Laboratory of the Cl ´ ´ınica Universidad de Navarra and Associate Professor at the School of Medicine in the University of Navarra, Pamplona, Spain. His main area of research is obesity and related morbidities, from a clinical and molecular point of view. His research combines basic research in experimental animals and cells with the clinical setting, trying to disentangle the pathophysiological mechanisms responsible of the impact of excess adiposity on the development of comorbidities. He has published more than 200 articles (h-index 58) and has been the PI in more than 20 research projects.

### *Editorial* **Recent Progress in the Management of Obesity**

**Javier Gómez-Ambrosi 1,2,3**


Obesity represents the most prevalent metabolic disease nowadays, posing a significant public health risk. This situation has led to a better understanding of the systems that regulate body weight and energy homeostasis. Obesity shortens life expectancy by increasing the risk of developing comorbidities such as type 2 diabetes (T2D), cardiovascular disease, fatty liver disease, and several types of cancer, among other conditions [1]. Reduced calorie intake and increased energy expenditure have traditionally been the cornerstones of the therapeutic strategy for patients living with obesity. Obesity-related comorbidities can significantly improve even with a small amount of weight loss [2]. This Special Issue includes some of the most notable progress achieved in recent years in the treatment of patients with obesity.

A better understanding of the ethiopathology of obesity should represent the pillar on which to base a good management for this condition. In this sense, in recent years, we have expanded our knowledge about the wide array of drivers that can facilitate or contribute to the development of obesity. Compiling most of these factors, the review by Catalán et al. summarizes many of the obesogens that may explain the increasing prevalence of obesity worldwide [3]. Besides "classical" direct causes, such as genetic and behavioral determinants of energy intake and expenditure, the review includes some less appreciated drivers of the excess adiposity epidemic, such as the microbiota, infectobesity, the influence of chronobiology, and the roles of endocrine disrupters, urban planning and climate change. Their review evidences the relevance of the "exposome" in the development and perpetuation of the obesity epidemic [3]. Archer and Lavie bring an interesting perspective according to which effective management strategies need a personalized approach that takes into account the subtyping of obesity phenotypes. They distinguish between acquired and inherited obesity. The former refers to the development of excessive adiposity after puberty; because acquired obesity is behavioral in origin, it can be responsive to dietary and exercise-based therapies. On the other hand, inherited obesity includes all types of obesities that occur before pubescence (infancy and childhood) and are present at birth, which would be less susceptible to treatment [4]. Having accessible tools that allow us to properly phenotype patients with obesity considering their cardiometabolic risk is essential to establish the most appropriate treatment [1]. In this sense, Sanchez et al. [5] describe the use of the measurement of skin autofluorescence (SAF), a non-invasive estimator of advanced glycation endproducts (AGEs), in patients with obesity. Although SAF correlates with body fat percentage estimated with the CUN-BAE [6], it is not increased in individuals with obesity, being more related to the presence of cardiometabolic risk factors. The authors suggest that SAF may represent a useful tool for the identification of individuals with unhealthy obesity, opening the door to new approaches to managing obesity in clinical practice [5].

A change in dietary habits is still the first step in the treatment of obesity. With a focus on components of the Mediterranean diet (MD) that may help to maintain proper mitochondrial function, Portincasa's group extensively reviews the benefits of this diet,

**Citation:** Gómez-Ambrosi, J. Recent Progress in the Management of Obesity. *Nutrients* **2023**, *15*, 2651. https://doi.org/10.3390/ nu15122651

Received: 23 May 2023 Accepted: 25 May 2023 Published: 6 June 2023

**Copyright:** © 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

providing cellular and animal models as well as clinical trials in individuals with metabolic syndrome assessing the efficacy of MD components on mitochondrial structure and activity [7]. On the other hand, a high intake of ultra-processed food (UPF) has been related to an increased risk of obesity and obesity-associated comorbidities. It has been debated for a long time whether ultra-processing itself is harmful or if UPFs just have a reduced nutritional content. Dicken and Batterham, in an exhaustive review, demonstrate that, consistently across different studies, adjustment for fat, sugar and sodium intake, or for adherence to a variety of healthy or unhealthy dietary patterns, has a very limited impact on the detrimental relationship between UPF intake and a diverse range of health-related outcomes [8]. These findings cast doubt on the claim that the negative effects of UPFs can be entirely attributable to their nutritional content and clearly suggest that features of ultra-processing are significant determinants that have an impact on obesity and on health in general [8].

Phase angle (PA) could be used as marker of health status in relation to nutrition, including in patients with obesity, to monitor the efficacy of weight loss and skeletal muscle mass preservation [9]. Basiri and colleagues show in this Special Issue that a treatment with nutritional supplements and diet education in addition to the standard care in patients with overweight or obesity and diabetic foot ulcers has positive ponderal and metabolic effects, including a tendency towards a lower decrease in PA. Given that an increase in PA is associated with a reduction in the risk of mortality in patients with diabetes, their findings may be considered clinically relevant [10].

Having tools capable of reliably predicting weight loss throughout a nutritional intervention has been shown to be very useful during dietary treatment in patients with overweight or obesity. Markovikj et al. report that a modification of the Wishnofsky equation, described several decades ago to determine the body mass loss in a dietary intervention based on the timeframe of energy intake reduction, accurately predicts weight loss in 100 adults with overweight or obesity under a ketogenic diet [11].

When lifestyle modification fails, and before considering bariatric surgery, pharmacological interventions should be considered as an alternative therapy for weight loss. In this sense, achieving a normal weight via long-term drug therapy with appropriate tolerability and safety has remained a difficult challenge until recently. However, in recent years, new drugs or combinations of thereof, for example semaglutide and tirzepatide, providing mean weight loss well above 10% and improving cardiovascular outcomes in patients with T2D give hope for the future [12]. The scoping review by le Roux's group reports that the results of the Semaglutide Treatment Effect in People with Obesity (STEP) trials confirm the efficacy of once weekly 2.4 mg semaglutide on weight loss in patients with obesity [13]. Although semaglutide produced some gastrointestinal-related side effects, it was in general safe and well tolerated. Given the effectiveness of the drug, the authors wonder if nutritional therapy may have to be redefined and indicated to achieve better health instead for weight loss [13]. An original study included in the Special Issue carried out by the same group tried to delve into the mechanisms by which the duodenal-jejunal bypass liner (endobarrier) induces more pronounced weight loss than a conventional dietary treatment in patients with obesity and T2D. They conclude that the greater weight loss was due to mechanisms other than a reduction in energy intake or a change in food preferences [14].

The outbreak of the COVID-19 pandemic and the lockdown that accompanied it had a very notable impact on our lives, as well as on our health [15]. Due to the lockdown, health providers were forced to increase the use of telehealth and telemedicine. Gilardini and colleagues investigated the interest of patients with obesity in taking part in a remotely delivered multidisciplinary program for weight loss [16]. According to their findings, males and elder people were more reluctant than females and younger people to be involved in an online nutritional intervention. They also conclude that the use of telemedicine in the management of obesity could reduce lost workdays and patient travel time, increasing the number of subjects who could receive treatment and improving treatment adherence [16].

Finally, Abeltino et al. describe the usefulness of Personalized Metabolic Avatar (PMA) to predict the response to a diet [17]. By means of deep learning, they develop a data-driven metabolic model, derived from the information provided by smart bands and impedance balances, which allows simulations of diet programs, allowing the setting of customized targets for obtaining optimal weight [17,18].

We have witnessed progress in the treatment of obesity in recent years with, for example, the advances mentioned above. However, much remains to be done and further research must be carried out to improve and optimize the management of patients with obesity and to increase their quality of life.

**Funding:** Supported by ISCIII–FEDER (PI20/00080) and CIBEROBN, ISCIII, Spain; and PC098-099 MEPERTROBE and Department of Health 58/2021, Gobierno de Navarra-FEDER, Spain.

**Conflicts of Interest:** The author declares no conflict of interest.

#### **References**


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## *Review* **Time to Consider the "Exposome Hypothesis" in the Development of the Obesity Pandemic**

**Victoria Catalán 1,2,3, Iciar Avilés-Olmos 4, Amaia Rodríguez 1,2,3, Sara Becerril 1,2,3, José Antonio Fernández-Formoso 2, Dimitrios Kiortsis 5, Piero Portincasa 6, Javier Gómez-Ambrosi 1,2,3,\* and Gema Frühbeck 1,2,3,7,\***


**Abstract:** The obesity epidemic shows no signs of abatement. Genetics and overnutrition together with a dramatic decline in physical activity are the alleged main causes for this pandemic. While they undoubtedly represent the main contributors to the obesity problem, they are not able to fully explain all cases and current trends. In this context, a body of knowledge related to exposure to as yet underappreciated obesogenic factors, which can be referred to as the "exposome", merits detailed analysis. Contrarily to the genome, the "exposome" is subject to a great dynamism and variability, which unfolds throughout the individual's lifetime. The development of precise ways of capturing the full exposure spectrum of a person is extraordinarily demanding. Data derived from epidemiological studies linking excess weight with elevated ambient temperatures, in utero, and intergenerational effects as well as epigenetics, microorganisms, microbiota, sleep curtailment, and endocrine disruptors, among others, suggests the possibility that they may work alone or synergistically as several alternative putative contributors to this global epidemic. This narrative review reports the available evidence on as yet underappreciated drivers of the obesity epidemic. Broadly based interventions are needed to better identify these drivers at the same time as stimulating reflection on the potential relevance of the "exposome" in the development and perpetuation of the obesity epidemic.

**Keywords:** obesogens; "exposome"; environment; epigenetics; microbiota; antibiotics; viral infection; sleep; endocrine disruptors; brown adipose tissue; thermogenesis

#### **1. Introduction**

If practitioners are asked about the current key public health challenges, in addition to the COVID-19 pandemic, many will mention obesity among the top priorities. The prevalence of obesity has tripled during the last decades, imposing an enormous burden not only on people's health, but also on society at large with obesity increasing worldwide [1–3]. Risk factor exposure, relative risk, and imputable disease burden have been addressed in a comprehensive and standardized way by the Global Burden of Diseases, Injuries, and Risk Factors Study [4]. A rigorous analysis of the trends and specific levels

**Citation:** Catalán, V.; Avilés-Olmos, I.; Rodríguez, A.; Becerril, S.; Fernández-Formoso, J.A.; Kiortsis, D.; Portincasa, P.; Gómez-Ambrosi, J.; Frühbeck, G. Time to Consider the "Exposome Hypothesis" in the Development of the Obesity Pandemic. *Nutrients* **2022**, *14*, 1597. https://doi.org/10.3390/nu14081597

Academic Editor: Jean-François Landrier

Received: 2 March 2022 Accepted: 8 April 2022 Published: 12 April 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

of risk factor exposure together with a quantitative assessment of the plausible human health effects is of utmost importance. In this context, deep knowledge is required about when current efforts are being inadequate as opposed to when public health initiatives are showing fruitful effects. Identifying the ecological factors and external drivers of change that are currently tipping the balance may prove extraordinarily useful. This approach represents a biomedical challenge and public health need. Thus, it is worthwhile considering the conceptual basis to better understand alterations at the population level as well as their potential interaction with the surrounding with an innovative perspective on, as yet, underappreciated but conceivable factors. A search for original articles and reviews published between January 1990 and February 2022 focusing on causes and contributors was performed in PubMed and MEDLINE using the following search terms (or combination of terms): "obesity", "epidemic or pandemic", "comorbidity or comorbidities", "outcomes", "mortality", "drivers", "sedentarism", "physical inactivity", "environment or environmental", "antibiotics", "microbiota", "genetics", "epigenetics", "viral infection", "infectobesity", "sleep", "chronobiology", "obesogens", "endocrine disrupters", "thermogenesis", "urban planning", "climate change" and "exposome". Only English-language, full-text articles were included. Additional articles that were identified from the bibliographies of the retrieved articles were also used, as well as selected very recent references from March 2022. Articles in journals with explicit policies governing conflicts-of-interest, and stringent peer-review processes were favored. Data from larger replicated studies with longer periods of observation, when possible, were systematically chosen to be presented. More weight was given to randomized controlled trials, prospective case–control studies, meta-analyses and systematic reviews.

Up-to-date our thinking on the obesity epidemic has focused mainly on direct causes, such as genetic and behavioral determinants of energy intake and expenditure [5,6]. The combination of increased sedentarism and life expectancy have contributed to the obesity epidemic and its comorbidities with people exhibiting a poorer physical function [7–9]. Exercise produces extraordinarily complex physiological responses at the same time as inducing changes in cellular energy balance, leading to intensity-dependent activation of AMP-activated protein kinase (AMPK) in skeletal muscle [7,10], via effects on diverse intramuscular and hormonal factors adaptations to increased physical activity include amelioration of the cardiorespiratory fitness, as shown by an augmented maximal oxygen uptake together with an elevated muscle oxidative capacity promoted by an increased mitochondrial biogenesis and angiogenesis. Elicited signals include enhanced catecholamine signaling, sarcoplasmic calcium release, changes in mechanical stretch and force, metabolic alterations, disruptions to the redox state and acid–base balance, increased muscle temperature, and increased circulating adrenaline concentrations. These signals operate on transmembrane receptors, thereby activating downstream signaling pathways, or directly stimulate the release of exercise-responsive signaling molecules. Interestingly, exercise stimulates the secretion of metabolites, extracellular vesicles, and myokines that enable crosstalk with other organs, like adipose tissue, pancreas, liver, heart, gut, and brain as well as the vascular and immune systems.

When focusing on the time scale, two quite diverse influences can be distinguished that exert their effects on ingestive behavior, as well as on other aspects of energy homeostasis [11]. The evolutionary time frame, on the one hand, determines the selection of metabolic and behavioral traits embedded within a concrete genome. Famine, as a continuous peril to survival, has led to the selection of the so-called "thrifty genes". Within a given environmental context, this thriftiness can be manifested at different levels, such as (i) the 'energy-sparing' metabolism to increase efficiency (metabolic), (ii) the proclivity to quick adipose tissue accretion (adipogenic), (iii) the capability to slow down or even switch off non-essential processes (physiologic), (iv) the propensity to hastily swallow available food (gluttony), (v) the proneness towards sedentarism to spare or conserve energy (sloth), and, finally, (vi) behavioural adaptations that can even result in selfish hoarding to warrant survival (Figure 1).

**Figure 1. Schematic diagram of the factors involved in energy homeostasis.** The classical Venn diagram shows how in obesity the intersection between increased food intake, nutrient absorption, and fat accumulation, together with decreased energy expenditure, the main factors determining energy homeostasis, are simultaneously under the broader influence of the environment as well as genetics and epigenetics.

The life-course time frame, on the other hand, is responsible for determining the phenotype. The early embryo's nutritional environment can exert major influences on its survival as well as on its short- and long-term physiological milieu. Thereafter, fetuses are still susceptible to nutritional intake, determined via the utero-placental unit and the maternal energetic supply. Through childhood, the adaptive plasticity is maintained and continues into adolescence and adulthood. Thereby, satiety and appetite, which encompass ingestive behavior, underlie a huge array of adaptations aimed first at survival. Thus, our "thrifty genes", the "nutrition transition", and the "technology-driven sedentariness" have been the main causes blamed, with regard to the obesity epidemic. However, recent mounting evidence obtained in diverse scientific settings is challenging this view. This narrative review reports the available evidence on the potential relevance of the "exposome" and the impact of yet underappreciated drivers of the obesity pandemic.

#### **2. Emerging Evidence Working as Warning Signs**

The past half-century has witnessed a particularly rapid increase in obesity, localized initially in high-income countries and urban settings, but also spreading, subsequently, to both low- and middle- income countries, as well as rural areas [3,12]. In this context, a conceptual framework may need to be put forward, focusing on more profound drivers embedded within society together with their interaction with biological, psychological, and socioeconomic processes.

#### *2.1. Genetics*

Rare, severe, early-onset monogenic obesity is often opposed to common or polygenic obesity as polarized and quite distinct entities. Studies for both forms of obesity, however, report shared genetic and biological underpinnings, thereby highlighting the pivotal role of the brain in body weight control [6]. New insights come from genome-wide association studies (GWAS) which are characterized by advanced sequencing technology in huge sample sizes. Moreover, cross-disciplinary post-GWAS approaches, combining novel analytical techniques and omics technologies, are opening new ways of understanding, and fostering the translation of genetic loci into meaningful biological pathways.

Genome-wide association scans for obesity-related traits have shown small size effects of the implicated genes that can be even reversed by physical activity [13–17]. Additionally, obesity appears to spread more through social than family ties [18], thereby further decreasing the relative relevance of genetics. On the contrary, the human genome is regulated via epigenetics whereby concrete ecological exposures bear risk for excess weight and associated comorbidities [19–24]. Given that survival of organisms is determined by the adequacy of nutrient intake to parallel energy expenditure, excess adiposity originally emerged as an advantageous developmental plasticity adaptation encompassing both intrauterine and intergenerational effects that bear maladaptive consequences in the current inappropriate scenario. While maternal nutrition and metabolism were well-established critical determinants of adult offspring health, adverse offspring outcomes are also reportedly associated with the father's diet [25,26], thereby indicating non-genetic inheritance of paternal influence. In this sense, men with moderate obesity display distinct DNA methylation profiles as well as small non-coding RNA expression in sperm [27]. However, it is unknown to what extent epigenetic influences on gametes impact on the metabolic profile of the progeny. Moreover, lately, reproductive performance changes have taken place, including higher fertility among people with elevated fatness and increasing maternal age [28]. A noteworthy point is that the mother's age influences excess weight risk via its impact on birth weight, whereby older women are at risk of delivering either larger or smaller babies as would be expected according to their gestational age, a circumstance that, in turn, augments the chances of originating adults with excess weight. In fact, the pregnant mother's age and body mass index (BMI), as well as the father's, together with the natal weight, the post-natal weight, and fat depot gain profiles reportedly exert an impact on the offspring's life [29].

Assortative mating, i.e., the non-random mating of people as regards their phenotype and cultural factors, may have further contributed to the obesity epidemic [30]. The shift in the development of obesity earlier in time allows the univocal identification of partners with a specific phenotype concerning weight already in the late teens and early twenties [31]. Thus, the increase in excess weight evidenced recently in descendants may also relate to the impact of both simple and complex interactions on the non-random coupling of people based on BMI. People with high adiposity may go out with people with a similar phenotype and may be more comfortable as well as be attracted by persons with the same physical characteristics rather than by those with a normal weight. In addition, sharing the same sociocultural interests among people with similar BMI may also take place. Whilst matching of couples with excess body fat may accentuate the genetic susceptibility in the progeny, the underlying mechanism is still unclear [32]. Interestingly, married couples formed by people with elevated BMI already at school age have been shown to tend to increase alongside the excess weight pandemic, that, in turn, can elevate the progeny's susceptibility to obesity [32].

#### *2.2. Microbiome*

The gut microbiome has also proven to be a key player in energy homeostasis [33,34], whereby specific gut microbial communities may be contemplated as another plausible factor for obesity development. Broad modifications in the gut microbiome have been evidenced in people with excess weight, which are reactive to changes in body weight [35–38]. Although a huge interindividual variability has been observed, in obesity, an overall reduction in microbial diversity, together with a particular decreased amount of *Bacteroidetes* at the same time as a consequent elevation of *Firmicutes*, have been reported. More precisely, observational obesity studies indicate less gut bacterial diversification with augmented levels of *Bacteroides fragilis*, *Fusobacterium, Lactobacillus reuteri,* and *Staphylococcus aureus*, at the same time as a lower representation of *Lactobacillus plantarum, Methanobrevibacter, Akkermansia muciniphila*, *Dysosmobacter welbionis*, and *Bifidobacterium animalis* in people living with obesity as compared to non-obese persons [38,39]. Mechanistically, the microbiome of people living with obesity has been associated with increasing energy-harvesting efficiency

from the diet and alterations in gut permeability leading to metabolic endotoxemia, as well as changes in host gene expression that regulate inflammation, insulin resistance, fat storage, and fatty liver [40–42]. Latest findings indicate that microbiomes obtained from people with normal weight and obesity are different in how they interact with the host and its metabolism [43].

#### *2.3. Infectobesity*

Infection is getting more attention as a possible cause or inducing factor of obesity. The supporting findings come from both epidemiological data and the biological plausibility derived from the direct roles of some viral agents on reprogramming of the host's metabolism towards adipogenesis. Over the past decades, evidence has been growing with regard to an increased incidence in children and adults living with obesity of both nosocomial and community-acquired infections, suggesting that specific infections may be involved in the development of obesity [44]. More recently, the COVID-19 syndemic has further shown how people living with obesity are more likely to become infected with the coronavirus SARS-CoV-2 and exhibit an elevated risk of hospitalization, complications, and mortality, in probable relation to an altered immune response to infection, a chronic low-grade inflammation, together with an increased cardiometabolic risk [45–48].

Viral infections, as well as by other microorganisms, have been put forward as a plausible explanation for the excess weight epidemic with the concept of "infectobesity" harbouring the possibility that some viruses and microbes may wield an etiological role in the development of obesity [49–52]. The specific impact of excess weight on the risk of infections and the immune response triggered by infections has been addressed in a small number of studies in the population with obesity [44,53,54]. It is noteworthy that obesity augments the susceptibility to infections via an impaired immune response [55]. In addition, excess weight can also affect the pharmacokinetics of antimicrobial drugs as well as the response to vaccines [56,57]. A direct role on the host's metabolism reprogramming towards adipogenesis has been put forward as a causative or inducing factor of obesity. The existence of circulating antibodies against certain infectious agents (e.g., *Chlamydia pneumoniae* and adenovirus-36) has been associated with the suffering of excess weight [58,59]. Viral agents involved in the genesis of obesity can be classified into five main categories expanding from *Adenoviruses* and *Herpes* viruses to phages, slow viruses of transmissible spongiform encephalopathies, and other encephalitides, as well as hepatitides. Of all the viruses analyzed, adenovirus-36 (Ad-36) emerged as an appropriate candidate, according to clinical and modelling data [60]. Although mechanisms by which this adenovirus may prompt excess weight development need to be fully unraveled, it has been postulated that weight gain occurs via a direct adipogenic effect, whereby Ad-36 enters adipocytes modifying enzymatic and transcriptional factors leading to triacylglycerol accretion, increased oxidative stress, inflammation, and differentiation of preadipocytes into mature adipocytes [61,62]. A potential link between Ad-36 and obesity-related nonalcoholic fatty liver disease (NAFLD) development relies on leptin gene expression and insulin sensitivity reduction, glucose uptake increase, lipogenic and pro-inflammatory pathway activation in adipose tissue, and macrophage chemoattractant protein-1 elevation [63]. The possibility of the exchange of components of the microbiota, including the virome and virobiota, should not be discarded. In this context, the gut microbiota reportedly sustains intrinsic interferon signaling [63].

Of note, under persistent viral infections, the adaptation of the host's metabolism and immunity may be jeopardized. In addition to fructose-rich diets, decreased insulin sensitivity, chronic systemic low-grade inflammation and mitochondrial alterations, and gastrointestinal microbiota are reportedly involved in the development and worsening of NAFLD [64–66]. Due to the affected hepatic metabolism, the secretion of organokines (adipokines, myokines, hepatokines, and osteokines, among others) can be altered [67]. Changes in the secretion pattern of hepatokines can indirectly or directly contribute to aggravating NAFLD. In particular, reciprocal alterations with a decrease in fibroblast

growth factor (FGF) 19 and an increase in FGF21 concentrations have been reported in obesity [68,69]. Plausible organ-specific changes in the reactiveness to the FGFs are characteristic in excess weight with adipose and hepatic changes taking differing directions in β-Klotho expression.

#### *2.4. Chronobiology*

Energy balance conservation constitutes a dynamic process with circadian rhythmicity acting as a "timekeeper" playing a decisive role in systemic homeostasis [70]. Under physiological circumstances, clock-primed biological functions synchronize to anticipate daily demands to warrant survival. Light exposure, physical activity, and sleep patterns, as well as meal timing and composition are common factors involved in energy homeostasis. It is noteworthy that the disruption or desynchronization of these factors can favor the genesis of a wide number of non-communicable diseases (NCDs), among them obesity and its comorbidities [71]. Chronological features delineate the integration in time of prediction by clock genes and metabolic and bioenergetics reactions to nutrients, whereby molecular chronotypes might be further participating in the genesis of obesity.

The internal clock makes the organism ready for regular physiological functions, such as eating and sleeping, with alterations in clock priming causing disturbances in biological rhythms and metabolism [72]. The worldwide obesity prevalence increases and metabolism alterations concur with sleep debt together with an increase in shift work as well as night exposure to light [73–76]. Sleep curtailment, as well as alterations in the chronobiology, foster elevations in BMI and sabotage dietary efforts to diminish adiposity [77]. Lack of sleep was reportedly followed by augmented hunger, elevated circulating ghrelin concentrations, and decreased circulating leptin levels, when their energy intake was restricted, as opposed to when people were in positive energy balance. Moreover, reduced sleep reportedly impacts on numerous neuroendocrine signals coordinating substrate use such as the concentrations of catecholamines, thyroid, cortisol, and growth hormone. Sleep privation and sleep alterations relate to maladaptation of the hypothalamic–pituitary–adrenal axis, translating into increased production of glucocorticoids [78,79], which can compromise the immune system [80] and increase abdominal obesity in the long term [81]. It has been recently shown that people with excess weight curtailing their sleep regularly experienced a negative energy balance by extending their sleep duration in a real-life scenario [82]. A better knowledge of the interaction between circadian rhythm disturbance and energy homeostasis may help to explain the pathophysiological processes fundamental to weight gain, thereby paving the path towards identifying novel therapeutic approaches.

#### *2.5. Endocrine Disrupters–Obesogens*

The hypothesis relating to the evolutionary origination of well-being and sickness stems from decades ago [83,84]. Subsequently, diverse epidemiological studies evidenced the relation between maternal obesity while pregnant and the possibility of the progeny to develop certain chronic adult diseases or NCDs. Among the plausible underlying mechanisms, early developmental insulin resistance stands out. Additional factors include an increased placental nutrient transfer and fetal exposure to endocrine-disrupting chemicals (EDCs), which cross the placenta, exhibit diverse tissular bioaccumulation levels, and show gender-specific vulnerability, with male fetuses being more vulnerable than female ones [85,86]. In utero environment modifications may also underlie the transmittable epigenetic changes that can endure over various generations, thereby supporting the rationale for disease development later in life. Accumulating evidence shows that EDCs interfere with endocrine regulation and metabolism, leading to lifestyle-related cardiometabolic risk factors [87,88].

Interestingly, EDCs are widespread in the environment and our daily life, with exposure encompassing the air and foods, as well as habitual items as close as personal care products [89]. Whilst the effects of individual compounds have been extensively studied, the combination of chemicals needs to be analyzed in more detail to better understand

the realistic landscape of exposure to EDCs. While a dose-response relationship has not been clearly established and may not always be predictable, accumulating evidence shows that already low exposures taking place in daily life may exert a notable impact on the individual's susceptibility [90]. Moreover, in utero EDCs exposure exerts transgenerational effects reaching even the F4 generation [23]. EDCs impinge on pre- and postnatal growth, metabolism, body weight control, thyroid function, sexual development, puberty, and reproduction, among others. Though the exact mechanisms of how phenotypic features are transferred from an exposed organism to the progeny remain largely unknown strong evidence is mounting regarding a variety of epigenetic mechanisms including differential methylation of both DNA and histones, together with histone retention, non-coding RNAs expression and deposition, as well as chromatin organization and structure changes [23].

Obesity is positively associated with the exposure to EDCs [87,91]. The hypothesis of obesogens in the environment purports that pollutants of a chemical nature have the capacity to induce excess weight modifying metabolism and homeostatic set-points, affecting appetite regulation, altering lipid metabolism to stimulate adipocyte hypertrophy, and promoting adipogenic pathways aimed at fat cell hyperplasia, thereby predisposing, initiating or exacerbating weight gain [92,93]. Phthalates, per- and polyfluoroalkyl substances, polycyclic aromatic hydrocarbons, bisphenol A (BPA), heavy metals (cadmium, arsenic and mercury), and pesticides are well-known EDCs [94]. Important concepts regarding the potential impact of EDC include window and duration of exposure, role of combinations or mixtures, transgenerational effects, and epigenetic mechanisms. EDCs interrupt hormonal signaling, alter adipocyte differentiation, and interfere with metabolism, in particular during early developmental stages for several generations [94]. Various EDCs like BPA, diethylstilbestrol, phthalates and organotins, to mention a few, can interfere with signaling by targeting pathways of nuclear hormone receptors (glucocorticoid receptors, sex steroid, retinoid X receptor, and peroxisome proliferator-activated receptor γ) relevant to adipocyte proliferation and differentiation. At the adipocyte level, this is achieved by disrupting body weight homeostasis promoting long-term obesogenic changes with the epidemiological impact that can be multiplied when the interference takes place in moments of particular sensitivity like the fetal period and childhood. Thus, individuals exposed to obesogens may be preprogrammed towards an adipogenic fate worsened by socioeconomic circumstances favoring unhealthy diets as well as insufficient physical activity that promote poor diet and inadequate exercise and struggle lifelong to maintain a healthy weight. It is of note that BPA, polybrominated diphenyl ethers, phthalates, together with perfluoro products have been steadily increasing their levels in humans establishing a specific connection among adipogenic phenotypes with exposure and transcriptional network control [95].

The metabolism of xenobiotics is commonly viewed as a process of detoxification, but occasionally the metabolites of some compounds, which are usually inert or harmless, can become biologically active [96]. EDCs, in addition to stimulating adipogenesis and lipogenesis, can also repress lipolytic signaling, thereby inducing altered phenotypes [97]. Neurohormonal regulation of lipolytic rate classically underlies catecholamine-induced activation and insulin-stimulated suppression [98]. However, a large number of lipolytic mediators include mitogen-activated protein kinase, AMP-activated protein kinase, atrial natriuretic peptides, adipokines, and structural membrane proteins [99–105]. Among the latter ones, aquaglyceroporins (AQP3, AQP7, AQP9, and AQP10) represent a subfamily of aquaporins participating in glycerol movement across cell membranes. Due to their glycerol permeability, aquaglyceroporins are involved in energy balance. Glycerol influx and efflux control in metabolically relevant organs by aquaglyceroporins plays a pivotal role with the dysregulation of these glycerol channels being associated with metabolic diseases, such as obesity, insulin resistance, non-alcoholic fatty liver disease, and cardiac hypertrophy [106]. In fact, glycerol embodies a key metabolite as a substrate for de novo synthesis of triacylglycerols and glucose as well as an energy substrate for ATP production via mitochondrial oxidative phosphorylation. Noteworthy, the control of glycerol release by aquaglyceroporins in adipocytes plays a pivotal role in energy homeostasis reportedly

associated with NCDs, such as insulin resistance, and obesity [107]. The potential interference of EDCs with a number of lipolytic factors deserves further analysis. Furthermore, EDCs also disrupt activity of brown and beige fat, the thermogenic adipose tissues [108].

Given the habitual exposure to multiple EDCs, the assessment of public health effects is complicated. In this respect, special care during pregnancy and childhood would be desirable. Sound knowledge about plausible mechanistic explanations on how specific exposures in a given environment translate into making individuals more susceptible to suffer some diseases like obesity [23]. Adequate determination of the surrounding toxicology together with its derived health risks might be achieved via advanced computational and prediction tools, and investigations of both systematic and integrative approaches further validating novel reliable metabolic biomarkers. Additionally, integration efforts aimed at mimicking the surrounding's specific circumstances are needed in new studies pursuing the evaluation of the effects of EDCs.

#### *2.6. Urban Planning*

Interestingly, urban environment characteristics may also contain upstream drivers of obesity [109,110]. Nonetheless, consideration of the simultaneous combination of environmental factors is not normally addressed. When looking at the same time at 86 elements characterizing the urban "exposome" relating to BMI via geocoded exposures including individual home addresses, traffic noise, air pollution, built environment, and green-space, as well as neighborhood socio-demographic factors, relevant insight can be obtained. Exposure-obesity associations were identified after adjustment for individual socio-demographic characteristics. Associations of BMI with the mean neighborhood house cost, food facilities within a close reach, oxidation capacity of particulate elements, air pollution, low-income neighborhoods, and one-person households exhibited the strongest consistency [109]. BMIs were more elevated in low-income neighborhoods, in people with lower mean house cost, lower proportion of single-people households, and areas with lower numbers of healthy food facilities. The holistic analysis of the obesogens of the environment emphasizes the mounting information as regards the relevance of socioeconomics, urban planning, and air pollution as regards the neighborhood.

#### *2.7. Climate Change*

Global warming is a well-known public health challenge and bidirectional influences regarding adiposity and global warming have been established [111]. Since 1950, carbon emissions worldwide have increased at an exponential rate. Transport, construction, manufacturing, housing, forestry, and agriculture modifications, together with the world population increase in important obesity rates, can be considered as principal contributors to carbon emissions. With increasing atmospheric temperature, less adaptive thermogenesis can be expected in people with obesity who may simultaneously be less physically active, at the same time as increasing their carbon footprint. Thus, over the last centuries environmental influences like an increase in ambient temperature in relation to climate change and global warming together with transportation, temperature insulation of both edifices, and individuals have decreased the necessity of people to generate energy by inducing thermogenesis. Therefore, it is important to consider the environmental impact of the rising obesity rates to learn more about how to tackle the excess weight pandemic, at the same time as how to minimize energy consumption, food waste, greenhouse gas emissions, in general, and carbon footprint, in particular. Of note, the Mediterranean diet, which is characterized by low in meat intake, reportedly reduces by 72% greenhouse gas emissions, by 58% land use, and by 52% energy consumption [111].

In this context, it is important to consider that human fat consists mainly of white adipose tissue (WAT) and brown adipose tissue (BAT) [112]. Whereas WAT stores energy surplus and releases it according to the needs of the organism, BAT converts it to heat playing a role in body temperature control [113–117]. Patches of brown-like adipocytes that appear in WAT constitute beige fat [118]. Like BAT, beige fat also represents a further

thermogenic adipose depot with increased levels of thermogenic genes and respiration rates. Interestingly, beige adipocytes, also termed brite (derived from the contraction of "brown-in-white") cells, resemble white adipocytes in the basal state, but are rich in mitochondria and release heat when activated in response to thermogenic stimuli [119]. Thus, beige or brite adipocytes exhibit a distinct gene expression pattern to that of brown or white fat cells. The worldwide temperature increase might be also playing a role in the obesity epidemic via a concomitant reduction in BAT activity [120]. BAT as well as beige fat have been greatly underestimated in adults. For many years the BAT contribution in adults to energy expenditure both in terms of amount and effectiveness was presumed to be trivial due to the presence of only marginal brown fat depots [114]. BAT and beige fat express uncoupling protein 1 (UCP1), which rapidly generates heat when activated. UCP1 is stimulated by cold-exposure and diet leading to increased activity of the sympathetic nervous system as well as oxidation of huge quantities of glucose and lipids. The identification of functional BAT in adult humans that can be stimulated by cold exposure has changed our understanding of cellular bioenergetics, especially with regard to adaptive thermogenesis in humans [113–117].

Whilst BAT research has mainly addressed its participation in non-shivering thermogenesis, the identification of its highly dynamic secretory capacity has revealed its endocrine and paracrine function via the release of "batokines" [121]. These plentiful BAT-derived molecules impinge on the physiology of diverse cell types and multiple organ systems like adipose tissue, skeletal muscle, liver, and cardiovascular system, among others [122]. Interestingly, the variety of signaling molecules encompassed by batokines extends from peptides and lipids to metabolites and microRNAs [123]. Further research in humans aimed at delineating the role of batokines beyond the BAT-mediated energy expenditure is required. Among the endocrine batokines peptide factors like adiponectin, FGF21, interleukin-6, neuregulin-4, myostatin, and phospholipid transfer protein, as well as some microRNAs like miR-92a and miR-99b, stand out, whereas the lipids include lipokines, bioactive compounds, derived from adipose tissue, that regulate diverse molecular signaling pathways. Recently, an oxylipin, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), has attracted interest. The elevation in serum 12,13-diHOME has been associated with improved metabolic health with the action of this molecule appears to be mediated by brown adipose tissue (BAT). Its circulating concentrations are negatively correlated with BMI and insulin sensitivity. Exposure to cold and physical exercise result in an increase in circulating levels of 12,13-diHOME, which promotes browning of WAT and stimulates fatty acid absorption by BAT via stimulating the translocation of the fatty acid transporters CD36 and FATP1 to the cell membrane [124,125]. Moreover, the existence of other as yet unidentified factors involved in energy balance regulation should not be discarded [126,127].

#### *2.8. Plurality of Obesity Epidemics*

A noteworthy, elegant cross-species analysis has clearly shown a plurality of epidemics of excess weight among domestic mammals, even without the presence of the elements characteristically conceived as the main predetermining factors of the obesity epidemic via their impact on lifestyle habits like diet and physical activity [128]. These findings indicate that excess weight genesis over the last decades depends on the confluence of additional yet underappreciated environmental influences.

#### **3. The "Exposome" as a Plausible Underlying Mechanism of Action**

The word "exposome" stands for the assessment over the whole life of a person of all the exposures and its relationship to disease. This concept has been fostered by the success in mapping the human genome [129,130]. Of note, the exposure of a person starts at conception and in utero, continuing over childhood and adolescence (Figure 2). Job-related insults as well as influences from leisure time and the environment further accumulate during adulthood progressing up to senescence. Many single nucleotide polymorphisms

(SNPs) are genetic variants of low penetrance involved in the control of food intake, body weight, and lipid metabolism, among others.

Despite their low penetrance, the SNPs' high prevalence implies a potential substantial contribution to the disease burden at the population level. This means that in a concrete exposure scenario the majority of SNPs, although being of low penetrance, will emerge because of strong environmental influences. While exposures of the surrounding exhibit an exceedingly relevant protagonism in the development of NCDs, a clear association is not easy to unravel. The "exposome" will be best deciphered by obtaining deeper knowledge on how dietary and lifestyle exposures interplay with the individual's unique genetic, epigenetic, and physiologic characteristics translate into disease. In this scenario, the "exposome" can be contemplated from a conventional point of view, in which insults are randomly distributed along the whole lifecycle, or with the lens of the critical window exposure, in which insults are non-randomly allocated to specific time-periods during life [131]. Improvement in disease etiology identification at the population level will come from complementing the emphasis on genotyping by a detailed analysis of the plentiful environmental exposures [132,133], with its accurate assessment remaining a formidable and pending demand in obesity assessment. Moreover, the development of methods that accurately capture both the external environment as well as the internal chemical background of the individual are urgently needed (Figure 3). In order to complement the "genome" with its matching "exposome" the same precision for an individual's environmental exposure as we have for the subject's genome should be pursued.

**Figure 3. Characterization of the "exposome".** The "exposome" of a given person represents the combined exposures from all external sources that reach the internal chemical environment. Specific biomarkers or potential signatures of the "exposome" might be detected in the bloodstream.

#### *Need for an Integral Consideration of the Collective Impact of Simultaneously Acting Drivers*

Contrarily to the genome, the "exposome" is subject to a great dynamism and variability, which unfolds throughout the individual's lifetime. The development of precise ways of determination that capture the full exposure spectrum of a person is extraordinarily demanding. These considerations are particularly relevant for children and adolescents with obesity, given that the increased exposure is expected to translate into larger adverse effects than weight gain only during adulthood [134,135]. Furthermore, the concept of epigenetics comprises the study of changes in the organism caused by alterations in gene expression rather than modifications of the genetic code itself [136,137]. Interestingly, epigenetic marks can be affected by air pollution, organic pollutants, exposure to benzene, metals, and electromagnetic radiation. Other potential environmental stressors capable of changing the epigenetic landscape include chemical and xenobiotic compounds present in the atmosphere or water.

Moreover, while responses to certain specific exposures are invariable, to other external insults responses may change ("resposome"), with disparity depending on genome and epigenome changes (Figure 4). While some alterations reveal chronicity in exposure, certain cases reveal a latent response, based on "priming" for a late pathogenesis via epigenetic changes.

Analysis of the current human "exposome" emphasizes the challenges represented by the concepts of lifelong exposure and the need to compute all environmental factors in order to obtain the whole real life exposomic scenario [131]. To overcome these limitations and establish the relation between human health and the "exposome" focusing on critical-window periods can be combined with data- and hypothesis-driven exposomics. Moreover, analysis of high-throughput and multidimensional data of both internal and external exposure factors are welcome [131]. Useful tools to analyze the "exposome" and foster exposomics should comprise different steps, i.e., (i) the development of biomarkers capturing exposure effect, susceptibility to exposure, and disease progression; (ii) the application of advances that integrate systems biology with environmental big data; and (iii) exploratory data mining to analyze the relationships between exposure effects, and other factors that ultimately lead to obesity development and thereby provide potential mechanistic information (Figure 5). Artificial intelligence will broadly reshape medicine, thereby improving the experiences of both patients and clinicians. In fact, artificial intelligence is already being applied in an ever-increasing number of medical fields moving from what might have been considered speculation years ago to reality right now. Progress in data analysis, including image deconvolutions, non-image data sources, unconventional problem formulations, sophisticated algorithms, and human–artificial intelligence collaborations, will reduce the gap between research and clinical practice. While these challenges are being addressed, artificial intelligence will develop exponentially, making healthcare more accessible, efficient, and accurate for patients worldwide [138].

**Figure 4. Factors influencing the resposome.** Schematic diagram on how the genetic predisposition (genome) interacts with the environmental exposure ("exposome") to influence an individual's genetic and acquired susceptibility shaping its responses (resposome) that yield the ultimate health outcome as regards body weight control.

**Figure 5. Evolution of the individual's genetic and environmental framework across the lifespan.** Over a lifetime, genetic and environmental influences may change reciprocally with acute and chronic exposures translating into a specific information with predictive interest as well as effective biomarkers that may provide mechanistic insight of pragmatic application.

In order to be particularly helpful, "exposome" assessment should combine GWAS together with epigenome-wide association trials and detailed metabolic-endocrinological phenotyping of the individuals. Moreover, these combined analyses should be applied at multiple time-points to establish the potential interaction effect. The large amount of data on exposures provided by these projects hinders the interpretation of their relationship with health outcomes and omics. In this regard, similar or parallel databases to genetics (OMIN, dbSNP, or TCGA) may be developed for exposomics. Together with handling and archiving large data volumes, the lack of standard nomenclature, the quality of output from each analytical platform, or the heterogeneity of data constitute important issues to be resolved. Given the important public health problem posed by the rise in NCDs like obesity, the presented proposal of integration of elements that constitute the "exposome" will strengthen the better comprehension of the intricate underlying mechanisms, thereby opening pathways to innovative preventive and therapeutic strategies.

#### **4. Conclusions**

The more simplistic energy balance model of obesity has been surpassed by epidemiological, biological, psychological, and socioeconomic evidence. Far-reaching holistic modelling of obesity is required in order to establish effective interventions aimed at its efficient treatment and better prevention. The origins of excess weight are rooted in an extremely complicated biological network, set within a similarly intricate societal and environmental organization (Figure 6), which needs to be carefully considered.

**Figure 6.** Multidimensional view of the complex interaction of the main drivers involved in excess weight development and obesity-associated comorbidities. OSA, obstructive sleep apnea; MAFLD, metabolic-associated fatty liver disease; T2D, type 2 diabetes; CVD, cardiovascular diseases.

Analysis of alternative and less researched etiologies is needed. The gut microbiome, circadian rhythms, and infectobesity, to mention only a few, constitute other candidate alternate etiologies. More multidisciplinary, translational research must analyze the intricacies of such alternate etiologies, as well as develop unprecedented stratagems for fending off a multifactorial and plurietiological pathology via, for example, prioritization of root cause interrogation and group risk assessment. Knowledge gaps persist in this relevant area whereby a comprehensive, leveraged patient-centered research would be welcome. Due to the struggle in the coming years to override the key factors steering the present excess weight epidemic, an inclusive, detailed, pro-active, durable program and fresh perspectives to unravel the whole panoply of causative factors is needed to outline a feasible counter reply to manage the defiance imposed by the pandemic. A comprehensive understanding of the causative factors of obesity might provide more effective management approaches.

**Author Contributions:** Conceptualization and first draft, G.F. Writing and editing, V.C., I.A.-O., A.R., S.B., J.A.F.-F., D.K., P.P., J.G.-A., G.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was funded by the Spanish Institute of Health ISCIII (Subdirección General de Evaluación and Fondos FEDER project PI19/00785, PI19/00990, PI20/00080 and PI20/00927), and CIBEROBN. Funding sources had no role in manuscript writing or the decision to submit it for publication.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**Edward Archer 1,\* and Carl J. Lavie <sup>2</sup>**


**Abstract:** The etiology of obesity is complex and idiosyncratic—with inherited, behavioral, and environmental factors determining the age and rate at which excessive adiposity develops. Moreover, the etiologic status of an obese phenotype (how and when it developed initially) strongly influences both the short-term response to intervention and long-term health trajectories. Nevertheless, current management strategies tend to be 'one-size-fits-all' protocols that fail to anticipate the heterogeneity of response generated by the etiologic status of each individual's phenotype. As a result, the efficacy of current lifestyle approaches varies from ineffective and potentially detrimental, to clinically successful; therefore, we posit that effective management strategies necessitate a personalized approach that incorporates the subtyping of obese phenotypes. Research shows that there are two broad etiologic subtypes: 'acquired' and 'inherited'. Acquired obesity denotes the development of excessive adiposity after puberty—and because the genesis of this subtype is behavioral, it is amenable to interventions based on diet and exercise. Conversely, inherited obesity subsumes all forms of excessive adiposity that are present at birth and develop prior to pubescence (pediatric and childhood). As the inherited phenotype is engendered in utero, this subtype has irreversible structural (anatomic) and physiologic (metabolic) perturbations that are not susceptible to intervention. As such, the most realizable outcome for many individuals with an inherited subtype will be a 'fit but fat' phenotype. Given that etiologic subtype strongly influences the effects of intervention and successful health management, the purpose of this 'perspective' article is to provide a concise overview of the differential development of acquired versus inherited obesity and offer insight into subtype-specific management.

**Keywords:** inherited; acquired; obesity; diet; exercise

#### **1. Introduction**

Obesity is a global health concern [1–5], with the prevalence in the U.S. exceeding 40% in adults and nearly 20% in children and adolescents [6]. Although efforts to stem the increasing prevalence have been unsuccessful, research has led to a clearer understanding of its etiology and how obesity impacts cardiometabolic diseases, such as type-2 diabetes mellitus (T2DM), dyslipidemia, cardiovascular disease, and hypertension [7,8].

Despite these conceptual advances, the development of effective prevention and management protocols has been less successful. Although lifestyle modifications are the cornerstone of obesity management, few individuals achieve long-term benefits with 'onesize-fits-all' diet and exercise approaches [9]. We posit that this lack of success is not due to a deficiency of willpower or adherence by participants and patients but is engendered by the failure to recognize that the obese phenotype is not a single homogenous condition [10]. To be precise, obesity, despite being an increasingly common phenomenon, has a complex, idiosyncratic etiology—with inherited, behavioral, and environmental factors determining the age and rate at which excessive adiposity and cardiometabolic diseases develop.

Thus, because research suggests that that the etiology of an obese phenotype (how and when it developed initially) strongly influences the short-term effectiveness and long-term

**Citation:** Archer, E.; Lavie, C.J. Obesity Subtyping: The Etiology, Prevention, and Management of Acquired versus Inherited Obese Phenotypes. *Nutrients* **2022**, *14*, 2286. https://doi.org/10.3390/ nu14112286

Academic Editor: Javier Gómez-Ambrosi

Received: 19 April 2022 Accepted: 27 May 2022 Published: 30 May 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

outcomes of lifestyle interventions [1,3,11,12], successful obesity management necessitates the subtyping of phenotypes. As such, the purpose of this 'perspective' article is to provide a concise overview of the differential development of acquired versus inherited obese phenotypes and offer insight into subtype-specific obesity prevention and management.

#### **2. Etiologic Subtypes of Obesity**

Although the defining characteristic of obesity is an excess of bodyfat [2,12], the age and rate at which excessive adiposity develops vary as a result of inherited, behavioral, and environmental factors. Thus, because the obese phenotype may be engendered at any point in an individual's development—from the prenatal period to senescence—research suggests two broad etiologic subtypes: 'acquired' and 'inherited' [1,3].

Acquired obesity, also known as 'adult-onset', denotes the disproportionate development of adiposity after puberty. The genesis of this phenotypic subtype is essentially behavioral, with physical activity (PA) and subsequent hyperphagia (overconsumption) being the major determinants. Stated simply, 'moving too little' leads to 'eating too much' and together these pathologic behaviors lead to acquired obesity and cardiometabolic diseases, such as T2DM [1].

Conversely, inherited obesity—also known as pediatric or childhood—subsumes all forms of excessive adiposity that are present at birth or develop prior to pubescence. Inherited obesity can be further subdivided into 'non-genetic' (common) and 'genetic' (rare) obesity. Common inherited obesity is a ubiquitous, complex, *quantitative* (continuously distributed) phenotype characterized by altered fat, muscle, and pancreatic beta-cell development and function. These structural (anatomic) and physiologic (metabolic) alterations are engendered during prenatal development, and as such, are largely irreversible [3,11,13].

Genetic obesity refers to Mendelian disorders that result in discrete, *qualitative* phenotypes that display excessive adiposity (e.g., leptin deficiency, Prader-Willi syndrome). As explained in detail below, because the genesis of common inherited obese phenotypes differs considerably from the genesis of the genetic inherited phenotype, it is important to distinguish between these subtypes in prevention, diagnosis, and management. As genetic obesity is rare [4], and the role of 'genes' in common obesity is limited (see Section 3 below), in this review, we limit our discussion to common (nongenetic) inherited forms of obesity.

#### **3. Nongenetic versus Genetic Inheritance and the Role of Genes in Obesity**

We have written extensively on the role of nongenetic inheritance in the development of obesity and T2DM, and how the conflation of the term 'inherited' with 'genetic' has led to confusion [3,14,15]. Given that a detailed exposition of the conceptual and empirical foundation for our work is beyond the scope of this article, we offer a concise overview below and direct our readers to select publications [1,3,12–16].

Briefly, the functional unit in biology and biological inheritance is the cell, and because each cell's idiosyncratic nature and spaciotemporal context determines gene expression, it is important to distinguish between nongenetic (cellular) inheritance and the two forms of genetic inheritance (nuclear and mitochondrial) [3,17–19]. For example, the fundamental difference between monozygotic (identical) and dizygotic (fraternal) twins is inherent in the nomenclature—identical twins develop from a single cell (a fertilized egg) whereas fraternal twins develop from two different cells (two fertilized eggs). Thus, fraternal twins differ in both cellular and genetic inheritance whereas identical twins do not. Therefore, the greater phenotypic disparity displayed by fraternal twins is due to differences in the genotypic expression induced by different cells in concert with inter-twin differences in genotype. Yet despite the variability in the developmental competence of any given population of eggs, the functional distinction between cellular and genetic inheritance is ignored routinely by those who infer genetic causality from 'twin-studies' and heritability statistics.

To be precise, our work demonstrated that "*there are no 'genes for' quantitative (i.e., nondiscrete) phenotypes, such as common obesity and metabolic diseases (e.g., T2DM)*." [1]. We further detailed the "*fatal flaws of twin studies*" and showed why "*estimates of genetic heritability*

*are misused, and often meaningless statistical abstractions derived from attempts to impose an artificial and false dichotomy (i.e., nature* vs. *nurture* (genes vs. environment)) *on demonstrably non-dichotomous biologic processes*" [1].

These conclusions—which form the basis for our perspective on the limited role of 'genes' in obesity—are most clearly supported by the nonlinear processes that lead to 'one-to-many', 'many-to-one', and 'many-to-many' genotype–phenotype relations. These processes include reaction norms, phenotypic accommodation, alternative splicing, RNA editing, chimeric transcripts, protein multifunctionality, epistatic variance, maternal effects, the metabolic regulation of transcription, and post-translational modifications.

Thus, a 'great deal of biology'—both established and undiscovered—links an individual's genotype, the cellular expression of that genotype, and the development of specific phenotypes; therefore, as Felder and Lewontin wrote, there is *"a vast loss of information in going from a complex machine* [an organism] *to a few descriptive parameters* [heritability estimates]*"* [20]. Moreover, because estimates of genetic heritability are mere statistical associations, they cannot be used to quantify the relative contributions of presumed etiologic factors outside of highly controlled animal and plant breeding operations [1,21]. In other words, 'correlation does not equal causation'—especially when the relations are nonlinear, and the fundamental constructs are inherently flawed or misconstrued.

In sum, the emerging field of non-genetic inheritance [17–19] and our work suggests that genes are *"tools of the cell"*, and as such, "*are merely a necessary but not sufficient component for the development of obesity/T2DM phenotypes*" [14]; therefore, an understanding of the etiology, prevention, management, and treatment of these phenotypes *"will not be found in the genome"* [3].

As detailed below, because the etiologies of acquired and 'non-genetic' (common) inherited obese phenotypes differ markedly, strategies for their prevention and management must be subtype-specific.

#### **4. Acquired Obesity: Its Etiology and Response to Intervention**

Although the etiology of acquired obesity is often contested [1], there is strong evidence dating from the mid-20th century that reductions in PA, high physical inactivity (PI), and excessive sedentary behavior (SB) are strong determinants of this phenotype in both human and non-human animals [1,12,22–33]. To summarize briefly, first, PA is the major *modifiable* determinant of caloric consumption [27,28,31,34–37]. Second, when individuals reduce their PA, their consumption declines more slowly than their caloric expenditure [27,28,31,34–36]. This leads to relative hyperphagia (overconsumption) and positive energy balance—with individuals consuming more calories than they expend.

Third, as PA declines, the energetic demands of skeletal muscle decline. This reduces the number of calories partitioned to skeletal-muscle and increases the number of calories available for storage in fat-cells (adipogenic partitioning). Fourth, PI decreases skeletal muscle insulin-sensitivity, which induces hyperinsulinemia (higher levels of insulin) during and after each meal with concomitant increments in adipogenic partitioning and decrements in lipolysis. The confluence of PI-induced hyperphagia and hyperinsulinemia causes a greater percentage of the calories consumed at each meal to be stored and sequestered in fat cells (reduced lipid turnover) with concomitant increments in body and fat mass.

When PI and excessive SB become habitual, the attendant metabolic perturbations [33] lead to acquired obesity via increments in fat-cell size, number (hypertrophy and hyperplasia, respectively), and ectopic development (fat-cell intrusions into non-adipose tissue). If the increased demands for insulin production and caloric storage cannot be met by parallel increments in pancreatic beta-cell functioning and fat-cell plasticity, the declining skeletal muscle insulin-sensitivity progresses to whole-body insulin-resistance, and over time, to overt T2DM [38–41]. Evidence for these phenomena was established decades ago, with the loss of skeletal muscle insulin sensitivity being the initial and primary metabolic insult in cardiometabolic diseases [38–41]. Thus, PI, high levels of SB, and concomitant

hyperphagia are the major etiologic factors leading to acquired obesity and cardiometabolic diseases [1,12,16,30,33,38].

Nevertheless, despite the strong influence of PA on the development of acquired obesity and T2DM, the management of these metabolic maladies *must* include dietary interventions because exercise-only interventions have trivial impacts on body mass and weight loss, despite clinically important impacts on body composition, and blood glucose and insulin levels.

#### **5. The Prevention and Management of the Acquired Obese Phenotype**

As the genesis and maintenance of the acquired obese phenotype are largely behavioral (moving less and eating more), prevention entails adequate levels of daily PA and relative caloric consumption from childhood to senescence. To be precise, 30–60 min of daily PA and a physical activity level (PAL) reaching 1.7–1.8, are necessary for the primary prevention of acquired obesity and the maintenance of a reduced (post-obese) phenotype [31,42,43]. Furthermore, in the early stages of development, the acquired subtype is extremely amenable to interventions emphasizing diet, PA, and exercise; however, it is important to note that despite the demonstrated impact on metabolic (glycemic and lipidemic) control, exercise-only interventions have a limited impact on weight-loss and body mass [44,45]. Thus, dietary and caloric restriction *must* play a dominant role if body mass is to be reduced.

This may be particularly important in patients with obesity and cardiometabolic diseases, such as dyslipidemia, especially hypertriglyceridemia, hypertension, and elevated blood glucose levels, including metabolic syndrome and T2DM. These patients require increased PA and exercise in concert with reductions in caloric intakes, particularly simple and complex carbohydrates and alcohol—even more so than reductions in fat intake—to improve both weight and metabolic control [46–48].

It is important to note, however, that if the chronic positive energy balance and metabolic perturbations induced by PI and excessive SB continue over time, the growth in the number of fat-cells (hyperplasia), in concert with the degradation of pancreatic beta-cell function and insulin sensitivity eventually lead to diminished health and responsiveness to lifestyle interventions. As such, long-standing acquired obesity will resemble the common inherited obese phenotype in its response to intervention [1,3,12].

#### **6. Inherited Obesity: Its Etiology and Response to Intervention**

In contrast to the behavioral genesis of the acquired (adult-onset) phenotype, the common inherited phenotype is engendered during in utero (prenatal) development. As briefly explained below, and detailed elsewhere [3,11–15], this subtype exhibits irreversible structural (anatomic) and physiologic (metabolic) perturbations engendered by the mother's behavioral and metabolic phenotypes (e.g., PA levels, adiposity, glycemic control).

Briefly, it is well-established that during pregnancy, a mother's cells compete for calories with those of her fetus [3,12,13,16]. Thus, to ensure that the fetus receives the number of calories it needs for development, pregnancy leads to hormonal changes that induce insulin-resistance in maternal skeletal muscle. This naturally developing insulin-resistance increases caloric consumption while decreasing the number of calories partitioned to maternal skeletal muscle. This leads to increased maternal serum lipid and glucose levels with concomitant increments in maternal body and fat mass, and caloric transfer to the fetus [3].

For comparison, stunting and common inherited obesity represent opposing ends of the maternal–fetal competitive continuum and they impact at least three generations: the mother, the fetus, and the germline of female fetuses. Stunting develops when a mother's diet and body-fat stores cannot keep pace with the competitive demands of her cells and fetal development. This causes fewer fetal muscle, fat, bone, and pancreatic beta-cells to be created, and permanently alters the offspring's structural (anatomic) and physiologic (metabolic) phenotypes (e.g., shorter height and impaired glucose and lipid metabolism). These changes are irreversible and substantially increase the risk of cardiometabolic diseases [49–51].

Conversely, common inherited obesity is engendered by insufficient maternal PA and metabolic control which reduces the competition for calories between mother and fetus. More specifically, when the naturally occurring insulin-resistance of pregnancy acts in concert with the pathological insulin-resistance induced by maternal PI and excessive SB, the escalation in insulin-resistance exponentially increases caloric consumption, while decreasing the number of calories partitioned to maternal skeletal muscle. This causes an excessive number of calories to be transferred to the fetus—which stimulates a disproportionate increment in fat-cell size and number, fetal insulin production, and dysfunctional skeletal muscle development (more structural and less contractile elements) [3,11–15].

These pathologic 'maternal-effects' (non-genetic mechanisms of inheritance) are irreversible and produce children who are predisposed to *'eating more and moving less'*, independent of genotype [3,11–15]. Infants and children with this subtype will consume more calories than those with normal phenotypes because their excessive fat-cell hyperplasia, reduced skeletal muscle function, and hyperinsulinemia, increase the number of calories stored and sequestered in fat-cells after each meal—both in adipose tissue and ectopically. Over time, this adipogenic partitioning causes increments in body and fat mass, and concomitant obesity [1,12,16]. These 'maternal-effects' offer a comprehensive explanation for the inheritance of compromised metabolic phenotypes in both human and nonhuman animals [3,12–15].

Thus, increments in childhood obesity and adolescent T2DM are most plausibly explained by the substantial decline in PA and increments in SB over the past 50 years by young women and mothers [52–54]. As the PI-driven maternal-effects escalated from one generation to the next, the prevalence of both obesity and T2DM increased markedly [3,11–15]. Our research suggests that these pathological maternal effects also explain the increased prevalence of obesity and cardiometabolic maladies in nonhuman mammals inclusive of dogs, cats, laboratory mice, monkeys, and feral moose [1,12].

#### **7. The Prevention and Management of the Inherited Obese Phenotype**

The inherited obese phenotype represents a continuum of metabolic perturbations instantiated during prenatal development. Thus, unlike acquired obesity, the structural (anatomic) and physiologic (metabolic) perturbations are not a behavioral manifestation, but are inherent to the phenotype, and therefore, are irreversible. This means that the prevention of common inherited obesity must begin with the current generation of female children and adolescents (future mothers). Sufficient increments in pre-pubertal, pubertal, pre-conception, and prenatal PA will ameliorate or prevent the pathologic maternal effects that lead to this phenotypic subtype. More specifically, as with the prevention of acquired obesity, future mothers must perform at least 30–60 min of daily PA and reach a PAL of 1.7–1.8 to prevent the development of common inherited obesity in future generations.

Nevertheless, once instantiated in utero, the structural and physiologic perturbations engendered by accumulative maternal effects are irreversible. To be precise, the inherited phenotype exhibits both hypertrophic and hyperplastic obesity (greater fat-cell size and number) in concert with dysfunctional pancreatic-cell function and reduced muscle-cell contractility. No behavioral interventions can reduce the number of fat-cells, nor wholly overcome the reduced muscle-cell function; therefore, individuals with this subtype will always find it more difficult to 'move more and eat less' than individuals with normal or acquired obese phenotypes.

Importantly, as detailed in the following section, the amount of PA and caloric restriction necessary to induce and maintain weight loss may be beyond many individuals' physical and/or psychological capacity for exercise and caloric deprivation. Thus, the inherited obese phenotype is less amenable to interventions than the acquired subtype and in many cases, the best health trajectory achievable will be a 'fit but fat' phenotype [7,55–59].
