Abstract

The global prevalence of obesity has been rising at an alarming rate, accompanied by an increase in both childhood and maternal obesity. The concept of metabolic programming is highly topical, and in this context, describes a predisposition of offspring of obese mothers to the development of obesity independent of environmental factors. Research published in this issue of Clinical Science conducted by Litzenburger and colleagues (Clin. Sci. (Lond.) (2020) 134, 921–939) have identified sex-dependent differences in metabolic programming and identify putative signaling pathways involved in the differential phenotype of adipose tissue between males and females. Delineating the distinction between metabolically healthy and unhealthy obesity is a topic of emerging interest, and the precise nature of adipocytes are key to pathogenesis, independent of adipose tissue volume.

Childhood obesity is increasingly recognized as a pertinent global health concern, promoting a significant rise in morbidity in mortality including developing type 2 diabetes and cardiovascular disease, with persistent obesity into adulthood [1]. The framework for obesity has shifted from exclusively a caloric imbalance to additional factors that confer vulnerability to metabolic disorders [2]. Maternal obesity is a predictive risk factor for early-onset obesity in children, a phenomenon termed as metabolic or developmental programming. Metabolic programming describes prenatal exposures or events in early postnatal development that elicits permanent alterations in physiology, metabolism, or epigenetics, thereby predisposing the child to disease [3]. Therefore, nutritional stressors or stimuli experienced during a critical window of development in the intrauterine environment evoke persistent metabolic changes in the fetus [3,4]. The predominantly abdominal fat accumulation in obese pregnant women results in increased exposure of the fetus to glucose and fat, thus favoring lipotoxicity, inflammation, and metabolic dysfunction [3]. The biological foundation of obesity has been of enhanced interest; however, it remains challenging to tease apart from the impact of environmental, behavioral, and psychological factors that all may contribute to enhanced adiposity in children. However, a meta-analysis conducted in twin and adoption studies found that although common environment may predict BMI in children, the strongest correlation is between parents and their biological children, an association which persists into adulthood, thereby suggesting genetics contribute substantially to the risk of childhood obesity [5]. In this recent issue of Clinical Science, Litzenburger and colleagues expand on previous knowledge to explore sex-dependent metabolic programming [6]. This study discusses the sex-specific implications of maternal obesity, with a particular focus on differential signaling, distribution, and the fraction of white adipose tissue (WAT) [6]. This commentary highlights the concept of metabolic programming and the role of sex-differences in this pathway, focusing on potential implications of this work in the context of adaptive and pathogenic obesity.

Prior to discussing the major findings of the present study, we must first appreciate the role of AT in metabolic dysfunction, especially as it pertains to adipogenesis (hyperplasia) versus adipocyte hypertrophy. The understanding of AT function has shifted from a neutral energy storage depot to that of an endocrine organ with a physiological role in metabolic homeostasis. Obesity favors a phenotype of chronic low-grade inflammation, shifting the balance toward a proinflammatory cytokine secretasome and immune cell recruitment [7]. However, the distinction between adaptive and pathogenic obesity is a relatively recent concept. AT mass is altered by either incorporating greater triglycerides into differentiated adipocytes, thus increasing fat cell volume, or by adipogenesis [8]. Notably, the number of adipocytes in a given depot is determined during childhood and adolescence and remains relatively stable through adulthood; therefore, the primary mechanism to increase AT mass in adults is through hypertrophy. This role is supported, as weight loss reduces adipocyte volume, yet has no detectable effect on adipocyte number [9]. Adiopogenesis is an adaptive process to compensate for caloric excess coupled with anti-inflammatory adipokine secretion, namely adiponectin, and angiogenesis to maintain AT vascularization [8]. On the other hand, hypertrophy leads to adipocyte hypoxia due to impaired perfusion, thus drives necrosis and subsequent macrophage recruitment, infiltration and a milieu of inflammation. Further, this propagates a vicious cycle of continuous adipocyte dysfunction and impaired nutrient storage [8]. In accordance, additional studies in metabolic disease support the uncoupling of AT weight and dysfunction, whereby animals may ameliorate weight and fat accumulation associated with high-fat diet (HFD), however, glucose intolerance, AT inflammation, and proinflammatory tissue macrophage recruitment is exacerbated [10].

To put this work in perspective, previous studies found sexually dimorphic influences of maternal obesity in mice. Male offspring demonstrate impaired glucose tolerance, adipocyte hypertrophy, and increased macrophage recruitment. On the contrary, females are relatively protected from the impact of maternal obesity and retain insulin sensitivity with increased adiposity [2], thus leading to the crucial question: what determines sex differences in susceptibility to metabolic programming? This recent study supports previous work regarding intra-generational obesity, yet takes it one step further by providing mechanistic insights into explain sex differences in metabolic dysfunction [6]. Further, the current study’s strength is the time course, demonstrating both the differential progression of males and females and delineating the female transition from pathogenic then subsequently adaptive AT alterations. Therefore, arguably the strongest evidence presented in the present study highlights the sex-specific phenotypic switching of adipocyte hypertrophy and adipogenesis.

The offspring were studied at an early phase (post-natal day 21: P21—3 weeks of age when mice are weaned and dependent on the mother’s diet), a late phase (P70—10 weeks of age when mice are considered sexually mature young adults), and finally at P120 (17 weeks of age equivalent to middle-aged adults). In the early stages (P21), female offspring demonstrate enhanced adiposity over male counterparts as operationalized as fat-fraction percent. Although adipocyte hypertrophy is characteristic of both male and female offspring of obese dams at this stage, this phenotype is only persistent in males at the final (P120) follow-up. Further, signaling pathways involved in cell survival, energy metabolism, and glucose homeostasis were persistently dysregulated in male mice and not in females [6]. WAT distribution shifts over time in both males and females from predominantly perigonadal in females and retroperitoneal and perigonadal in males at the early phase (P21), to primarily subcutaneous in the late phase (P70), suggesting sex- and age-dependent plasticity. The nature of AT dysfunction differs for males and females: females adopt an initial inflammatory response with concomitant adipocyte hypertrophy in early phase. This phenotype is resolved in late phase, however female animals retain a pro-adipogenic response [6]. Interestingly, a transient inflammatory response is considered adaptive for the tissue remodeling necessary for adipogenesis [8]. Males, however, have persistent adipocyte hypertrophy and inflammation that occurs in the late phase, denoted by the increase in IL-1β [6]. As adipocyte hypertrophy is strongly correlated with macrophage infiltration, and males have increased macrophage recruitment when exposed to maternal obesity, inflammatory status likely drives high-grade pathogenic obesity [2,8] (Figure 1). Overall, this current study highlights the propensity to reverse adipocyte hypertrophy, and offers clues to implicated pathways involved in nutrient response (PI3K/Akt), cell cycle regulation, and senescence [6]. However, future studies are necessary to identify therapeutic targets to promote adipogenesis and rescue adipocyte hypertrophy in caloric excess.

Sex-dependent metabolic programming of adipose tissue

Figure 1
Sex-dependent metabolic programming of adipose tissue

Maternal HFD results in persistent adipocyte hypertrophy in males for both the early phase (P21) and the late phase (P70). Females demonstrate a transient adipocyte hypertrophy and immune response in the early phase that is resolved in the late phase. Maternal obesity leads to a phenotype of high-grade pathogenic obesity in males and low-grade pathogenic obesity in females.

Figure 1
Sex-dependent metabolic programming of adipose tissue

Maternal HFD results in persistent adipocyte hypertrophy in males for both the early phase (P21) and the late phase (P70). Females demonstrate a transient adipocyte hypertrophy and immune response in the early phase that is resolved in the late phase. Maternal obesity leads to a phenotype of high-grade pathogenic obesity in males and low-grade pathogenic obesity in females.

This work’s potential implications are highly clinically relevant in the global context of increasing rates of obesity, and therefore in women of childbearing age. Initially, exposing the offspring of obese dams to HFD would determine the permanence of susceptibility to obesity, which may point to epigenetic alterations. There is now strong evidence for the genetic basis of obesity; however, the failure to identify monogenetic heritability in some cases suggests a few explanations: obesity is a complex polygenetic disease with multiple susceptibility genes interacting in concert, or that epigenetic alterations underscore developmental programming [5,11,12]. In this framework, maternal obesity induces lifelong epigenetic changes that predispose offspring to overnutrition and obesity. It is probable that both genetic and epigenetic determinants contribute, and epigenetic mosaicism or genomic imprinting are considered when genetic polymorphisms are an insufficient rationale for obesity predisposition (reviewed in [11]). Epigenetics describes sequence-independent changes of gene function, including DNA methylation, non-coding RNAs, chromatin interacting proteins, and post-translational histone modifications. Several studies examined changes in DNA methylation patterns upon maternal obesity, whereby the extremes of obesity compared with standard weight groups were significantly altered [13,14]. Therefore, determining the contribution of epigenetic modifications resulting from maternal obesity is another promising target for ameliorating offspring metabolic dysfunction.

Another sex-dependent pathway with a modulatory effect on AT is the renin–angiotensin system (RAS), more specifically the counter-regulatory angiotensin-converting enzyme 2 (ACE2) branch. Angiotensin 1-7, derived from ACE2-mediated proteolytic cleavage of Angiotensin II, and ACE2 confers beneficial modulatory effects on AT, including promoting browning of WAT, resolution of inflammation, and rescuing adipocyte hypertrophy [10,15–18]. Sex dependency has been suggested, as the ACE2 gene resides on the X-chromosone and escapes X-inactivation; therefore, women have a theoretical ‘double dosage’ of ACE2 [19].

The reversibility of high-grade pathogenic obesity characterized by stable adipocyte hypertrophy also offers a potential tailored therapeutic approach to targeting obesity in men and women. Based on the present study, the persistence of pathogenic obesity in males is intimately linked with chronic adipocyte hypertrophy and inflammation [6]. Therefore, shifting the balance to adipogenesis and resolution of inflammation would likely be an effective treatment option. Females, however, are characterized by an increased number of adipocytes with a transient adipocyte hypertrophy and inflammatory phenotype that is suggested as an adaptive mechanism to circumvent lipotoxicity and promote effective nutrient handling [6,8]. Therefore, delineating the functional mechanism for the phenotypic switch from metabolically unhealthy, or high-grade pathogenic obesity, to low-grade in females would offer targets to promote adaptive tissue remodeling and adipogenesis in males.

Inherent limitations to the present study result from the applicability of findings and from the chosen nomenclature. Although fat accumulation was statistically significant, the biological relevance to humans may be limited, as differences were relatively minor with no excessive alterations in body weight [6]. In accordance, it is arguable that animals in this study were not obese per se, rather that AT metabolism, hypertrophy, and accumulation were altered, yet it is challenging to delineate susceptibility to a true obese phenotype in the absence of an obesogenic diet [6]. However, in support, it has been demonstrated previously that offspring of obese dams are more prone to HFD-induced obesity with impaired glucose tolerance, insulin resistance, enhanced adiposity, and weight gain than offspring from control dams [4]. At last, as differences were reflected in post-weaned animals, the influence of reproductive maturity should not be ignored. Sex hormones determine AT depot-specific expansion due to both differential estrogen or androgen receptor expression and number of adipocyte precursor cells, thus would be independent of maternal metabolic programming [20].

The study by Litzenburger and colleagues reinforces the concept of metabolically healthy and unhealthy obesity, whereby ineffective lipid handling, inflammatory cell recruitment, and aberrant proinflammatory cytokine production are hallmarks of dysfunction rather than increased adiposity alone. In fact, a compensatory increase in adipogenesis and transient adipocyte remodeling and inflammation with overnutrition may maintain a metabolically healthy phenotype, as in female animals in the present study [6,8]. There has been enhanced interest in elucidating the physiological mechanisms that foster effective energy sequestration rather than pathological metabolic outcomes, including insulin resistance and dyslipidemia, that the present study has started to address. Therefore, targeting the pathways leading to this differential fate of AT to combat adverse developmental programming offers a novel therapeutic approach, indicating that AT quality rather than quantity determines adaptive or pathogenic obesity.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Canadian Institute of Heath Research (CIHR) [grant number PJ-664532]; and the Heart and Stroke Foundation (HSF) [grant number 55342].

Abbreviations

     
  • ACE2

    angiotensin-converting enzyme 2

  •  
  • AT

    adipose tissue

  •  
  • BMI

    body mass index

  •  
  • HFD

    high-fat diet

  •  
  • RAS

    renin-angiotensin system

  •  
  • WAT

    white adipose tissue

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