The Endocrine Society Centennial: Genes and Hormones in Obesity… or How Obesity Met Endocrinology Free

There is no doubt that obesity has become a major public health problem worldwide. The rates of obesity, a condition of excess of body fat and body mass index more than or equal to 30 kg/m², have experienced exponential growth during the last decades (1, 2). This is epitomized by statistics showing that obesity affects around one third of the adult American population, and its prevalence has increased between 10% and 40% in most European countries, with the United Kingdom having more than 22%–23% of adult men and woman being obese. Even more worrying, the number of overweight children in the Unites States and Europe has increased steadily from 1990 to 2010, with a prediction that more than 60% of infants who are overweight will remain so in early adulthood (1, 3). These trends are especially perturbing considering the enormous disease burden linked to obesity. Indeed, obesity is associated with increased risk of cardiovascular and metabolic complications, including hypertension, myocardial infarction, type 2 diabetes, fatty liver, and a constellation of related disorders, as well as sleep apnea, orthopedic problems, psychological alterations, and several types of cancer, among others (4, 5). As a result, obesity causes a significant reduction in life expectancy, with increased risk of premature all-cause mortality. Basic and clinical research aiming to better understand the neurohormonal mechanisms controlling energy homeostasis is essential for deciphering the basis of obesity and designing new and improved therapeutic strategies to combat it.

There is no doubt that obesity is a complex, multifaceted chronic disease with different etiological factors (6), including genetic and endocrine components (7). However, the important endocrine dimension of obesity, which is nowadays universally recognized, was not so evident to the scientific community just some decades ago. Indeed, for a long time, obesity was (merely) regarded as a behavioral problem, in which the lack of sufficient willpower rendered the affected individuals hyperphagic and, thereby, overweight. As such, the pathophysiological mechanisms of obesity were not of great interest for endocrinologists. Of equal importance, the hormonal control of body weight was not actively investigated by endocrine physiologists either.

The turning point for linking hormones and obesity likely came in the 1950s and 1960s, when the first genetic (rodent) models of obesity became available for experimental studies (8). Of note, these models arose spontaneously in the course of extensive breeding strategies at institutions such as The Jackson Laboratory, where the ob/ob (in 1950) (9) and db/db (in 1965) (10) mouse lines were first obtained, and the Laboratory of Comparative Pathology of Theodore and Lois Zucker, where the fatty (fa) trait appeared spontaneously in the 13M strain, which gave rise to the Zucker rat (11). These natural mutants preceded the generation of sophisticated genetically engineered rodents by several decades, but proved to be extraordinarily important for unraveling the neuroendocrine basis of body weight control and obesity. Interestingly, however, most of the initial characterization of these models was directed towards mapping the chromosomal location of the genetic defect leading to the obese phenotype (8), and the characterization of the metabolic phenotype of some of the mutants (eg, the marked hyperlipemia but normal glycaemia of Zucker rats) (11–13). These further illustrate the lack of endocrine focus of obesity research during these initial years.

Ultimately, recognition of the obese and diabetic phenotypes of these genetic models paved the way for interesting endocrine studies, which were initially dominated by the analysis of relationships between insulin functionality and obesity. This is well illustrated by the seminal paper published in 1972 in Endocrinology by Lois M. Zucker and Harry N. Antoniades, who used the Zucker fatty rat to evaluate changes in insulin levels and functionality during the course of development of obesity and following nutritional (diet) manipulation (14). As stated by the authors, “The status and functional activity of serum insulin in these animals is of great interest, both in the developed obese adult and in relation to the etiology of the obesity.” This work concluded that “… degree of obesity… correlated with serum insulin elevation, suggesting a causal relation, [indicating] that obesity precedes hyperinsulinemia.” Thus, well before the molecular substrate for the obese phenotype of the Zucker rat was even suspected, this seminal work emphasized the endocrine dimension of obesity and one of its major metabolic complications, namely insulin resistance (see Figure 1).

Figure 1

The Centennial Papers chosen were among the first to provide a detailed characterization of key aspects of the hormonal phenotype of genetic models of obesity, as the Zucker rat and the ob/ob mouse. These studies, which were produced much before the disclosure of the molecular basis of obesity had begun, and the adipose hormone, leptin, was first identified, contributed to emphasize the endocrine dimension of obesity and some of its comorbidities, such as insulin resistance (see Zucker and Antoniades [14]) and reproductive impairment (Swerdloff et al [23]). These pioneering studies set the scene for later major breakthroughs in our understanding of how body weight and energy homeostasis are regulated by numerous (neuro)hormonal signals, whose perturbation may explain (some forms of) obesity and its complications.

Open in new tabDownload slide

Even more instrumental for setting the endocrine basis of body weight control and obesity was the pioneering work in 1960s of Douglas Coleman, who was responsible not only for the first characterization of the db/db mouse, but also conducted the heroic studies involving parabiosis of ob/ob and db/db mice, with the ultimate aim of revealing the factor(s) causing the obese phenotype in these genetic models (8, 15). This work unambiguously demonstrated that soluble signal(s), abundantly produced in the db/db mouse but missing in the ob/ob mouse, played an essential role in suppressing feeding and body weight; the obese phenotype in db/db mice stemming from their inability to respond to such factor(s) (8, 15). Although preceding work from Gordon Kennedy had postulated the lipostat hypothesis, suggesting that circulating metabolites are responsible for body weight homeostasis (16), the work of Coleman, along with additional parabiosis experiments in rodent models of hypothalamic lesions targeting key areas in food intake control, illuminated a tenable neuroendocrine network, in which satiety factor(s) of hormonal nature, acting on specific receptors mainly located in the hypothalamus, would play an essential role in the physiological control of body weight and presumably its pathological deviations.

The groundbreaking work of Coleman set the scene for the identification of the products of the ob and db genes, as a key hormone-receptor tandem in the control of feeding and energy homeostasis (8, 15). However, the tools for such endeavor were underdeveloped in 1960s, and it was not until mid-1990s when the nature of these factors was finally disclosed. This was due to the illuminating work of Friedman and coworkers, who using positional cloning in the ob/ob mouse, were able to isolate in 1994 the ob gene, whose product was named leptin, form the Greek root, leptos (thin) (17). Soon after that, the leptin receptor, encoded by the db gene, was cloned (18); Zucker rats were also found to harbor mutations in this gene. A vibrant description of the 8-year tour de force that led Friedman to the discovery of leptin can be found elsewhere (15). We have just celebrated the 20th anniversary of such discovery, which is certainly one of the major breakthroughs in modern endocrinology, as illustrated by the fact that nearly 30 000 articles have been published on this hormone since its identification.

From an historical perspective, the discovery of leptin was extraordinarily relevant to readers of Endocrinology in numerous ways. Among others, it provided conclusive evidence for the endocrine control of feeding and body weight, substantiating the previous hypothesis of Coleman (8, 15), and fueled an unprecedented upsurge of experimental and clinical studies that have opened up a new era in our understanding of which and how peripheral hormones and central neural pathways interplay to maintain body energy homeostasis. In addition, studies on leptin physiology unambiguously documented the essential roles of this hormone in the control of numerous functions, other than body weight homeostasis, ranging from blood pressure to the immune system, puberty, and reproduction (19, 20); a feature that is shared by other metabolic hormones, such as ghrelin (20). This feature is likely at the heart of the numerous systemic complications of obesity, in which deregulated leptin (and other hormones) levels, together with different degrees of leptin resistance, impact on different body systems.

In this context, a tight link between body weight and reproduction had been long anticipated on the basis of intuitive knowledge, but became scientifically formulated only in the mid-1960s and early 1970s by the work of Kennedy (in rodents) and Frisch (in humans) that set the hypothesis that threshold levels of body fuel (fat) stores are needed for puberty to proceed and to maintain reproductive competence (21, 22). In addition, evidence from genetic models, mainly the ob/ob mouse, had also illustrated that obesity is associated with reproductive impairment; in fact, the failure to breed was already described at the time this obese mutant was first described (9). However, despite some initial characterization of the basis for this infertile phenotype, the endocrine substrate for such a phenomenon remained virtually unexplored until the seminal work by Swerdloff et al, published in 1976 in Endocrinology (23). As stated in that work, “The following experiments [were] the first of a series intended to define in detail the reproductive defect in the ob/ob mouse with the hope of characterizing the nature of abnormalities responsible for the multiple system defects.” To this end, serum LH, FSH, and testosterone concentrations were thoroughly analyzed in male ob/ob mice during the pubertal-to-adult transition and after withdrawal of negative feedback signals from the gonads. These studies demonstrated a profound state of hypogonadotropic hypogonadism in ob/ob mice, suggesting a primary central (likely hypothalamic) failure (23), tentatively leading to a defective GnRH drive in this obese model. These assumptions, made largely on the basis of indirect evidence, turned out to be totally right. Discovery of leptin, as major permissive factor for puberty onset and fertility acting primarily at the hypothalamus, allowed to explain why ob/ob mice, as well as children with inactivating leptin mutations, display lack of puberty onset and central hypogonadism, which can be rescued by leptin replacement. Similarly, db/db mice and Zucker rats suffer from breeding problems.

Arguably, one could speculate that reproductive abnormalities in the above genetic models of obesity likely stem not from obesity itself but from the lack of leptin or its actions. Although this is certainly true, in recent years, it has been conclusively documented in humans and animal models that hyperleptinemic forms of obesity are commonly linked to pubertal alterations and fertility problems (24, 25). Indeed, male obesity is frequently associated to some degree of hypogonadism, for which central and peripheral mechanisms have been proposed (20, 25). This hypogonadal state might be relevant not only to explain some sexual and reproductive perturbations seen in obese patients, but also as putative modifier of their metabolic profile, as low testosterone levels in males has been linked in some studies to increased insulin resistance. Therefore, obesity and hypogonadism may be connected in a vicious circle, in which obesity-induced hypogonadism might contribute to perpetuate or augment the metabolic complications of excessive body fat/weight, which in turn might aggravate gonadal dysfunction. Although the precise mechanisms for such a pathological interplay are yet to be fully elucidated, the initial work of Swerdloff et al (23) more than 4 decades ago was essential to begin surfacing the endocrine features and basis of the reproductive complications of obesity.

In summary, although obesity has become a major health thread in numerous countries, where its rates have escalated dramatically in the last decades, we have witnessed enormous progress in our understanding of how hormones drive brain and peripheral pathways to precisely control body weight, and how these regulatory pathways may become deregulated in disease conditions. To a large extent, the basis for such rapid progress is founded on the pioneering work on genetic models of obesity, and their endocrine characterization (as illustrated by the 2 articles selected for this commentary), which led the way for the identification of key molecules in body weight regulation. Despite these advances, our arsenal of therapeutic strategies and targets to fight obesity has not increased proportionally, likely due to 1) the polygenic nature of most forms of obesity, in which numerous genes and environmental factors cooperate to perturb body weight homeostasis; and 2) the difficulties of selectively targeting specific neuronal and/or endocrine pathways governing energy balance. This urges further deepening of our knowledge on how body weight is controlled by the concerted action of food intake and energy dissipation mechanisms. In its first century in print, our journal Endocrinology has contributed to the foundations of this research, and this is a priority for its second century. Recent data in the field forecast exciting developments. For instance, compelling evidence suggest that different peripheral hormones, such as leptin, ghrelin, or estradiol, regulate key metabolic tissues (eg, the adipose tissue and the liver) by acting centrally to modulate the autonomic (eg, sympathetic) output to such metabolic organs (26). In addition, hormones with key roles in the homeostatic control of feeding, such as ghrelin, leptin, and insulin, have been found to be relevant also in the hedonic regulation of food intake (27), therefore emphasizing the close connection between hormones and motivational forces involved in eating behavior. These are just but 2 examples that illustrate our high expectations for a rapid progress of the field of endocrinology of obesity in the near future.

Acknowledgments

CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII.

The author has been supported by the Spanish Ministry of Science, Grants BFU2011-25021 and BFU2014-57581 (cofunded by the FEDER Program of European Union); the Instituto de Salus Carlos III (Spanish Ministry of Health) Grant PIE14/00005; and Junta de Andalucía Grant P12-FQM-01943.

Disclosure Summary: The author has nothing to disclose.

References