A quantum approach to the endocrinology of obesity

Conventional endocrinology has always been based on Newtonian principles. The classic negative feedback that governs the hypothalamic–pituitary–glandular axis has traditionally been deemed sufficient to explain the physiology and pathology of the endocrine system (1). Development of novel diagnostic tools and discovery of newer hormones and hormone-like substances (hormonoids) (2) have led to an upsurge in our understanding of the endocrine system. In a way, this is similar to the seismic shift that look place when Einsteinian or quantum physics disrupted classic Newtonian approach to physics.Just as Einstein changed the way we view our environment, modern tests and techniques have encouraged us to appraise physiology, especially endocrine function, in a quantum, rather than linear, manner. The pandemics of diabetes and obesity, in fact, demand and deserve such an analysis. Their multifactorial etiology, coupled with multifaceted clinical presentation, aligns with the cobweb of causation model, rather than a uni-hormonal or unipolar defect (3).It takes time, however, to change clinical attitudes and behavior. Most analysis and action in endocrinology involves the correction of a single offending hormone, whether excess or deficiency. Endocrine ratios, such as insulin:glucagon or cortisol:testosterone ratios (4), are still limited to academic discourse. Other pairings, such as the luteinizing hormone:follicle-stimulating hormone ratio, are no longer utilized in routine practice.In such a scenario, Yoshimichi’s discussion (which appeared in volume 15, part 7, article ID e260317), of three cases of obstinate obesity, holds great relevance (5). From a diagnostic and therapeutic viewpoint, as well as a pedagogic perspective, the authors encourage us to think beyond the boundaries of Newtonian constructs and explore the expanse of endocrine (dys)function through Einsteinian eyes.Obesity is well known to be a multifactorial neuroendocrine syndrome of excess adiposity (6). The main players are the four Bs, the brain, bowel, beta/alpha cell, and brawn (liver). While attention is paid to the hypothalamus, and its array of orexigenic and anorexigenic peptides, there is absence of focus on the pituitary, as well as its downstream endocrine targets. Through his cases, Yoshimichi highlights the role of the growth hormone (GH)–insulin-like growth factor 1 (IGF-1) axis in weight homeostasis. Initially thought to be involved in growth in children, this axis is now known to contribute to cardiovascular and metabolic health, as well as longevity (7).GH is produced from the anterior pituitary in response to various stimuli; mediated by the hypothalamus, IGF-1, a hepatic hormone, is considered a downstream effector molecule of GH, with a high mitogenic:metabolic activity ratio. This differentiates it from insulin, a similarly named and structured hormone, which is equipotent from a mitogenic and metabolic standpoint. IGF-1 hypersecretion may cause excessive weight gain, through its mitogenic properties (8). It may also be a consequence of obesity, with its levels being increased as a result of insulin resistance. At the same time, it may just be a confounding factor, contributing to various clinical manifestations, such as skin tags, acanthosis nigricans and cherry angiomas.Yoshimichi demonstrates how rationally chosen therapy can help modify the GH–IGF-1 axis and assist in weight management. Newer anti-obesity medications, such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dual agonists, have been studied for their effect on IGF-binding proteins (9). Results suggest that semaglutide has a beneficial effect on IGF-1.The author also points to the importance of ghrelin in weight homeostasis. Ghrelin increases GH secretion, and suppression of ghrelin, whether by medical or surgical means, leads to lowering of IGF-1 along with body weight (10). At the same time, one of his cases had persistently low GH and IGF-1, despite significant weight loss with behavioral therapy. This reinforces the metabolic and hormonal heterogeneity that characterizes obesity.Incorporation of IGF-1 levels in the screening and monitoring of short stature is a relatively recent phenomenon (11). Whether this will be integrated in obesity medicine is an interesting question to address. We concur with Yoshimichi’s suggestion that GH–IGF1 axis assessment be done for individuals with severe, syndromic, refractory or resistant obesity.Mechanistic and clinical studies point to the role of this axis in weight homeostasis. Just as Einstein and Newton coexist in the field of physics, and just as various components of the ominous octet contribute to the pathophysiology of diabetes, the GH–IGF axis will find its place in obesity etiopathogenesis and therapeutic modulation. This will enhance the quality of our clinical and biochemical evaluation of obesity and lead to improvement in clinical care. We caution, however, against indiscriminate use of endocrine assays in clinical medicine. The first step in assessment should always remain an anamnesis, i.e. history taking, followed by physical examination. Only if, and only if there exists a strong clinical ground to assess IGF-1 levels, and if the report will influence choice of therapy, should the test be ordered.Yoshimichi’s cases also open up a wider spectrum of use of anti-obesity medications. Though approved for the management of the so-called ‘exogenous’ obesity, they have the potential to be used for the management of syndromic and endocrine obesity. They are also being evaluated as adjuvant treatments for substance abuse disorders and as neuroprotective agents in degenerative diseases such as Alzheimer’s disease (12).Till then, the cases described in this edition of Endocrine Connections encourage healthy discussion and debate about the expanding universe of endocrinology and feed our hunger for heutagogy. As editors and as endocrine clinicians, we welcome this.The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.