Hope in Hopeless Times: Gearing Up to Fight the Obesity Pandemic

In this issue of Endocrinology, Dr. Harvey Grill reviews therapeutic options to counter the obesity pandemic, probably the largest medical and socioeconomic threat of our time (1). The detailed analysis of the current situation is, in fact, disheartening: around 1.9 billion of the global population is overweight, with 650 million diagnosed as being obese (2). Facing an uphill battle against intrusive marketing of high-calorie food combined with the frustrating realization that diet and exercise fail to bring relief, these patients are left with just the hope for the proverbial silver bullet. To complete the disastrous picture, only 1% to 2% of obese patients are treated with weight loss medication; thus, there is virtually no mitigation of the increased risk to die prematurely, no improvement in quality of life, and no reduction of partially life-threatening comorbidities. The billions of dollars that these individuals spend on “alternative,” partially obscure and borderline unethical remedies shed a light on the level of their desperation, thus replacing evidence-based medicine with belief. To avoid this scenario, we need to offer overweight and obese individuals better treatment options. Grill’s review is an excellent inventory of the arsenal currently at our discretion. However, a closer look is sobering: the best drugs on the market, in the best-case scenario, only achieve a 3% to 8% weight loss in a limited number of subjects wherein their optimal weight goal, as self-assessed by these individuals, would be a loss of 30% to 40%. Furthermore, even small successes are known to be volatile as maintenance of weight loss is a major challenge for the majority of people. And yet, there is hope because our knowledge of obesity has advanced significantly over the recent years: we now understand that obesity is a chronic disease resulting from fundamental alterations in neuronal circuits controlling feeding behavior and energy homeostasis. This insight is the basis for new therapeutic principles and strategies, and the revelation that treating obesity is rather a marathon than a sprint. Although most obesity therapeutics are still in their infancy, with prohibitive side effects and treatment costs, significant and encouraging inroads have been made recently. It is a function of time and smart strategic choices that need to be made by researchers and pharmaceutical companies to turn this progress into measurable successes. In this regard, it is meritorious to focus the comprehensive overview of contemporary treatment options on the central effects of Roux-en-Y gastric bypass (RYGB) surgery and glucagon-like peptide-1 receptor (GLP-1R) agonists (1), the advantages and disadvantages of both strategies together create a solution space for new ideas borrowing from both principles. Bariatric surgery is currently the most effective treatment for obesity, where weight loss primarily results from the increased secretion and combined peripheral and central effects of multiple hormones that reduce food intake. A key player in this hormone “cocktail” is GLP-1, which fueled the development of GLP-1R agonists as a single incretin therapy to promote weight loss in obesity. In 2014, the GLP-1R agonist liraglutide received US Food and Drug Administration approval for the indication weight loss; recent successes in cardiovascular outcome trials made it the leading drug in the field and a hopeful candidate for reimbursement. In 2018, the drug tirzepatide combined the beneficial effects of GLP-1R and GIPR agonists and set new standards for drug-induced weight loss (3). The interesting idea behind this combinatory pharmacological approach is partial mimicry of postoperative RYGB hormone profiles. In fact, the combination of enteroendocrine hormone therapies with orthogonal pharmacotherapies may help to further increase energy expenditure, improve metabolism, and finally manifest in further weight loss beyond that seen with bariatric surgery (4). The usefulness of such a magic potion can almost a priori be questioned with the primary caveat relating to the possible additive or even synergistic interaction of potential negative side effects of Glp-1R agonist therapy (eg, visceral malaise, renal impairment, hypersensitivity reactions). Nevertheless, given the current situation, it is certainly worth a try. The primarily encouraging aspect of contemporary research in the field is its mechanism-based approach. The review highlights the organization of appetitive control circuits, behaviors, and processes underlying hyperphagia and obesity. It describes the vicious cycle of dopamine-generating appetitive reward circuits that drive hedonic feeding (5) and are entrained by the consumption of tasty, energy-dense food. Because the latter is increasingly available, the perpetual presence of appetitive cues promotes hyperphagia and generation of appetitive behavior leading to chronic overeating and obesity. The ambition of every serious attempt to permanently reduce weight and effectively treat obesity is, therefore, nothing less than breaking this cycle. Ultimately, every therapeutic strategy needs to work on the various components in the central nervous system and our improved understanding of the contributing factors will pave the way. In a simplified view, satiety results from mechanical inputs, secretion of endogenous hormones in the intestine, and action of peripheral hormones at the brain level. Satiety follows the release of endogenous, intestinally derived GLP-1 and its detection by GLP-1R-laden vagal afferent neurons that terminate in central glutaminergic synapses in the nucleus tractus solitarius. Here, activated pre-proglucagon neurons secrete GLP-1 and signal to GLP-1R-expressing feeding-associated neurons of the hypothalamus (6). Because GLP-1 decreases feeding in humans (7) and, most likely, reduces appetitive food seeking, by inhibiting dopamine release during both feeding motivation and reward, incretin hormone-promoting RYGB also reduces appetitive drive. Interestingly, despite a remarkable overlap in mechanisms of action and molecular targets across the organism, and particularly in the brain, a large efficacy gap in treating obesity between RYGB and liraglutide remains. Although weight loss in RYGB subjects averages 18% to 25%, maximal effects of liraglutide do not exceed 7% to 11%. Furthermore, lost weight is rapidly regained when liraglutide treatment is discontinued, but remains stable in most RYGB patients. It is tempting to speculate on ways to close the efficacy gap. In fact, combination therapies as previously discussed have already started to go down this road, even when risking serious drawbacks along the way. We would like to end on a speculative note by posing the provocatively simple question as to why we do not just pharmacologically emulate RYGB surgery. Pharmacological secretagogues could emulate levels and patterns of release of endogenous incretin, as well as other gut hormones, as seen post-RYGB surgery to sufficiently restore incretin signaling in the central nervous system, induce satiety, and decrease hunger. Reduced incretin hormone levels in obese patients could even be restored and permanently serve the target neuronal circuits in the brain. Depending on the chemical nature of these secretagogues and their adverse effects profile, innovative local therapies could help to reduce the risk for the patient and the costs per treatment, both factors enabling long-term application. Given the rate by which the mere number of overweight and obese patients waiting for an effective treatment increases and the appalling level of treatment with current methods (only 1%-2% of that group), the need for new therapeutic principles is blatantly obvious and we might even need a miracle. However, a disruptive discovery might also suffice. Disclosure Summary: S.S.B. is an executive board member of APHAIA Pharma AG. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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