Tipping the Scales: Noninvasive Obesity Breakthroughs

June2022CoverEN

As the worldwide mortality rate linked to obesity and its comorbidities surpasses four million annually, new approaches to combating this condition are sorely needed. Thankfully, recent research from Endocrine Society journals shows promise in some surprisingly novel and safe noninvasive weight loss methods.

The obesity epidemic continues to pose serious health threats to populations worldwide. In the last 50 years, the prevalence of obesity has more than doubled in dozens of countries (and overall tripled worldwide), and the overall number of adults and children with obesity approaches 1 billion.

What this means in terms of morbidity and mortality is grave: comorbidities like type 2 diabetes mellitus, nonalcoholic steatohepatitis (NASH), cardiovascular disease, obstructive sleep apnea, and obesity-related malignancies are all-too common, and about 4 million people die from obesity-related conditions annually. Scientists and researchers have searched for mechanisms to explain and therapies to combat this colossal health problem for decades, and their breakthroughs are hard-won.

But two new studies are lightening the load. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy,” by Christos S. Mantzoros, MD, ScD, chief of Endocrinology, Diabetes, and Metabolism, Boston VA Healthcare System; director, Human Nutrition Unit, Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center in Boston, Mass., and team, published in Endocrine Reviews in October, and Diet-induced Fasting Ghrelin Elevation Reflects the Recovery of Insulin Sensitivity and Visceral Adiposity Regression,” by Gal Tsaban MD, MPH, of the Soroka University Medical Center and the Ben-Gurion University of the Negev, in Beer-Sheva, Israel, and team, published in The Journal of Clinical Endocrinology & Metabolism (JCEM) in November, come at obesity from promising new angles.

Novel Obesity Therapies

Mantzoros and team saw unmet clinical needs in obesity comorbidities, which prompted their review of potential new therapeutic approaches. “We have no U.S. Food and Drug Administration–approved medications for several comorbidities such as NASH, which affects 25% of the population, and treatment options for obesity itself remained truly suboptimal until very recently,” Mantzoros says. “We need to understand better the underlying mechanisms and leverage them to create optimal solutions for clinical conditions that have reached epidemic proportions in our societies.”

Although bariatric and other invasive procedures are available and effective, they come with significant risks and side effects. “After observing a significant number of obese subjects for more than 10 years after bariatric surgery (mainly Roux en Y and sleeve gastrectomy), we found that they largely maintain their weight loss up to 10 years,” Mantzoros says. “This is one of the longest observation periods to date, which has allowed us to monitor and report changes of hormonal mediators over time. We believe that if we can make and administer these hormones alone or in combination to obese people, we could induce a degree of weight loss similar to what we achieve with bariatric surgery. This is the direction we and several pharmaceutical companies are taking.”

Given the complexity of the pathways involved in the pathophysiology of obesity, the pharmacotherapeutic targets included in their exhaustive analysis run the gamut: the central nervous system, gastrointestinal hormones, adipose tissue, the kidney, liver, and skeletal muscle. They also explored novel drug delivery systems, chronotherapy, vaccines, modulation of the gut microbiome, and gene therapy. Here are some highlights.

With drugs, the researchers tease out the biochemical circuits involved in energy homeostasis, then discuss the agents that may agonize or antagonize receptors in those specific areas. Importantly, these agents are not intended to supplant lifestyle modification but should potentially be useful adjuncts.

“The root causes of obesity, which include not only biological and genetic but also environmental, psychological, and other factors, remain to be studied in depth, utilizing new tools including artificial intelligence, and this will eventually deliver novel approaches to our therapeutic armamentarium that could result in tangible benefits for those of us who struggle to keep our body weight under control to avoid metabolic complications and thus live healthier and longer lives.”

Christos S. Mantzoros, MD, ScD, chief, endocrinology, Diabetes, and Metabolism, Boston VA Healthcare System; director, Human Nutrition Unit, Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Mass.

In states of leptin deficiency, for example, setmelanotide, metreleptin, and methylphenidate act to physiologically replace leptin and, in addition, as Mantzoros puts it, “should, by definition, be the most appropriate and natural replacement therapy. For those obese subjects whose condition is due to mutations downstream of leptin (leptin receptor, melanocortins, etc.), it is reasonable to expect that setmelanotide, which acts to activate the MC4R (a receptor located downstream of the above molecules in the leptin pathway to regulate energy homeostasis), would have beneficial results.” He emphasizes that these conditions are rare, but for these patients, “a ‘personalized medicine’ approach with genetic-based diagnostics and targeted therapy would be expected to work very well.”

For the majority of patients with obesity, however, leptin has not proven effective. “Obesity in most humans,” says Mantzoros, “is a leptin-tolerant state, the exact nature of which remains to be fully elucidated.”

Although targeting the endocannabinoid system had seemed an intuitive approach until recently, unintended side effects have thwarted these aims. “Until and unless specific compounds act only to decrease body weight without any concomitant cross talk and activation of other pathways activated by the endocannabinoid system, this approach appears to hold limited promise,” Mantzoros says.

So-called “WAT browning,” however, is achieving some success. Removal of white adipose tissue (WAT), such as with liposuction, is only a temporary measure, as WAT grows back. Browning the WAT with various agents to become brown adipose tissue (BAT) in animal experiments has demonstrated that the resulting increased energy expenditure may decrease body weight. “This notion has been extremely difficult to replicate in humans, similar to many other hypotheses raised on the basis of observations in animal models, using standard drug-based approaches,” Mantzoros says. “It remains to be seen whether nanotherapeutic or other approaches targeting specifically WAT browning could overcome existing obstacles and lead to progress on that front.”

Another approach with potential is delivering anti-obesity peptides orally, which may enhance patient adherence. “Oral peptide delivery promises to be a revolution in obesity treatment and in medicine in general. Until recently this was not possible, but several novel technologies have delivered some results (positive outcomes, but at a very high cost of goods needed), and, with time, we hope that advances in this area will continue to lead to improvements in technology that allows us to deliver bioactive peptides orally. These strides in the delivery methods field promise to make this approach a more viable possibility in the near future,” Mantzoros explains.

Overall, in drug therapy, the news is good, with recently approved medications leading to 15% weight loss when combined with behavioral modification therapy. “This is significant progress versus what was available until a year ago, and dual or triple agonists currently in development promise to result in even higher weight loss in the near future,” Mantzoros says.

The team is further investigating the physiology of adipose tissue, muscle, and gastrointestinal tract–secreted peptides for their potential as druggable targets that will revolutionize how we treat obesity in the near future.

Apart from drug therapies, the researchers also looked at manipulating the gut microbiome, but with less-than-encouraging results. “Although this is a major focus of research by many investigators, most of the studies to date are observational and thus cannot prove causality,”  Mantzoros says. “Any intervention causes many changes in many species at the same time, and this non-specificity creates ‘noise’ that confuses our interpretation of the data. Finally, empirical evidence (e.g., from patients taking antibiotics for several conditions) does not support the notion that we could have material weight loss by manipulating the microbiome. I am thus very cautious and still waiting to see the breakthrough in this field that would be making me more enthusiastic.”

Although the results of their extensive analysis were mixed depending on the therapy, any

advancement in the understanding of the pathophysiologic basis of obesity counts as progress. Progress, says Mantzoros, “that will hopefully lead to multimodal, personalized approaches to obesity treatment that result in safe, effective, and sustainable weight loss, which, in turn, would also result in the decreased prevalence of obesity comorbidities.”

Ultimately, taming the many-headed Hydra that is obesity will take sustained effort. “The root causes of obesity, which include not only biological and genetic but also environmental, psychological, and other factors, remain to be studied in depth, utilizing new tools including artificial intelligence, and this will eventually deliver novel approaches to our therapeutic armamentarium that could result in tangible benefits for those of us who struggle to keep our body weight under control to avoid metabolic complications and thus live healthier and longer lives,” Mantzoros concludes.

Fasting Ghrelin Levels

Tsaban and team homed in on the “hunger hormone” for their study: a secondary analysis of the DIRECT-PLUS clinical trial in Israel that took place over 18 months starting in May 2017. DIRECT-PLUS was specifically designed to address the effects of the green-MED diet on adiposity and obesity. A total of 294 participants (mostly male) were evenly divided into three intervention groups: 1) healthy dietary guidance plus physical activity; 2) the vegetable-heavy and lean-protein Mediterranean diet plus physical activity and 28 g/day of walnuts; or 3) the Mediterranean diet (including everything from group 2) plus 3 to 4 cups/day of green tea and 100 g of frozen duckweed called Mankai (green-MED diet). The two Mediterranean diet groups were additionally restricted to under 1,800 calories a day for males and under 1,400 calories a day for females.

In Tsaban and team’s substudy, they sought to determine the relationship between fasting ghrelin levels (FGL), obesity, adiposity, and insulin resistance during the intervention. “We performed this analysis because the role of ghrelin in metabolic regulation of insulin sensitivity during prolonged (12 hours) fasting and its role in adiposity promotion is sparsely explored so far,” Tsaban explains. “We aimed to define the associations between FGL and adiposity and insulin resistance determinants to shed light on FGL’s possible role in this aspect of metabolism during weight loss-directed dietary intervention strategies.”

A healthy diet and exercise are the cornerstones of weight loss, but the addition of walnuts (Mediterranean diet and green-Med groups) was intentional and based on the results of some of their former studies. “Walnuts are rich in alpha-linolenic acid and polyunsaturated fats and are a fundamental ingredient in the Mediterranean diet we studied previously. The Mediterranean diet has many versions, but the inclusion of legumes or walnuts in this diet is associated with many cardiometabolic benefits in previous studies,” Tsaban says. The current study represents their best evidence-based version of the Mediterranean diet.

And Mankai? “We looked for an edible plant rich in bioavailable protein and polyphenols that can be consumed as a dinner substitute (meaning satiable and palatable),” Tsaban explains. “After a long search, we found Mankai (Wolffia globosa), which answered our expectations. We do not have any commercial relationship with the manufacturer of Mankai and do not advertise it.” Moreover, the company that markets Mankai was not involved in the design or handling of the study, had no access to the study’s data, and was not involved in the data analysis or publications from the study.

Baseline FGL were similar among the three intervention groups, and 52% were normo-glycemic, 37% were prediabetic, and 11% had type 2 diabetes. After 18 months, the FGL increased with weight loss and was associated with improvement in insulin sensitivity and reduced visceral adiposity in the two Mediterranean diet groups, but with FGL being twice as high in the green-MED group. Importantly, these changes persisted even after adjusting for weight loss, suggesting a dietary influence.

As for why the green-MED diet was so markedly effective even compared to the regular Mediterranean diet, Tsaban says this may be attributable to the higher amounts of polyphenols in the green-Med diet, compounds well known to benefit the human body and even fight disease. “We have also shown that the green-MED diet promoted distinct changes in the gut microbiome associated with some of the observed metabolic benefits,” he adds. These are just observations for now and remain to be specifically investigated.

“In my view as a clinician, this study highlights the importance of fasting ghrelin as a marker of insulin sensitivity recovery and adiposity regression during lifestyle interventions, which is often not reflected by weight loss alone. The findings of this study support the use of FGL as a laboratory marker to estimate the metabolic responsiveness of an individual to specific lifestyle interventions.”

Gal Tsaban MD, MPH, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel

To explain the seeming paradox that fasting levels of ghrelin (which is orexigenic) are lower in insulin resistance, Tsaban explains that ghrelin has different functions in short and prolonged fasting conditions. “We and others (as elaborated in the paper) show that ghrelin plays a vital role in metabolic and energy regulation during long fasting conditions (meaning more than eight hours), and higher levels of fasting ghrelin are associated with increased insulin sensitivity. This is the first study to show that fasting ghrelin is related to the recovery of sensitivity to insulin and adiposity regression during lifestyle intervention and that different dietary interventions have other effects on FGL increase.”

These findings burst with positive implications. “In my view as a clinician, this study highlights the importance of fasting ghrelin as a marker of insulin sensitivity recovery and adiposity regression during lifestyle interventions, which is often not reflected by weight loss alone. The findings of this study support the use of FGL as a laboratory marker to estimate the metabolic responsiveness of an individual to specific lifestyle interventions,” Tsaban says. The team has already undertaken additional sub-studies of DIRECT-PLUS under the leadership of Prof. Iris Shai (a coauthor of the current study), and they plan to continue investigating the effects of the green-MED diet on different aspects of human health.

The important leads by Mantzoros’s and Tsaban’s teams have brought us much closer to trimming the fat. The more we understand about obesity, the better our ability to develop effective therapies.

Horvath is a freelance writer based in Baltimore, Md. She wrote about the diabetes risk of gender-affirming hormone therapy in transgender women in the February issue.

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