Although diet and exercise have been the cornerstone of therapy for obesity, efficacy is suboptimal and short lived. Surgical procedures are durable but invasive therapy for obesity. Supplemental therapies for obesity that are minimally invasive, low risk, and effective are needed. Several therapeutic options are being developed that offer obese patients and their health care providers alternatives to what is currently available.
Key points
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Obesity involves multiple pathophysiologic processes that can be targets for treatment.
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Endobariatric procedures are effective weight loss therapies.
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Microbiome manipulation is a popular area of study that holds promise for the treatment of obesity.
Introduction
As outlined earlier in this issue, obesity has grown to epidemic proportions in the past 3 decades. However, there has been a major lag in the development of effective therapies for obesity. Although the obesity epidemic is largely explained by environmental factors, such as calorie-dense diets and sedentary lifestyles, the discovery of other contributing factors, such as altered intestinal microbiota and genetic derangement, has unlocked additional therapeutic pathways. Therefore, development of novel therapeutic interventions for obesity is in high demand and remains an active area of investigation. Although the mainstay of therapy is behavioral modifications via diet and exercise, innovative pharmaceutical, mechanical, hormonal, and device options are introduced in this article.
Introduction
As outlined earlier in this issue, obesity has grown to epidemic proportions in the past 3 decades. However, there has been a major lag in the development of effective therapies for obesity. Although the obesity epidemic is largely explained by environmental factors, such as calorie-dense diets and sedentary lifestyles, the discovery of other contributing factors, such as altered intestinal microbiota and genetic derangement, has unlocked additional therapeutic pathways. Therefore, development of novel therapeutic interventions for obesity is in high demand and remains an active area of investigation. Although the mainstay of therapy is behavioral modifications via diet and exercise, innovative pharmaceutical, mechanical, hormonal, and device options are introduced in this article.
Pharmacotherapy
There are numerous pharmacologic targets for the treatment of obesity. Pharmacotherapy for obesity is covered extensively (see Jeanette N. Keith’s article, “ Pharmacotherapy in Treatment of Obesity ,” in this issue), but this article discusses possible new therapies that may be used as a supplement to diet therapy and exercise. Therapeutic targets address 3 basic mechanisms: (1) decreasing caloric intake/absorption, (2) increasing energy expenditure, and (3) modulation of adipocytes. To date, most of the drugs approved for the treatment of obesity decrease oral intake by suppressing appetite via central nervous system neurotransmitters. However, other physiologic pathways hold promise as potential therapeutic targets.
Decrease Caloric Intake/Increase Energy Expenditure
Beloranib is a drug that inhibits methionine aminopeptidase 2, an enzyme involved in fat biosynthesis, oxidation, and breakdown. Caloric intake is also reportedly decreased in patients treated with beloranib and is associated with an increased level of serum adiponectin. Based on early data, beloranib seems to be an effective weight loss agent. In a 12-week, phase II trial, beloranib resulted in significantly greater weight loss compared with placebo (−10.9 ± 1.1 kg vs −0.4 ± 0.4 kg, respectively; P < .0001 vs placebo). Compared with the currently available pharmacotherapies, beloranib may have a promising future in light of the robust weight loss observed in early studies.
Gut hormones have been heavily investigated as potential therapeutic interventions for obesity. As an endocrine organ, the gastrointestinal tract secretes numerous neurohormones that affect energy intake and satiety. For example, amylin (synthetic analogue of Symlin) is a beta cell–derived peptide that slows gastric emptying and decreases food intake. Likewise, glucagonlike peptide 1(GLP-1) has similar physiologic effects and the synthetic GLP-1 agonist liraglutide (Saxenda) is US Food and Drug Administration (FDA) approved for weight loss. Other neurohormones that also decrease food intake include pancreatic polypeptide, which is secreted from the pancreas; ghrelin, which is secreted from the stomach; oxyntomodulin and peptide YY, which are secreted from intestinal L cells; and cholecystokinin, which is secreted from the small bowel. Given the many gut neurohormones involved in food intake, a combined pharmacologic approach targeting multiple physiologic pathways may offer optimal efficacy to treat obesity.
Adipocyte Modulation/Increase Energy Expenditure
Adipose tissue is metabolically active tissue and has been targeted as a potential therapeutic pathway for obesity. In particular, brown adipose tissue (BAT), which is less functional in obese versus lean individuals, is involved in fat burning and thermogenesis. In contrast, white adipose tissue (WAT) is responsible for obesity. A recent animal study used nanoparticles that selectively delivered rosiglitazone (peroxisome proliferator-activated receptor gamma) and prostaglandin E2 to adipose tissue leading to (1) transformation of WAT to the thermogenic BAT, and (2) increased angiogenesis-induced expansion of BAT. Increasing the conversion of WAT to thermogenic BAT is an attractive method to increase energy expenditure and ultimately weight loss. An recently proposed additional target for brown fat activation is mirabegron (Myrbetriq), which is a β3-adrenoceptor agonist currently used to treat overactive bladder. β3-Adrenoceptor agonism has been shown to increase resting the basal metabolic rate in humans, but whether this increase leads to substantial weight loss remains to be seen.
Endobariatrics
Endoscopic bariatric therapies (EBTs) represent an evolving and exciting therapy for obesity. Discussed in detail elsewhere in this issue, EBTs offer an effective weight loss option for individuals who fail traditional therapies and/or are not eligible for (or do not wish to) undergo weight loss surgery. These procedures also may serve as bridge procedures for patients who are at high operative risk given their obesity. These therapies are minimally invasive, well tolerated, and effective in achieving weight loss goals in the general population. As of 2016, the 3 FDA-approved EBTs are the Orbera Intragastric Balloon, the Reshape Dual Balloon, and the Aspire Assist, with more devices and procedures expected to be approved in the coming years.
Space-occupying Devices
Reduction of intragastric capacitance through space-occupying devices is the physiologic basis for restrictive EBTs, such as the Orbera Intragastric Balloon and the Reshape Dual Balloon. In addition to the mechanical restriction, reduction in hunger may also lead to decreased energy intake. Several other intragastric balloons are also currently being studied, including an adjustable saline-filled device called the Spatz Adjustable Balloon System, and gas-filled balloons that can be either orally ingested (Obalon Gastric Balloon, Ullorex) or endoscopically placed (Heliosphere). However, complications related to catheter migration, device rupture, and short-term efficacy have hindered their approval, with more studies being conducted to alter these devices to bring them safely to market.
The Transpyloric Shuttle is a bispherical device with smaller and larger bulbs that are deployed endoscopically through an overtube, resting within the gastric antrum and traversing the pylorus to delay gastric emptying and induce early satiety. It is currently undergoing a multicenter trial in the United States after preliminary data showed positive feasibility and safety profiles.
Gastroplasty
Traditionally, gastroplasty is a surgical procedure; however, with the advent of several new FDA-approved devices, this can now be achieved endoscopically. One method is the primary obesity surgery endoluminal procedure, which uses full-thickness tissue plication within the gastric fundus and distal body to limit gastric accommodation, delay gastric emptying, and promote early satiety. Endoluminal vertical gastroplasty is an alternative option, using suture or staple placement along the greater curvature of the stomach and producing results similar to a traditional gastric sleeve. These procedures remain under investigation in the United States, but have shown promising results in early studies.
Aspiration Therapy
Aspiration therapy is a method of weight loss that results from the disposal of approximately one-third of the gastric contents after each meal. The gastric contents are eliminated through the use of a specially formulated gastrostomy tube with a one-way valve known as the AspireAssist. The AspireAssist device was recently approved by the FDA after its efficacy was proved in the domestic and international literature with high excess weight loss at 6 months and low complications in patients with a broad body mass index range of 35 to 55 kg/m 2 .
Other modalities
Gastric Electric Stimulation
Although not a novel concept, gastric electric stimulation is a modality on the therapeutic horizon for the management of obesity. The rationale for gastric electric stimulation involves exerting control over vagal nerve–induced secretion of neuropeptides that signal satiety in the central nervous system. Since its inception more than a decade ago, there have been numerous iterations of the devices integrating this concept. One such device is the MAESTRO/Vbloc system, which also includes vagal nerve blockade. In addition to neurohormones (eg, GLP-1 and cholecystokinin), the vagus nerve is highly involved in energy intake. Among other factors, gastric distension induces satiety via vagal nerve afferent signals. Given the relation of the vagus nerve to energy metabolism, it is a worthy target as an obesity therapy. Early studies of the Vbloc system showed unimpressive weight loss with only small differences compared with placebo. More recently, a double-blind placebo-controlled study by Morton and colleagues showed significantly greater weight loss in subjects in the treatment group (11% total weight loss) compared with the sham group (6% total weight loss). Through continued research, it is hoped that this product will be added to the therapeutic arsenal in the future.
Gene Therapy
Although environmental factors account for most obesity cases, genetic alterations of single, and in some cases multiple, genes result in the predisposition to and development of obesity. To date, hundreds of obesity-linked genes have been identified. Although a detailed review is beyond the scope of this article, some of the significant genes and their potential therapeutic impacts are highlighted.
To date, one of the most notable models of genetically linked obesity is the leptin-deficient ob/ob mouse model. Leptin is a multifunction neurohormone secreted by WAT that acts in the hypothalamic region of the brain to regulate food intake. The leptin-deficient ob/ob mouse develops obesity in the setting of excessive caloric intake. In addition, a leptin receptor gene defect has also been shown in animal models and humans to cause early-onset obesity. In contrast with the leptin-deficient model, in the setting of a leptin receptor gene defect, administration of leptin does not reverse obesity. Pro-opiomelanocortin (POMC) is also involved in the regulation of food intake. Its action is partially mediated via melanocyte-stimulating hormone and adrenocorticotrophic hormone and it is deficient in obese individuals. Individual patients with impaired POMC function developed early-onset obesity, adrenal insufficiency, and red hair pigmentation. Uncoupling proteins (UCPs) are a group of proteins involved in thermogenesis and several defective UCP genes have been associated with weight gain in adulthood. Furthermore, given that the process of thermogenesis is under autonomic nervous system control, knockout models with defective adrenergic receptors showed an increased propensity toward obesity with ingestion of a high-fat diet. The aforementioned genes are only a few of many that may serve as potential candidates for therapeutic gene therapy. In particular, treatment of the leptin-deficient ob/ob mouse with leptin delivered via an adenovirus vector resulted in significant weight loss. Using the data from observations in the ob/ob mouse model, humans treated with physiologic doses of recombinant leptin therapy have shown successful weight loss. There are also polygenic and syndromic forms of obesity that result from multiple genetic defects and/or chromosomal abnormalities. Gene therapy may prove more challenging in these patients given the multiple defects that result in the obesity phenotype.
Intestinal Microbiome Manipulation
The gut microbiome has been implicated as a potential contributor to the obesity epidemic following several observations in animal models. Backhead and colleagues showed that gut microbes are involved in the regulation of fat storage, energy harvest, glucose intestinal absorption, short-chain fatty acid (SCFA) fermentation, and triglyceride synthesis. There are also epidemiologic data linking antibiotic exposure in the perinatal period and infancy to altered gut flora and childhood obesity, respectively. Thus, manipulation of the intestinal microbiome has been proposed as a prospective therapeutic target for obesity. Alteration of the microbiome may be achieved via a variety of methods like diet/diet supplements, and the use of prebiotics and probiotics.
Prebiotics are oligosaccharides that bypass intestinal absorption and are in turn fermented by colonic microbes to produce SCFAs. SCFAs may be used by colonocytes as fuel and also alter the intestinal flora. Intestinal bifidobacteria, a species that has been associated with a favorable metabolic profile, are increased with prebiotic use. Furthermore, prebiotic ingestion in rats causes increased peptide YY and GLP-1 and decreased gastric emptying and food intake. When examined in a randomized control trial, oligofructose supplementation resulted in a small but significant proportion of weight loss compared with weight gain in the placebo group. The observed weight loss was associated with decreased ghrelin and increased peptide YY levels as well. More recently, a prebiotic formulation selectively delivered to the colon was shown to reduce weight gain, intra-abdominal adipose tissue distribution, and hepatic fat, and prevented progression of insulin sensitivity. In the Fat-1 mouse model of antibiotic-induced obesity, omega-3 fatty acid supplementation decreases antibiotic-induced obesity. This mouse makes endogenous n-3 polyunsaturated fatty acids (PUFAs) from n-6 PUFAs and ultimately leads to a reduced Firmicutes/Bacteroidetes ratio and bifidobacteria/Enterobacteriaceae ratio as well as inflammatory markers such as tumor necrosis factor alpha and interleukin 6.
Probiotics are microorganisms that provide a health benefit to the host. The obesity phenotype is associated with altered microbial profiles; for example, decreased Bifidobacterium and increased Firmicutes species. Altered gut microbiota results in greater energy harvest with subsequent weight gain and increased body fat in mouse models. Furthermore, a lesser degree of gut microbiota richness is linked to increased adiposity, insulin resistance, and dyslipidemia in humans. Hence, it is possible that supplementation with favorable bacteria may tip the scales in the direction of a nonobese phenotype, whereas antibiotics that diminish the favorable bacterial profile may promote an obese phenotype. Although the data are mixed, there are several studies that suggest that probiotic supplementation is associated with weight loss and an improved metabolic profile. One of the largest and longest studies (6 months) evaluating the effect of supplemental probiotics (in addition to a calorie-restricted diet) showed no significant difference in weight in the treatment and placebo groups. However, in women, there was significantly greater weight loss in the group receiving probiotic supplementation compared with the placebo group despite equal amounts of calorie restriction.
Fecal microbiota transplant is the quintessential modality to manipulate the intestinal microbiota. In this procedure, the recipient’s intestinal tract is populated with the fecal material from a healthy donor. This method has been used to restore the intestinal flora after recurrent Clostridium difficile infection with success and may be a promising option in the future for obesity. Thus far, data in this area are limited; however, fecal microbiota transplant from lean donors to obese recipients has been shown to improve insulin sensitivity.
Bioengineering/Biomaterial
As mentioned previously, BAT is an important contributor to thermogenesis and an obvious potential therapeutic target for obesity, whether by genetically modulated upregulation of uncoupling protein synthesis or pharmacologic expansion of uncoupling protein-positive BAT. Transplant of biologically active BAT has been investigated in mouse models but tissue transplant bears the risk of graft-versus-host immunologic reactions. As a result, alternative techniques have been investigated. Specifically, Tharp and colleagues reported a novel method of transplanting BAT-like cells via a process called matrix-associated transplant. This method involves isolating stem cells from adipose tissue, differentiating them into beige adipose tissue cells, and then delivering them via a hyaluronic acid hydrogel matrix. Mice that received the transplanted beige adipose tissue showed improved metabolic profiles compared with their WAT-transplanted mice counterparts, including lower resting glucose levels, lower serum triglyceride levels, and less weight gain when fed a 60% fat diet.
Gelesis100 is a novel intervention consisting of a capsule filled with a biocompatible hydrogel that expands in the stomach after absorbing water. The expanded material results in increased intragastric volume and ultimately early satiety. The Gelesis100 material also acts as a barrier to glucose absorption in the small intestine. Similar to bariatric surgery, this product provides restrictive, maldigestive, and malabsorptive mechanisms to induce weight loss. Gelesis100 is currently under study, but is not yet FDA approved. However, early data have shown that a significantly greater proportion of overweight/obese subjects in the low-dose treatment arm lost 10% of their baseline body weight compared with placebo. The adverse effects were similar in both groups. It remains to be seen whether Gelesis100 will prove to be an effective, minimally invasive supplemental therapy to standard behavioral modifications for obese individuals.
Complementary and Alternative Medicine
Complementary and alternative medicine (CAM) is a growing trend in recent years, augmenting traditional Western practices for the treatment of a variety of diseases, including obesity. Although not generally recommended as a sole therapy, CAM for weight loss has become increasingly popular as a way to take a more natural approach to healthy eating habits and lifestyle modifications through mediums such as hypnosis, mindfulness-based practices, acupuncture, and dietary supplements. Some of the available CAM therapies for obesity are listed in Table 1 .
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