Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy

Abstract

Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.

Keywords: adipose tissue; central nervous system; gastrointestinal hormones; nanotherapy; novel drug delivery systems; obesity; pharmacotherapy.

Graphical Abstract

A synopsis of major target tissues/organs for current antiobesity pharmacotherapeutic approaches.

Figure 1.

Potential antiobesity strategies. The figure outlines the potential antiobesity strategies discussed in the review. Abbreviations: CB1R, cannabinoid-1 receptor antagonists; CCK, cholecystokinin; CNS, central nervous system; CRISPR, clustered regularly interspaced short palindromic repeats; CRMP, controlled-release mitochondrial protonophore; DACRAs, dual amylin- and calcitonin receptor agonists; DBZ, dibenzazepine; DNPME, 2,4-dinitrophenol methyl ether; FGF21, fibroblast growth factor 21; GDF-15, growth differentiation factor-15; GI, gastrointestinal; GLP-1RA, glucagon-like peptide 1 receptor agonists; GPR, G protein-coupled receptor; NPY, neuropeptide Y antagonists; OXM, oxyntomodulin; PYY, peptide YY; SGTL1/2, dual inhibitors of sodium-glucose cotransporters 1 and 2; SGLT2is, sodium-glucose cotransporter-2 inhibitors; TALENs, transcription activator-like effector nucleases; VLPs, virus-like proteins; WAT, white adipose tissue.

Figure 2.

Energy homeostasis and weight regulation. Energy intake and energy expenditure are tightly coupled through integrated central nervous system (CNS) networks and peripheral organ hormones that act in concert to regulate feeding behavior and energy homeostasis. Energy intake is governed by 5 major CNS networks that include the homeostatic, reward, emotion/memory, attention, and cognitive control systems. Afferent neurohormonal signals from peripheral organs influence these CNS networks. Energy expenditure is comprised of resting energy expenditure, physical activity, caloric losses, and diet-induced thermogenesis. Cumulative imbalances in energy intake and expenditure over time caused by a myriad of genetic, developmental, and environmental factors may result in obesity. Abbreviation: GI, gastrointestinal.

Figure 3.

The figure summarizes the hormonal pathways and their main hypothalamic targets discussed in this review. Two major opposing types of output neurons, neuropeptide Y–agouti-related protein (AgRP/NPY) and pro-opiomelanocortin (POMC) expressing neurons, are identified within the arcuate nucleus of the hypothalamus. AgRP/NPY and POMC-expressing neurons are associated with orexigenic and anorexigenic signals, respectively. POMC neurons act in part through melanocortin-3 and 4 receptors (MC3R and MC4R, respectively). POMC is processed to α-melanocyte-stimulating factor (α-MSH), which acts as an agonist at the MC3R and MC4R. At the same time, AgRP is an inverse agonist, opposing the central melanocortin action and the anorexigenic effects of POMC neurons. On the other hand, NPY is an inhibitory neuropeptide promoting food intake and suppressing energy use. POMC and NPY/AgRP neurons signal to the paraventricular nucleus (PVN) and other hypothalamic nuclei to decrease or increase appetite, respectively. Moreover, hypothalamic neurocircuits are also connected with other brain centers, which control appetite and the “hedonic” aspects of food intake. The ARC is essential in integrating hormonal signals involved in energy homeostasis control. Furthermore, afferent signals from gastrointestinal and adipose tissue can directly stimulate the previously mentioned areas, influencing appetite and food intake. Abbreviations: CCK, cholecystokinin; DMH, dorsomedial nucleus of the hypothalamus; GIP, glucose-dependent insulinotropic polypeptide; PYY, peptide YY; VMH, ventromedial nucleus of the hypothalamus.

Figure 4.

Adipose tissue can be classified as white, brown, or beige. Recent insights into the distinct roles of each of these adipocyte populations in energy homeostasis have informed investigations of antiobesity drugs targeting adipose tissue. β3-adrenergic receptor agonists (eg, mirabegron) activate brown adipose tissue (BAT) and increase energy expenditure through the induction of uncoupling protein 1 on the inner mitochondrial membrane, which dissociates oxidative phosphorylation, generating heat rather than adenosine triphosphate. Beige adipocytes are a subpopulation of adipocytes within white adipose tissue (WAT) that are functionally similar to BAT and can be “recruited” through various stimuli in a process known as WAT browning. Brown adipogenesis is regulated by several molecular targets, including PRDM16, which forms a transcriptional complex with CCAAT/enhancer-binding protein-β (C/EBPβ) and stimulates the differentiation of brown adipocytes from precursor cells through activation of peroxisome proliferator activated receptor γ (PPARγ) and PPAR-γ coactivator 1α (PGC1α). While these molecular targets of WAT browning have been explored in rodent studies, none have advanced to clinical studies in humans. Finally, adipokines are bioactive peptides released by WAT that play an important role in energy homeostasis. Several adipokines have been identified as plausible antiobesity targets, of which leptin is the most well-studied. Abbreviations: β3-AR, beta-3 adrenoreceptor; BMP7, bone morphogenetic protein 7; FGF21, fibroblast growth factor 21; IL-1β, interleukin-1β; NAMPT, nicotinamide phosphoribosyltransferase; PRDM16, PR domain zinc finger protein 16; TNFα, tumour necrosis factor α; UCP1, uncoupling protein 1.

Figure 5.

A summary of the major nanotechnology-mediated (nanotherapeutic) antiobesity strategies tested in preclinical studies in diet-induced obese rodents. (A) prohibitin (PHB)-targeted nanotherapy for inhibition of angiogenesis. (B) White adipose tissue (WAT) browning [dibenzazepine (DBZ)]. (C) WAT browning by noninvasive transcutaneous microneedle patch (rosiglitazone). (D) Photothermal lipolysis using nanospheres as photosensitizing agents. These data in animal models of obesity suggest that it is feasible to reverse obesity and improve the metabolic phenotype by directly targeting WAT and its vasculature using nanotherapeutic angiogenic inhibitors (A), WAT browning agents (B and C), and photothermal agents (D). See the text for further details on experimental design. Source: The artwork of the figure has been performed by Vassiliki Koliaki (architect engineer). Abbreviations: AHP, adipose homing peptide; HA, hyaluronic acid; NIR, near infrared; NP, nanoparticle; PLGA, poly(lactide-co-glycolide); Rosi, rosiglitazone; sc, subcutaneous; Ucp-1, uncoupling protein 1.