No Guts, No Loss: Toward the Ideal Treatment for Obesity in the Twenty-First Century

Abstract

Over the last century, our knowledge of the processes which control appetite and weight regulation has developed significantly. The understanding of where gut hormones fit into the control of energy homeostasis in addition to the rapid advancement of pharmacotherapeutics has paved the way for the development of novel gut hormone analogs to target weight loss. Currently, bariatric surgery remains the most efficacious treatment for obesity. The emergence of gut hormone analogs may provide a useful non-surgical addition to the armamentarium in treating obesity. Simply targeting single gut hormone pathways may be insufficiently efficacious, and combination/multiple-agonist approaches may be necessary to obtain the results required for clear clinical impact.

Keywords: GLP-1; Oxyntomodulin; diabetes mellitus; gastric bypass surgery; glucagon; gut hormones; obesity.

Figure 1

Treatment gap in obesity therapy.

Figure 2

Gut brain axis schematic. The hypothalamus integrates anorexigenic and orexigenic signals. Peripheral signals such as gut peptides, leptin from adipose tissue and pancreatic signals are able to cross the blood-brain barrier at the median eminence (a circumventricular organ) or activate their cognate receptors at other circumventricular organs such as the area postrema (AP). These signals relay to the hypothalamic arcuate nucleus (ARC) via direct activation or indirectly via brainstem regions including the dorsal vagal complex (DVC) and nucleus tractus solitarus (NTS). Within the ARC, two key populations of neurons include those that express the orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP—an inverse agonist of the melanocortin receptor MC4R) and those expressing the anorexigenic pro-opiomelanocortin (POMC), processed to the MC4R agonist alpha-MSH, and cocaine- and amphetamine regulated transcript (CART). The ARC signals to second-order neurons in various hypothalamic nuclei including the paraventricular nucleus (PVN), dorsomedial nucleus (DMN), ventromedial nucleus (VMN) and lateral hypothalamic area (LHA). Second-order neurons express anorexigenic and orexigenic neuropeptides further modulating appetite and energy homeostasis. Vagal afferents also signal directly to brainstem regions. Higher central nervous system centers including the mesolimbic pathways also signal to the hypothalamic nuclei.

Figure 3

Post-translational products of Preproglucagon (17). Tissue specific processing by proprotein convertase 1 (PC-1) in the intestine and brain of proglucagon leads to formation of glicentin, GLP-1, GLP-2, oxyntomodulin. Note that GLP-1's C-terminal residue 108 is processed to the C-terminal amide. Processing of proglucagon by proprotein convertase 2 (PC-2) in the pancreas leads to the formation of glucagon, glicentin-related polypeptide (GRPP), and major proglucagon fragment (MPGF).