Recent advances in clinical practice challenges and opportunities in the management of obesity

Abstract

Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut-brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity.

Keywords: BRAIN/GUT INTERACTION; GASTROINTESTINAL HORMONES; OBESITY.

Figure 1. Complex Mechanism of Food Intake Regulation

The food intake process initiates when nutrients enter the gastrointestinal tract. Digestion starts when the nutrients enter the stomach and produce mechanic-dilation decreasing acyl-ghrelin and increasing desacyl-ghrelin and gastric leptin. Stomach dilation sends signals through the vagus nerve and peripheral nervous system to the brainstem and hypothalamus. The digested nutrient passes to the small intestine and colon producing further mechanic-dilation, GI hormones release, bile acid and pancreatic juices secretion. These GI hormones have a local effect (paracrine) and peripheral effect, when secreted into circulation, passed through the liver and affect the muscle, adipose tissue, gastrointestinal motility and function, and nucleus of the hypothalamus and brainstem. The paracrine and endocrine effect induces satiation and satiety. The muscle and adipose tissue release hormones which affect similar nuclei in the brain. The effect on the hypothalamus and brainstem trigger higher brain area responses, modulating behavior and enhancing nutrient-related reward. In the hypothalamus, first order neurons in the arcuate nucleus (ARC) modulate appetite by NPY/AGRP pathway and satiation by the POMC/CART pathway. The neurons interact with second order neurons in the Paraventricular nucleus (PVN) and Lateral hypothalamic (LHA) area to send signals to higher brain areas and to the brainstem. In the brainstem, the Nucleus of the tractus solitarius (NST) and dorsal vagal complex (DMNV) interact with the periphery and gastrointestinal system and brings signals to the higher brain areas and the hypothalamus. Abbreviations in alphabetical order: 5-HT: serotonin, ACTH: Adrenocorticotropic hormone, AGRP: Agouti-related peptide, ARC: arcuate nucleus, AVP: arginine vasopressin, BA: bile acids, CART: Cocaine- and amphetamine-regulated transcript, CCK: cholecystokinin, CRH: Corticotropin-releasing hormone, D: Dopamine, DMNV: dorsal vagal complex, FGF, Fibroblast growth factor -19, GABA: gamma-Aminobutyric acid, GLP-1: glucagon-like peptide-1, IL-6: interleukin-6; LHA: Lateral hypothalamic, MSH: melanocortin stimulating hormone, NA: noradrenaline, NPY: neuropeptide Y, NST: Nucleus of the tractus solitaries, NT: neurotensin, OT: oxytocin, Orex: orexin, OXM: oxyntomodulin, PP: Pancreatic polypeptide, PVN: Paraventricular nucleus, PYY3-36: peptide tyrosine-tyrosine 3-36, POMC: proopiomelanocortin, TNF: tumor necrosis factor, TRH: Thyroid-releasing hormone, TSH: Thyroid stimulating hormone.

Figure 2. Biological Relevance of RYGB Surgery

RYGB is a complex procedure with at least five distinct components, all of which may have biological relevance in the induction of weight loss or ameliorating hyperglycemia: (1) isolation of the gastric cardia by creation of a small gastric pouch, (2) exclusion of the distal stomach from contact with food, (3) exclusion of the proximal intestine from contact with food, (4) exposure of the jejunum to partially digested nutrients, (5) and partial vagotomy.

Figure 3. Duodenal-Jejunal Bypass Sleeve

The duodenal-jejunal bypass sleeve deploys in the duodenal bulb, this impermeable fluoropolymer sleeve extending 60 cm into the small bowel creates a mechanical barrier that allows food to bypass the duodenum and proximal jejunum, thus potentially manipulating the enteroinsular system (EndoBarrier®, GI Dynamics, Lexington, MA, USA).