Challenges and Opportunities in the Management of Obesity
Challenges and Opportunities in the Management of Obesity
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.
The search for effective treatments for obesity has led to a greater understanding of adiposity, GI and adipocyte-related hormones, inflammatory mediators, the gut–brain axis and the hypothalamic nervous system involved in appetite regulation (figure 1). The effects of different interventions on the pathophysiological mechanisms of obesity are the subject of ongoing research. Understanding the pathophysiological mechanisms of obesity provides an opportunity to develop novel approaches to treat, at relatively low cost and enhanced safety, the ever-expanding population of obese people.
(Enlarge Image)
Figure 1.
Complex mechanism of food intake regulation. The food intake process initiates when nutrients enter the GI 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, GI 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 behaviour 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 GI 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; peptide tyrosine–tyrosine (PYY3)-36, peptide tyrosine-tyrosine 3-36; POMC, proopiomelanocortin; TNF, tumour necrosis factor; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone.
Abstract and Introduction
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.
Introduction
The search for effective treatments for obesity has led to a greater understanding of adiposity, GI and adipocyte-related hormones, inflammatory mediators, the gut–brain axis and the hypothalamic nervous system involved in appetite regulation (figure 1). The effects of different interventions on the pathophysiological mechanisms of obesity are the subject of ongoing research. Understanding the pathophysiological mechanisms of obesity provides an opportunity to develop novel approaches to treat, at relatively low cost and enhanced safety, the ever-expanding population of obese people.
(Enlarge Image)
Figure 1.
Complex mechanism of food intake regulation. The food intake process initiates when nutrients enter the GI 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, GI 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 behaviour 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 GI 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; peptide tyrosine–tyrosine (PYY3)-36, peptide tyrosine-tyrosine 3-36; POMC, proopiomelanocortin; TNF, tumour necrosis factor; TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone.
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