Obesity surgery: happy with less or eternally hungry?

Abstract

The superior efficacy of bariatric surgery compared with intensive medical treatment in reversing metabolic disease is now well accepted, but the critical mechanisms remain unknown. Unlike dieting, which triggers strong counter-regulatory responses such as hunger and craving, some obesity surgeries appear to permanently reset the level of defended body weight. Understanding the molecular mechanisms behind successful surgery would thus go a long way in developing future 'knifeless' treatment options. Major candidates include changes in gut-brain signaling by hormones, bile acids, and other still unidentified factors. By re-sensitizing homeostatic regulatory circuits in the hypothalamus and hedonic-motivational processing in corticolimbic systems to internal signals, bariatric surgery could thus lead to a state of being content with less.

Fig. 1. Flow of information potentially involved in the physiological and behavioral consequences of gastric bypass surgery

The primary surgical insult in the gut leads to progressive adaptive changes in structure (e.g. mucosal hypertrophy) and function (e.g. shift in microbiota composition, hormone release patterns, and bile acid metabolism). These combined changes signal to other organs, such as the liver, adipose tissue, pancreas, muscle, and brain, through either the circulatory or nervous system and ultimately lead to changes in energy intake, food choice, and energy expenditure. Changes in signaling to the brain not only affect food intake, but also autonomic and endocrine outflow back to the gut as well as to the other organs. ANS: Autonomic nervous system.

Fig. 2. Potential mediation of beneficial effects of bariatric surgery by the classical hypothalamic homeostatic regulator of energy balance

Primary neurons in the arcuate nucleus sensitive to leptin and other metabolic state signals connect with secondary neurons in other parts of the hypothalamus to orchestrate activation of appropriate behavioral, autonomic, and endocrine anabolic and catabolic effector pathways. Major secondary neurons include Thyrotropin-releasing (TRH) and corticotrophin-releasing hormone (CRH) expressing neurons in the paraventricular nucleus (PVN) engaging the neuroendocrine axis, oxytocin (OT) expressing neurons in the PVN as well as orexin (Orex), melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) expressing neurons in the lateral hypothalamic area (LHA) projecting to autonomic outflow pathways and oromotor and locomotor control areas in the caudal brain stem and spinal cord. Most of the lateral hypothalamic secondary neurons also project to corticolimbic structures involved in reward as well as cognitive and emotional processes. By acting on components of this regulatory system, bariatric surgery may be able to reset the defended level of body weight/adiposity to a less obese state. NPY, Neuropeptide Y; AGRP, agoutirelated protein; GABA, gamma-aminobutyric acid; POMC, proopiomelanocortin; NT, neurotensin; Gal, galanin; Dyn, dynorphin; SCN, suprachiasmatic nucleus; 3V, third Ventricle; GLP-1, glucagon-like peptide-1; PYY, peptide tyrosine tyrosine; FGFs, fibroblast growth factors (Modified after )

Fig. 3. Potential effects of bariatric surgery on brain areas involved in reward

Brain areas involved inreward, cognitive, and emotional functions contributing to the control of food intake and representing the expanded homeostatic system regulating energy balance. Changes in circulating hormones and metabolites as well as changes in neuronal inputs from visceral afferents may affect (1) processing of sensory information all along the specific input pathways, (2) reward computation in the mesocorticolimbic dopamine system including the nucleus accumbens, (3) emotional valence computation in the amygdala, (4) formation and modification of “food memories” in insular and prefrontal cortex mediated by the hippocampal complex, and (5) decision making and executive control.