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Gastric bypass surgery stimulates the dormant gut-brain axis in obesity

2017; Elsevier BV; Volume: 92; Issue: 1 Linguagem: Inglês

10.1016/j.kint.2017.05.001

1523-1755

Stephanie P. B. Caligiuri, Paul J. Kenny,

Diet, Metabolism, and Disease

To truly reduce the rates of chronic kidney disease, a root cause of kidney damage, obesity, must be targeted. Weight loss is often unsustainable because imbalances in satiety regulators are frequently not addressed to ensure maintenance of weight loss. In a recent study, gastric bypass surgery rebalanced satiety signals through resensitization of the gut-brain axis in obesity. This research may lead to noninvasive strategies to reduce obesity and obesity-related kidney disease. To truly reduce the rates of chronic kidney disease, a root cause of kidney damage, obesity, must be targeted. Weight loss is often unsustainable because imbalances in satiety regulators are frequently not addressed to ensure maintenance of weight loss. In a recent study, gastric bypass surgery rebalanced satiety signals through resensitization of the gut-brain axis in obesity. This research may lead to noninvasive strategies to reduce obesity and obesity-related kidney disease. Obesity, independent of hypertension and diabetes, increases the risk of end-stage renal disease up to 7-fold.1Hsu C.Y. McCulloch C.E. Iribarren C. et al.Body mass index and risk for end-stage renal disease.Ann Intern Med. 2006; 144: 21-28Crossref PubMed Scopus (1031) Google Scholar This increased risk is attributed to maladaptive changes such as glomerular hyperfiltration, glomerular matrix expansion, and glomerulomegaly, which eventually lead to glomerulosclerosis, interstitial fibrosis, and chronic kidney disease.2Caligiuri S.P. Blydt-Hansen T. Love K. et al.Evidence for the use of glomerulomegaly as a surrogate marker of glomerular damage and for alpha-linolenic acid-rich oils in the treatment of early obesity-related glomerulopathy in a diet-induced rodent model of obesity.Appl Physiol Nutr Metab. 2014; 39: 951-959Crossref PubMed Scopus (9) Google Scholar, 3Kovesdy C.P. Furth S.L. Zoccali C. et al.Obesity and kidney disease: hidden consequences of the epidemic.Kidney Int. 2016; 91: 260-262Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Weight loss can improve proteinuria and kidney function.4Afshinnia F. Wilt T.J. Duval S. et al.Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts.Nephrol Dial Transplant. 2010; 25: 1173-1183Crossref PubMed Scopus (172) Google Scholar However, weight loss is often refractory and unsustainable, with 5-year success rates of approximately 50%.5Anderson J.W. Konz E.C. Frederich R.C. et al.Long-term weight-loss maintenance: a meta-analysis of US studies.Am J Clin Nutr. 2001; 74: 579-584Crossref PubMed Scopus (856) Google Scholar The lack of success in maintaining weight loss is often because of the failure to address the imbalance of many homeostatic controls of body weight. Obesity is characterized by blunted satiety signals, as evidenced by reduced dopamine release, increased reward thresholds, and decreased dopamine receptor expression.6Johnson P.M. Kenny P.J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.Nat Neurosci. 2010; 13: 635-641Crossref PubMed Scopus (1052) Google Scholar More recently, weight gain and high fat intake have been shown to induce gut desensitization to lipids and reduced production of the lipid satiety amide, oleoylethanolamine (OEA).7Tellez L.A. Medina A. Han W. et al.A gut lipid messenger links excess dietary fat to dopamine deficiency.Science. 2013; 341: 800-802Crossref PubMed Scopus (202) Google Scholar When OEA is administered to mice consuming a high-fat diet, dopamine levels increase and abnormalities in brain reward pathways improve.7Tellez L.A. Medina A. Han W. et al.A gut lipid messenger links excess dietary fat to dopamine deficiency.Science. 2013; 341: 800-802Crossref PubMed Scopus (202) Google Scholar Imbalances in the brain satiety signals contribute to the insatiable intake of large quantities of high-calorie food, which in turn perpetuates weight gain and obesity. Addressing the alterations in gut-brain satiety signals is of key importance to establish effective maintenance of weight loss and thus decrease the sequelae of obesity, including chronic kidney disease. In a recent article in Cell Metabolism, Hankir and colleagues suggested an approach to resensitize the gut-brain axis by learning from a successful weight loss technique, bariatric surgery8Hankir M.K. Seyfried F. Hintschich C.A. et al.Gastric bypass surgery recruits a gut PPAR-α-striatal D1R pathway to reduce fat appetite in obese rats.Cell Metab. 2017; 25: 335-344Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar (summarized in Figure 1). Utilizing a rat model of gastric bypass, the authors investigated the role of the lipid satiety amide, OEA, and how it led to the success and maintenance of weight loss. The authors performed a Roux-en-Y gastric bypass in male Wistar rats with diet-induced obesity. As expected, the rats exhibited a reduction in body weight, an attenuation of weight gain, a decrease in high fat preference, and a decrease in total calories consumed after the operation.8Hankir M.K. Seyfried F. Hintschich C.A. et al.Gastric bypass surgery recruits a gut PPAR-α-striatal D1R pathway to reduce fat appetite in obese rats.Cell Metab. 2017; 25: 335-344Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Secondly, Hankir and colleagues investigated the levels of the lipid satiety amide OEA in the rat intestine. Rats consuming a high-fat diet exhibited lower levels of intestinal OEA versus low-fat controls. In rats with diet-induced obesity, gastric bypass induced a striking elevation in intestinal OEA; approximately 3-fold higher concentrations were observed in the ileum versus the sham-operated control. Gastric bypass surgery also stimulated reward pathways in the striatum, a subcortical region of the brain that mediates reward behavior. In rats undergoing the bypass operation, a doubling of dorsolateral striatal dopamine release and ∼50% higher striatal dopamine 1 receptor density were observed versus the sham-operated control. Thus, the authors concluded that bariatric surgery activated the OEA-striatal dopamine pathway, and hypothesized that activation of this pathway was dependent on peroxisome proliferator–activated receptor alpha (PPARα) and the vagus nerve. Vagotomy or administration of the PPARα antagonist GW-6471 with gastric bypass surgery resulted in a return to high fat preference and weight gain. Weight loss and decreased food intake were also dependent on dopamine. Striatal infusion of the dopamine receptor antagonist α-flupenthixol also reinstated high fat preference and food intake. The authors then studied whether modulation of these pathways without surgery induced similar changes as those occurring after gastric bypass surgery. Intestinal infusion of the PPAR-α–specific agonist WY-14643 resulted in a reduction in high fat intake and preference in sham-operated animals. However, blockade of the dopamine receptors in the dorsal striatum negated the effects of PPARα on high fat preference. Thus, activation of the -PPARα-striatal dopamine pathway was speculated to be the mechanism by which bariatric surgery induced such a profound effect to attenuate high-fat food preference, intake, and weight gain. These results hold exciting potential for the future of obesity and the ability to target the dormant gut-brain axis and imbalanced satiety signals often seen with obesity and high-fat diets. The mechanism by which gut OEA propagates striatal dopamine transmission via vagal input, and whether this pathway can be stimulated via other methods, are key areas of future exploration. Currently, clinical trials are underway to investigate the pharmacokinetics of selective inhibitors of fatty acid amide hydrolases, which may increase levels of OEA.9A Study to Assess the Effect of Race on How a Single Dose of ASP3652 Is Taken up, Metabolized and Distributed Through the Bodies of Young, Healthy Male and Female Subjects, and Its Safety and Tolerability. Clinical Trial Identifier: NCT01958047. Available at: https://clinicaltrials.gov/ct2/show/NCT01958047?term=oleoylethanolamide&rank=2. Accessed March 21, 2017.Google Scholar There is great potential in dietary manipulation or pharmaceutical development to alter the levels of OEA and other N-acylethanolamines that regulate appetite and satiety. Manipulation of gut lipid sensitivity, OEA, and thus dopamine may lead to truly effective strategies for the treatment of obesity and its sequelae, including chronic kidney disease. All the authors declared no competing interests. We thank the National Institutes of Health and the Canadian Institutes of Health Research.