The CNS regulates body weight; however, we still lack a clear understanding of what drives decisions about when, how much and what to eat. A vast array of peripheral signals provides information to the CNS regarding fluctuations in energy status. The CNS then integrates this information to influence acute feeding behaviour and long-term energy homeostasis. Previous paradigms have delegated the control of long-term energy homeostasis to the hypothalamus and short-term changes in feeding behaviour to the hindbrain. However, recent studies have identified target hindbrain neurocircuitry that integrates the orchestration of individual bouts of ingestion with the long-term regulation of energy balance.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Svendsen, B. et al. An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. Endocrinology 156, 847–857 (2015).
Psichas, A. et al. Gut chemosensing mechanisms. J. Clin. Invest. 125, 908–917 (2015).
Steinert, R. E. et al. Ghrelin, CCK, GLP-1, and PYY (3–36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB. Physiol. Rev. 97, 411–463 (2017). This paper is the pinnacle of the reviews on gut peptides that regulate feeding.
Batterham, R. L. et al. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab. 4, 223–233 (2006).
Scrocchi, L. A., Hill, M. E., Saleh, J., Perkins, B. & Drucker, D. J. Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action. Diabetes 49, 1552–1560 (2000).
Chambers, A. P. et al. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab. 25, 927–934 (2017).
Sandoval, D. A. & D'Alessio, D. A. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 95, 513–548 (2015).
Holst, J. J. The physiology of glucagon-like peptide 1. Physiol Rev. 87, 1409–1439 (2007).
West, D. B., Fey, D. & Woods, S. C. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am. J. Physiol. 246, R776–R787 (1984).
Miller, L. J., Holicky, E. L., Ulrich, C. D. & Wieben, E. D. Abnormal processing of the human cholecystokinin receptor gene in association with gallstones and obesity. Gastroenterology 109, 1375–1380 (1995).
Inoue, H. et al. Human cholecystokinin type A receptor gene: cytogenetic localization, physical mapping, and identification of two missense variants in patients with obesity and non-insulin-dependent diabetes mellitus (NIDDM). Genomics 42, 331–335 (1997).
Bagdade, J. D., Bierman, E. L. & Porte, D. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J. Clin. Invest. 46, 1549–1557 (1967).
Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).
Halaas, J. L. et al. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl Acad. Sci. USA 94, 8878–8883 (1997).
Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979). This study is one of the first to demonstrate the role of insulin with the CNS to regulate feeding.
Sipols, A. J., Baskin, D. G. & Schwartz, M. W. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 44, 147–151 (1995).
Tschöp, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).
Cummings, D. E. et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat. Med. 8, 643–644 (2002).
Zigman, J. M. et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J. Clin. Invest. 115, 3564–3572 (2005).
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000).
Leinninger, G. M. et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 14, 313–323 (2011).
Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).
van de Wall, E. et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149, 1773–1785 (2008).
Myers, M. G. & Olson, D. P. SnapShot: neural pathways that control feeding. Cell Metab. 19, 732–732.e1 (2014). This paper contains many perceptive schematic figures of the neural pathways of feeding control.
Marston, O. J., Garfield, A. S. & Heisler, L. K. Role of central serotonin and melanocortin systems in the control of energy balance. Eur. J. Pharmacol. 660, 70–79 (2011).
Burmeister, M. A. et al. The hypothalamic glucagon-like peptide 1 receptor is sufficient but not necessary for the regulation of energy balance and glucose homeostasis in mice. Diabetes 66, 372–384 (2017).
Batterham, R. L. et al. Gut hormone PYY3-36 physiologically inhibits food intake. Nature 418, 650–654 (2002).
Wren, A. M. et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 50, 2540–2547 (2001).
Sandoval, D. A., Bagnol, D., Woods, S. C., D'Alessio, D. A. & Seeley, R. J. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57, 2046–2054 (2008).
Kinzig, K. P., D'Alessio, D. A. & Seeley, R. J. The diverse roles of CNS GLP-1 in the control of food intake and the mediation of visceral illness. J. Neurosci. 22, 10470–10476 (2002).
Woods, S. C., Begg, D. P. & Woods, S. C. The endocrinology of food intake. Nat. Rev. Endocrinol. 9, 584–597 (2013).
Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351–355 (2011). This study uses optogenetics to demonstrate the melanocortin-independent effects of AGRP neurons on regulation of feeding behaviour.
Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011). This study uses DREADD technology to demonstrate the role of AGRP neurons on regulating feeding behaviour.
Zhan, C. et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624–3632 (2013).
Steculorum, S. M. et al. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016).
Berthoud, H. R., Blackshaw, L. A., Brookes, S. J. H. & Grundy, D. Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol. Motil. 16, 28–33 (2004).
Berthoud, H.-R. Anatomy and function of sensory hepatic nerves. Anat. Rec. 280A, 827–835 (2004).
Woods, S. C. Metabolic signals and food intake. Forty years of progress. Appetite 71, 440–444 (2013).
Wang, P. Y. et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 452, 1012–1016 (2008).
Grabauskas, G., Song, I., Zhou, S. & Owyang, C. Electrophysiological identification of glucose-sensing neurons in rat nodose ganglia. J. Physiol. 588, 617–632 (2010).
Lal, S., Kirkup, A. J., Brunsden, A. M., Thompson, D. G. & Grundy, D. Vagal afferent responses to fatty acids of different chain length in the rat. Am. J. Physiol. 281, G907–G915 (2001).
Randich, A. et al. Responses of celiac and cervical vagal afferents to infusions of lipids in the jejunum or ileum of the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278, R34–R43 (2000).
Liu, C. et al. PPARγ in vagal neurons regulates high-fat diet induced thermogenesis. Cell Metab. 19, 722–730 (2014).
Mansuy-Aubert, V. et al. Loss of the liver X receptor LXRα/β in peripheral sensory neurons modifies energy expenditure. eLife 4, e06667 (2015).
Ritter, S. & Taylor, J. S. Vagal sensory neurons are required for lipoprivic but not glucoprivic feeding in rats. Am. J. Physiol. 258, R1395–R1401 (1990).
Darling, R. A. et al. Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R35–R43 (2014).
Li, A.-J., Wang, Q., Dinh, T. T., Simasko, S. M. & Ritter, S. Mercaptoacetate blocks fatty acid-induced GLP-1 secretion in male rats by directly antagonizing GPR40 fatty acid receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R724–R732 (2016).
Williams, E. K. et al. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166, 209–221 (2016). This study finds that there are distinct projections of vagal neurons to the GI tract that provide nutritive and mechanical information from the gut to the CNS.
Moran, T. H., Baldessarini, A. R., Salorio, C. F., Lowery, T. & Schwartz, G. J. Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. Am. J. Physiol. 272, R1245–R1251 (1997).
Raybould, H. E. et al. Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G367–G372 (2003).
Babic, T., Troy, A. E., Fortna, S. R. & Browning, K. N. Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons. Neurogastroenterol. Motil. 24, e476–e488 (2012).
Baumgartner, I. et al. Hepatic-portal vein infusions of glucagon-like peptide-1 reduce meal size and increase c-Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats. J. Neuroendocrinol. 22, 557–563 (2010).
Kim, D.-H., D'Alessio, D. A., Woods, S. C. & Seeley, R. J. The effects of GLP-1 infusion in the hepatic portal region on food intake. Regul. Pept. 155, 110–114 (2009).
Hayes, M. R. et al. The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1479–1485 (2011).
Abbott, C. R. et al. The inhibitory effects of peripheral administration of peptide YY3–36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal–brainstem–hypothalamic pathway. Brain Res. 1044, 127–131 (2005).
Plamboeck, A. et al. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1117–G127 (2013).
Kanoski, S. E., Fortin, S. M., Arnold, M., Grill, H. J. & Hayes, M. R. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology 152, 3103–3112 (2011).
Baraboi, E.-D. et al. Effects of albumin-conjugated PYY on food intake: the respective roles of the circumventricular organs and vagus nerve. Eur. J. Neurosci. 32, 826–839 (2010).
Halatchev, I. G. & Cone, R. D. Peripheral administration of PYY3–36 produces conditioned taste aversion in mice. Cell Metab. 1, 159–168 (2005).
Ripken, D. et al. Cholecystokinin regulates satiation independently of the abdominal vagal nerve in a pig model of total subdiaphragmatic vagotomy. Physiol. Behav. 139, 167–176 (2015).
Reidelberger, R. D., Hernandez, J., Fritzsch, B. & Hulce, M. Abdominal vagal mediation of the satiety effects of CCK in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R1005–R1012 (2004).
Diepenbroek, C. et al. Validation and characterization of a novel method for selective vagal deafferentation of the gut. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G342–G352 (2017).
de Lartigue, G., Ronveaux, C. C. & Raybould, H. E. Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity. Mol. Metab. 3, 595–607 (2014).
Sisley, S. et al. Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J. Clin. Invest. 124, 2456–2463 (2014).
Krieger, J.-P. et al. Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia. Diabetes 65, db150973 (2015).
Ritter, R. C. Gastrointestinal mechanisms of satiation for food. Physiol. Behav. 81, 249–273 (2004).
Hayes, M. R. et al. Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab. 13, 320–330 (2011).
Hisadome, K., Reimann, F., Gribble, F. M. & Trapp, S. Leptin directly depolarizes preproglucagon neurons in the nucleus tractus solitarius: electrical properties of glucagon-like peptide 1 neurons. Diabetes 59, 1890–1898 (2010).
Barrera, J. G. et al. Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J. Neurosci. 31, 3904–3913 (2011).
Gaykema, R. P. et al. Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight. J. Clin. Invest. 127, 1031–1045 (2017). This study uses DREADD technology to understand the role of preproglucagon neurons in the regulation of energy homeostasis.
Lachey, J. L. et al. The role of central glucagon-like peptide-1 in mediating the effects of visceral illness: differential effects in rats and mice. Endocrinology 146, 458–462 (2005).
Scott, M. M., Williams, K. W., Rossi, J., Lee, C. E. & Elmquist, J. K. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J. Clin. Invest. 121, 2413–2421 (2011).
Hayes, M. R. et al. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 11, 77–83 (2010).
Grill, H. J. et al. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143, 239–246 (2002).
Garfield, A. S. et al. Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract. Endocrinology 153, 4600–4607 (2012).
Hisadome, K., Reimann, F., Gribble, F. M. & Trapp, S. CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs. Diabetes 60, 2701–2709 (2011).
Alhadeff, A. L., Golub, D., Hayes, M. R. & Grill, H. J. Peptide YY signaling in the lateral parabrachial nucleus increases food intake through the Y1 receptor. Am. J. Physiol. Endocrinol. Metab. 309, E759–E766 (2015).
Alhadeff, A. L., Baird, J.-P., Swick, J. C., Hayes, M. R. & Grill, H. J. Glucagon-like peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed. Neuropsychopharmacology 39, 2233–2243 (2014).
Alhadeff, A. L., Hayes, M. R. & Grill, H. J. Leptin receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R1338–R1344 (2014).
Campos, C. A., Bowen, A. J., Schwartz, M. W. & Palmiter, R. D. Parabrachial CGRP neurons control meal termination. Cell Metab. 23, 811–820 (2016). This study shows that specific populations of neurons within the parabrachial nucleus are important in regulated feeding.
Roman, C. W., Derkach, V. A. & Palmiter, R. D. Genetically and functionally defined NTS to PBN brain circuits mediating anorexia. Nat. Commun. 7, 11905 (2016).
Essner, R. A. et al. AgRP neurons can increase food intake during conditions of appetite suppression and inhibit anorexigenic parabrachial neurons. J. Neurosci. 37, 798–717 (2017).
Stachniak, T. J., Ghosh, A. & Sternson, S. M. Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior. Neuron 82, 797–808 (2014).
Weissbourd, B. et al. Presynaptic partners of dorsal raphe serotonergic and GABAergic neurons. Neuron 83, 645–662 (2014).
Nectow, A. R. et al. Identification of a brainstem circuit controlling feeding. Cell 170, 429–442.e11 (2017). This study identifies specific neurons in the dorsal raphe nucleus a novel feeding regulator.
Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J. & Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678–693 (2008).
Katsuma, S., Hirasawa, A. & Tsujimoto, G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem. Biophys. Res. Commun. 329, 386–390 (2005).
Alemi, F. et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144, 145–154 (2013).
Nies, V. J. M. et al. Fibroblast growth factor signaling in metabolic regulation. Front. Endocrinol. 6, 193 (2016).
Fu, L. et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 145, 2594–2603 (2004).
Ryan, K. K. et al. Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154, 9–15 (2013).
Lan, T. et al. FGF19, FGF21, and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia. Cell Metab. 26, 709–718.e3 (2017).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1131 (2006).
Turnbaugh, P. J., Bäckhed, F., Fulton, L. & Gordon, J. I. Diet-Induced Obesity Is Linked to Marked but Reversible Alterations in the Mouse Distal Gut Microbiome. Cell Host Microbe 3, 213–223 (2008). This paper links altered microbiome populations to dietary-induced obesity.
Kahles, F. et al. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 63, 3221–3229 (2014).
Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).
Rao, S. et al. Pathogen-mediated inhibition of anorexia promotes host survival and transmission. Cell 168, 503–516.e12 (2017).
Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).
Perry, R. J. et al. Acetate mediates a microbiome–brain–β-cell axis to promote metabolic syndrome. Nature 534, 213–217 (2016).
Hsu, J.-Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).
Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157 (2017).
Emmerson, P. J. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 23, 1215–1219 (2017).
Yang, L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158–1166 (2017).
Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl Med. 9, eaan8732 (2017).
Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N. Engl. J. Med. 366, 1567–1576 (2012). This paper demonstrates the much greater efficacy of bariatric surgery in diabetes treatment than that of intensive medical therapy.
Seeley, R. J., Chambers, A. P. & Sandoval, D. A. The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes. Cell Metab. 21, 369–378 (2015).
le Roux, C. W. et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann. Surg. 246, 780–785 (2007).
Yousseif, A. et al. Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans. Obes. Surg. 24, 241–252 (2014).
Wilson-Pérez, H. E. et al. The effect of vertical sleeve gastrectomy on food choice in rats. Int. J. Obes. 37, 288–295 (2013).
Mokadem, M., Zechner, J. F., Margolskee, R. F., Drucker, D. J. & Aguirre, V. Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Mol. Metab. 3, 191–201 (2014).
Wilson-Pérez, H. E. et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide-1 receptor deficiency. Diabetes 62, 2380–2385 (2013).
Ye, J. et al. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306, R352–362 (2014).
Chambers, A. P. et al. Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy. Am. J. Physiol. Endocrinol. Metab. 306, E424–E432 (2014).
Nguyen, N. Q. et al. Rapid gastric and intestinal transit is a major determinant of changes in blood glucose, intestinal hormones, glucose absorption, and postprandial symptoms after gastric bypass. Obesity 22, 2003–2009 (2014).
Myronovych, A. et al. Vertical sleeve gastrectomy reduces hepatic steatosis while increasing serum bile acids in a weight-loss-independent manner. Obesity 22, 390–400 (2014).
Patti, M.-E. et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity 17, 1671–1677 (2009).
McGavigan, A. K. et al. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut 66, 226–234 (2017).
Ding, L. et al. Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 64, 760–773 (2016).
Ryan, K. K. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188 (2014).
Shin, A. C., Zheng, H. & Berthoud, H.-R. Vagal innervation of the hepatic portal vein and liver is not necessary for Roux-en-Y gastric bypass surgery-induced hypophagia, weight loss, and hypermetabolism. Ann. Surg. 255, 294–301 (2012).
Gautron, L., Zechner, J. F. & Aguirre, V. Vagal innervation patterns following Roux-en-Y gastric bypass in the mouse. Int. J. Obes. 37, 1603–1607 (2013).
Hao, Z. et al. Vagal innervation of intestine contributes to weight loss after Roux-en-Y gastric bypass surgery in rats. Obes. Surg. 24, 2145–2151 (2014).
Hankir, M. K. et al. Gastric bypass surgery recruits a gut PPAR-α-striatal D1R pathway to reduce fat appetite in obese rats. Cell Metab. 25, 335–344 (2017). This study demonstrates that vagal innervation is necessary for surgery-induced changes in food choice.
Benoit, S. C., Hunter, T. D., Francis, D. M. & De La Cruz-Munoz, N. Use of Bariatric Outcomes Longitudinal Database (BOLD) to study variability in patient success after bariatric surgery. Obes. Surg. 24, 936–943 (2014).
Geary, N. in Satiation. From Gut to Brain (ed. Smith, G. P.) 164–197 (Oxford Univ. Press, 1998).
Pocai, A. et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258–2266 (2009).
Finan, B. et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856 (2012).
Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl Med. 5, 209ra151 (2013).
Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2014).
Wren, A. M. & Bloom, S. R. Gut hormones and appetite control. Gastroenterology 132, 2116–2130 (2007).
Williams, D. L., Grill, H. J., Cummings, D. E. & Kaplan, J. M. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 144, 5184–5187 (2003).
Masuda, Y. et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem. Biophys. Res. Commun. 276, 905–908 (2000).
Sato, T. et al. Structure, regulation and function of ghrelin. J. Biochem. 151, 119–128 (2012).
Foster-Schubert, K. E. et al. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J. Clin. Endocrinol. Metab. 93, 1971–1979 (2008).
Batterham, R. L. et al. Inhibition of food intake in obese subjects by peptide YY 3–36. N. Engl. J. Med. 349, 941–948 (2003).
Mentlein, R., Dahms, P., Grandt, D. & Krüger, R. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Pept. 49, 133–144 (1993).
Magnus, C. J. et al. Chemical and genetic engineering of selective ion channel-ligand interactions. Science 333, 1292–1296 (2011).
Gomez, J. L. et al. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 357, 503–507 (2017).
Kim, K.-S. & Sandoval, D. A. in Comprehensive Physiology (ed. Pollock, D. M.) 783–798 (John Wiley & Sons, 2017).
The authors' work is supported in part by US National Institutes of Health awards DK082480 (D.A.S.) and DK093848 (R.J.S.).
K.-S.K. has no competing interest. R.J.S. has received research support from Ethicon Endo-Surgery, Novo Nordisk, Sanofi and Janssen. R.J.S. has served on scientific advisory boards for Ethicon Endo-Surgery, Daiichi Sankyo, Janssen, Novartis, Nestle, Takeda, Boehringer Ingelheim, Sanofi and Novo Nordisk. R.J.S. is also a paid speaker for Ethicon Endo-Surgery. D.A.S. has received research support from Ethicon Endo-Surgery, Novo Nordisk and Boehringer Ingelheim.
- Vagus nerve
The longest cranial nerve. It contains both motor and sensory fibres involved in the parasympathetic regulation of homeostatic processes.
- Enteroendocrine cells
Specialized endocrine cells within the intestine that secrete peptides important for regulating feeding and metabolism.
- Afferent neurons
Peripheral sensory neurons that carry ascending nerve impulses from peripheral organs to the brain and spinal cord.
- G-Protein-coupled receptor
(GPCR). Seven-transmembrane receptor that is coupled to, and activates, a heterotrimeric G protein, which subsequently activates a series of downstream signalling cascades; this receptor class is large and diverse and binds to a variety of nutrients and hormones.
- Nodose ganglion
Contains the cell bodies of neurons of the vagus nerve.
- Nutrient sensing
A process by which nutrients or their by-products directly activate cell signalling cascades that, in turn, regulate metabolism.
- Efferent neurons
Peripheral motor neurons that carry descending nerve impulses from the CNS to peripheral organs.
- Bariatric surgery
A surgical dissection and/or reorganization of the gastrointestinal tract that is used to induce weight loss.
About this article
Cite this article
Kim, KS., Seeley, R. & Sandoval, D. Signalling from the periphery to the brain that regulates energy homeostasis. Nat Rev Neurosci 19, 185–196 (2018). https://doi.org/10.1038/nrn.2018.8
Annual Review of Physiology (2021)
GWAS reveal a role for the central nervous system in regulating weight and weight change in response to exercise
Scientific Reports (2021)
Identification of Sox2 and NeuN Double-Positive Cells in the Mouse Hypothalamic Arcuate Nucleus and Their Reduction in Number With Aging
Frontiers in Aging Neuroscience (2021)