The anorexigenic hormone leptin and the orexigenic hormone ghrelin are crucial for metabolic regulation and energy homeostasis
Obesity-associated resistance to leptin and ghrelin promotes adiposity and might contribute to the diseases that are associated with this condition beyond metabolic disorders
Resistance to leptin and ghrelin is a multifactorial process that involves changes at several levels: from disturbed hormonal production to altered receptor trafficking and signalling in the brain
Several molecules and signalling pathways associated with leptin and ghrelin receptors have been identified as potential targets to overcome resistance to these hormones, but none has reversed the energy imbalance in the long term
The identification of novel molecular targets and pathways that can be modulated to enhance sensitivity to leptin and ghrelin and restore energy homeostasis is necessary for the development of efficient pharmacological treatments for obesity
Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.
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Stewart, S. T., Cutler, D. M. & Rosen, A. B. Forecasting the effects of obesity and smoking on U.S. life expectancy. N. Engl. J. Med. 361, 2252–2260 (2009).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).
Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).
Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).
Havel, P. J. et al. Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. J. Clin. Endocrinol. Metab. 81, 4406–4413 (1996).
Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97 (1996).
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).
Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).
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).
Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004).
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).
Rezai-Zadeh, K. et al. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol. Metab. 3, 681–693 (2014).
Dodd, G. T. et al. The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab. 20, 639–649 (2014).
Leal-Cerro, A. et al. Serum leptin levels in male marathon athletes before and after the marathon run. J. Clin. Endocrinol. Metab. 83, 2376–2379 (1998).
Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1, 1155–1161 (1995).
Lago, R., Gomez, R., Lago, F., Gomez-Reino, J. & Gualillo, O. Leptin beyond body weight regulation — current concepts concerning its role in immune function and inflammation. Cell. Immunol. 252, 139–145 (2008).
Lam, Q. L. & Lu, L. Role of leptin in immunity. Cell. Mol. Immunol. 4, 1–13 (2007).
Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L. & Sivitz, W. I. Receptor-mediated regional sympathetic nerve activation by leptin. J. Clin. Invest. 100, 270–278 (1997).
Rahmouni, K., Haynes, W. G. & Mark, A. L. Cardiovascular and sympathetic effects of leptin. Curr. Hypertens. Rep. 4, 119–125 (2002).
Elias, C. F. & Purohit, D. Leptin signaling and circuits in puberty and fertility. Cell. Mol. Life Sci. 70, 841–862 (2013).
Chen, X. X. & Yang, T. Roles of leptin in bone metabolism and bone diseases. J. Bone Miner. Metab. 33, 474–485 (2015).
Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).
Tartaglia, L. A. The leptin receptor. J. Biol. Chem. 272, 6093–6096 (1997).
Chua, S. C. Jr et al. Fine structure of the murine leptin receptor gene: splice site suppression is required to form two alternatively spliced transcripts. Genomics 45, 264–270 (1997).
Bates, S. H. & Myers, M. G. Jr. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol. Metab. 14, 447–452 (2003).
Scott, M. M. et al. Leptin targets in the mouse brain. J. Comp. Neurol. 514, 518–532 (2009).
Ihle, J. N. & Kerr, I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 11, 69–74 (1995).
Taniguchi, T. Cytokine signaling through nonreceptor protein tyrosine kinases. Science 268, 251–255 (1995).
Kloek, C. et al. Regulation of Jak kinases by intracellular leptin receptor sequences. J. Biol. Chem. 277, 41547–41555 (2002).
Devos, R. et al. Ligand-independent dimerization of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding. J. Biol. Chem. 272, 18304–18310 (1997).
Couturier, C. & Jockers, R. Activation of the leptin receptor by a ligand-induced conformational change of constitutive receptor dimers. J. Biol. Chem. 278, 26604–26611 (2003).
Allison, M. B. & Myers, M. G. Jr. 20 years of leptin: connecting leptin signaling to biological function. J. Endocrinol. 223, T25–T35 (2014).
Hekerman, P. et al. Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines. FEBS J. 272, 109–119 (2005).
Gong, Y. et al. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J. Biol. Chem. 282, 31019–31027 (2007).
Bjorbak, C. et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J. Biol. Chem. 275, 40649–40657 (2000).
Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006).
Harlan, S. M., Guo, D. F., Morgan, D. A., Fernandes-Santos, C. & Rahmouni, K. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. 17, 599–606 (2013).
Ottaway, N. et al. Diet-induced obese mice retain endogenous leptin action. Cell Metab. 21, 877–882 (2015).
Rosenbaum, M., Murphy, E. M., Heymsfield, S. B., Matthews, D. E. & Leibel, R. L. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J. Clin. Endocrinol. Metab. 87, 2391–2394 (2002).
Mark, A. L., Correia, M. L., Rahmouni, K. & Haynes, W. G. Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications. J. Hypertens. 20, 1245–1250 (2002).
Correia, M. L. et al. The concept of selective leptin resistance: evidence from agouti yellow obese mice. Diabetes 51, 439–442 (2002).
Rahmouni, K., Morgan, D. A., Morgan, G. M., Mark, A. L. & Haynes, W. G. Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes 54, 2012–2018 (2005).
Simonds, S. E. et al. Leptin mediates the increase in blood pressure associated with obesity. Cell 159, 1404–1416 (2014).
Mark, A. L. Selective leptin resistance revisited. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R566–R581 (2013).
Sinha, M. K. et al. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J. Clin. Invest. 98, 1277–1282 (1996).
Magni, P. et al. Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid profile and macronutrient preference. Clin. Endocrinol. 62, 189–196 (2005).
Houseknecht, K. L. et al. Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. Diabetes 45, 1638–1643 (1996).
Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J. & Porte, D. Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 2, 589–593 (1996).
Morgan, D. A., Thedens, D. R., Weiss, R. & Rahmouni, K. Mechanisms mediating renal sympathetic activation to leptin in obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1730–R1736 (2008).
Banks, W. A. & Farrell, C. L. Impaired transport of leptin across the blood–brain barrier in obesity is acquired and reversible. Am. J. Physiol. Endocrinol. Metab. 285, E10–E15 (2003).
Pan, W. et al. Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice. Endocrinology 149, 2798–2806 (2008).
Caro, J. F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).
Banks, W. A. Leptin transport across the blood–brain barrier: implications for the cause and treatment of obesity. Curr. Pharm. Des. 7, 125–133 (2001).
de Git, K. C. & Adan, R. A. Leptin resistance in diet-induced obesity: the role of hypothalamic inflammation. Obes. Rev. 16, 207–224 (2015).
Koga, S. et al. Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression. Neurobiol. Dis. 71, 180–192 (2014).
Jayaram, B. et al. Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity. J. Appl. Physiol. 114, 734–741 (2013).
Pierce, A. A. & Xu, A. W. De novo neurogenesis in adult hypothalamus as a compensatory mechanism to regulate energy balance. J. Neurosci. 30, 723–730 (2010).
Balland, E. et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 19, 293–301 (2014).
Lee, D. A. et al. Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat. Neurosci. 15, 700–702 (2012).
Zhang, C. et al. Tat-modified leptin is more accessible to hypothalamus through brain–blood barrier with a significant inhibition of body-weight gain in high-fat-diet fed mice. Exp. Clin. Endocrinol. Diabetes 118, 31–37 (2010).
Guo, D. F. & Rahmouni, K. Molecular basis of the obesity associated with Bardet–Biedl syndrome. Trends Endocrinol. Metab. 22, 286–293 (2011).
Guo, D. F. et al. The BBsome controls energy homeostasis by mediating the transport of the leptin receptor to the plasma membrane. PLoS Genet. 12, e1005890 (2016).
Seo, S. et al. Requirement of Bardet–Biedl syndrome proteins for leptin receptor signaling. Hum. Mol. Genet. 18, 1323–1331 (2009).
Irani, B. G., Dunn-Meynell, A. A. & Levin, B. E. Altered hypothalamic leptin, insulin, and melanocortin binding associated with moderate-fat diet and predisposition to obesity. Endocrinology 148, 310–316 (2007).
Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997).
Minamoto, S. et al. Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. Biochem. Biophys. Res. Commun. 237, 79–83 (1997).
Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).
Howard, J. K. et al. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat. Med. 10, 734–738 (2004).
Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739–743 (2004).
Pedroso, J. A. et al. Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity. Mol. Metab. 3, 608–618 (2014).
Reed, A. S. et al. Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 59, 894–906 (2010).
Ahmad, F., Li, P. M., Meyerovitch, J. & Goldstein, B. J. Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. J. Biol. Chem. 270, 20503–20508 (1995).
Maegawa, H. et al. Thiazolidine derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein-tyrosine phosphatase activities. J. Biol. Chem. 270, 7724–7730 (1995).
Seely, B. L. et al. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes 45, 1379–1385 (1996).
Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771–47774 (2001).
Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).
Cook, W. S. & Unger, R. H. Protein tyrosine phosphatase 1B: a potential leptin resistance factor of obesity. Dev. Cell 2, 385–387 (2002).
Zabolotny, J. M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).
Klaman, L. D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell. Biol. 20, 5479–5489 (2000).
Bence, K. K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12, 917–924 (2006).
Tsou, R. C., Zimmer, D. J., De Jonghe, B. C. & Bence, K. K. Deficiency of PTP1B in leptin receptor-expressing neurons leads to decreased body weight and adiposity in mice. Endocrinology 153, 4227–4237 (2012).
Tsou, R. C., Rak, K. S., Zimmer, D. J. & Bence, K. K. Improved metabolic phenotype of hypothalamic PTP1B-deficiency is dependent upon the leptin receptor. Mol. Metab. 3, 301–312 (2014).
He, R. J., Yu, Z. H., Zhang, R. Y. & Zhang, Z. Y. Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol. Sin. 35, 1227–1246 (2014).
Lantz, K. A. et al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obes. (Silver Spring) 18, 1516–1523 (2010).
Ahima, R. S. et al. Appetite suppression and weight reduction by a centrally active aminosterol. Diabetes 51, 2099–2104 (2002).
Takahashi, N., Qi, Y., Patel, H. R. & Ahima, R. S. A novel aminosterol reverses diabetes and fatty liver disease in obese mice. J. Hepatol. 41, 391–398 (2004).
Zasloff, M. et al. A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties. Int. J. Obes. Relat. Metab. Disord. 25, 689–697 (2001).
Isis Pharmaceuticals, Inc. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. PRNewswire www.prnewswire.com/news-releases/isis-pharmaceuticals-reports-positive-phase-2-data-for-isis-113715-in-patients-with-type-2-diabetes-65238987.html (2009).
Loh, K. et al. Elevated hypothalamic TCPTP in obesity contributes to cellular leptin resistance. Cell Metab. 14, 684–699 (2011).
Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).
Rousso-Noori, L. et al. Protein tyrosine phosphatase epsilon affects body weight by downregulating leptin signaling in a phosphorylation-dependent manner. Cell Metab. 13, 562–572 (2011).
Toledano-Katchalski, H. et al. Protein tyrosine phosphatase ε inhibits signaling by mitogen-activated protein kinases. Mol. Cancer Res. 1, 541–550 (2003).
Schmidt, M., Dekker, F. J. & Maarsingh, H. Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions. Pharmacol. Rev. 65, 670–709 (2013).
McKnight, G. S. et al. Cyclic AMP, PKA, and the physiological regulation of adiposity. Recent Prog. Horm. Res. 53, 139–159 (1998).
Almahariq, M., Mei, F. C. & Cheng, X. Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends Endocrinol. Metab. 25, 60–71 (2014).
Fukuda, M., Williams, K. W., Gautron, L. & Elmquist, J. K. Induction of leptin resistance by activation of cAMP–Epac signaling. Cell Metab. 13, 331–339 (2011).
Yan, J. et al. Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. Mol. Cell. Biol. 33, 918–926 (2013).
De Souza, C. T. et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146, 4192–4199 (2005).
Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).
Posey, K. A. et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 296, E1003–E1012 (2009).
Zhang, X. et al. Hypothalamic IKKß/NF-κB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008).
Romanatto, T. et al. Deletion of tumor necrosis factor-α receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. J. Biol. Chem. 284, 36213–36222 (2009).
Milanski, M. et al. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 61, 1455–1462 (2012).
Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009).
Hosoi, T. et al. Endoplasmic reticulum stress induces leptin resistance. Mol. Pharmacol. 74, 1610–1619 (2008).
Liu, J., Lee, J., Salazar Hernandez, M. A., Mazitschek, R. & Ozcan, U. Treatment of obesity with celastrol. Cell 161, 999–1011 (2015).
Williams, K. W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).
Perlmutter, D. H. Chemical chaperones: a pharmacological strategy for disorders of protein folding and trafficking. Pediatr. Res. 52, 832–836 (2002).
Carducci, M. A. et al. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin. Cancer Res. 7, 3047–3055 (2001).
Ma, X. et al. Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1–PGC1α transcriptional axis. Cell Metab. 22, 695–708 (2015).
Contreras, C. et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep. 9, 366–377 (2014).
Contreras, C. et al. Effects of neonatal programming on hypothalamic mechanisms controlling energy balance. Horm. Metab. Res. 45, 935–944 (2013).
Duque-Guimaraes, D. E. & Ozanne, S. E. Nutritional programming of insulin resistance: causes and consequences. Trends Endocrinol. Metab. 24, 525–535 (2013).
Lopez, M. et al. A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat. Diabetologia 48, 140–148 (2005).
Lopez, M. et al. Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood. Int. J. Obes. 31, 371–377 (2007).
Lucas, A. Programming by early nutrition: an experimental approach. J. Nutr. 128, 401S–406S (1998).
Morris, M. J., Velkoska, E. & Cole, T. J. Central and peripheral contributions to obesity-associated hypertension: impact of early overnourishment. Exp. Physiol. 90, 697–702 (2005).
Davidowa, H. & Plagemann, A. Different responses of ventromedial hypothalamic neurons to leptin in normal and early postnatally overfed rats. Neurosci. Lett. 293, 21–24 (2000).
Davidowa, H. & Plagemann, A. Decreased inhibition by leptin of hypothalamic arcuate neurons in neonatally overfed young rats. Neuroreport 11, 2795–2798 (2000).
Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).
Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).
Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001).
Muller, T. D. et al. Ghrelin. Mol. Metab. 4, 437–460 (2015).
Seoane, L. M. et al. Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats. Eur. J. Endocrinol. 143, R7–R9 (2000).
Peino, R. et al. Ghrelin-induced growth hormone secretion in humans. Eur. J. Endocrinol. 143, R11–R14 (2000).
Takaya, K. et al. Ghrelin strongly stimulates growth hormone release in humans. J. Clin. Endocrinol. Metab. 85, 4908–4911 (2000).
Wren, A. M. et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001).
Theander-Carrillo, C. et al. Ghrelin action in the brain controls adipocyte metabolism. J. Clin. Invest. 116, 1983–1993 (2006).
López, M. et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 7, 389–399 (2008).
Foster-Schubert, K. E. & Cummings, D. E. Emerging therapeutic strategies for obesity. Endocr. Rev. 27, 779–793 (2006).
Zorrilla, E. P. et al. Vaccination against weight gain. Proc. Natl Acad. Sci. USA 103, 13226–13231 (2006).
Muller, T. D., Perez-Tilve, D., Tong, J., Pfluger, P. T. & Tschop, M. H. Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia. J. Cachexia Sarcopenia Muscle 1, 159–167 (2010).
Lainscak, M., von Haehling, S., Doehner, W. & Anker, S. D. The obesity paradox in chronic disease: facts and numbers. J. Cachexia Sarcopenia Muscle 3, 1–4 (2012).
von Haehling, S., Morley, J. E. & Anker, S. D. From muscle wasting to sarcopenia and myopenia: update 2012. J. Cachexia Sarcopenia Muscle 3, 213–217 (2012).
Gutierrez, J. A. et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc. Natl Acad. Sci. USA 105, 6320–6325 (2008).
Yang, J., Brown, M. S., Liang, G., Grishin, N. V. & Goldstein, J. L. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132, 387–396 (2008).
Gonzalez, C. R., Vazquez, M. J., López, M. & Dieguez, C. Influence of chronic undernutrition and leptin on GOAT mRNA levels in rat stomach mucosa. J. Mol. Endocrinol. 41, 415–421 (2008).
Kirchner, H. et al. GOAT links dietary lipids with the endocrine control of energy balance. Nat. Med. 15, 741–745 (2009).
Delhanty, P. J., Neggers, S. J. & van der Lely, A. J. Mechanisms in endocrinology: ghrelin: the differences between acyl- and des-acyl ghrelin. Eur. J. Endocrinol. 167, 601–608 (2012).
Delhanty, P. J., Neggers, S. J. & van der Lely, A. J. Should we consider des-acyl ghrelin as a separate hormone and if so, what does it do? Front. Horm. Res. 42, 163–174 (2014).
Toshinai, K. et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 147, 2306–2314 (2006).
Heppner, K. M. et al. Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors. Diabetes 63, 122–131 (2014).
Zhang, J. V. et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310, 996–999 (2005).
Seoane, L. M., Al Massadi, O., Pazos, Y., Pagotto, U. & Casanueva, F. F. Central obestatin administration does not modify either spontaneous or ghrelin-induced food intake in rats. J. Endocrinol. Invest. 29, RC13–RC15 (2006).
Nogueiras, R. et al. Effects of obestatin on energy balance and growth hormone secretion in rodents. Endocrinology 148, 21–26 (2007).
Gourcerol, G., St Pierre, D. H. & Tache, Y. Lack of obestatin effects on food intake: should obestatin be renamed ghrelin-associated peptide (GAP)? Regul. Pept. 141, 1–7 (2007).
Kobelt, P. et al. Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents. Peptides 29, 1018–1027 (2008).
Tschop, M. et al. Post-prandial decrease of circulating human ghrelin levels. J. Endocrinol. Invest. 24, RC19–RC21 (2001).
Cummings, D. E. et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50, 1714–1719 (2001).
Drazen, D. L., Vahl, T. P., D'Alessio, D. A., Seeley, R. J. & Woods, S. C. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 147, 23–30 (2006).
Seoane, L. M. et al. Sensory stimuli directly acting at the central nervous system regulate gastric ghrelin secretion. an ex vivo organ culture study. Endocrinology 148, 3998–4006 (2007).
Briggs, D. I. & Andrews, Z. B. Metabolic status regulates ghrelin function on energy homeostasis. Neuroendocrinology 93, 48–57 (2011).
Zigman, J. M., Bouret, S. G. & Andrews, Z. B. Obesity impairs the action of the neuroendocrine ghrelin system. Trends Endocrinol. Metab. 27, 54–63 (2016).
Tschop, M. et al. Circulating ghrelin levels are decreased in human obesity. Diabetes 50, 707–709 (2001).
Otto, B. et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur. J. Endocrinol. 145, 669–673 (2001).
Otto, B. et al. Postprandial ghrelin release in anorectic patients before and after weight gain. Psychoneuroendocrinology 30, 577–581 (2005).
Cummings, D. E. et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat. Med. 8, 643–644 (2002).
DelParigi, A. et al. High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader–Willi syndrome. J. Clin. Endocrinol. Metab. 87, 5461–5464 (2002).
Feigerlová, E. et al. Hyperghrelinemia precedes obesity in Prader–Willi syndrome. J. Clin. Endocrinol. Metab. 93, 2800–2805 (2008).
Kweh, F. A. et al. Hyperghrelinemia in Prader–Willi syndrome begins in early infancy long before the onset of hyperphagia. Am. J. Med. Genet. A. 167A, 69–79 (2015).
De Waele, K. et al. Long-acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader–Willi syndrome. Eur. J. Endocrinol. 159, 381–388 (2008).
Neary, N. M. et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J. Clin. Endocrinol. Metab. 89, 2832–2836 (2004).
Schmid, D. A. et al. Ghrelin stimulates appetite, imagination of food, GH, ACTH, and cortisol, but does not affect leptin in normal controls. Neuropsychopharmacology 30, 1187–1192 (2005).
Druce, M. R. et al. Ghrelin increases food intake in obese as well as lean subjects. Int. J. Obes. Relat. Metab. Disord. 29, 1130–1136 (2005).
Druce, M. R. et al. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. Int. J. Obes. 30, 293–296 (2005).
Liu, J. et al. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J. Clin. Endocrinol. Metab. 93, 1980–1987 (2008).
Sun, Y., Ahmed, S. & Smith, R. G. Deletion of ghrelin impairs neither growth nor appetite. Mol. Cell. Biol. 23, 7973–7981 (2003).
Pfluger, P. T. et al. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G610–G618 (2008).
McFarlane, M. R., Brown, M. S., Goldstein, J. L. & Zhao, T. J. Induced ablation of ghrelin cells in adult mice does not decrease food intake, body weight, or response to high-fat diet. Cell Metab. 20, 54–60 (2014).
Nishi, Y. et al. Ingested medium-chain fatty acids are directly utilized for the acyl-modification of ghrelin. Endocrinology 146, 2255–2264 (2005).
Sangiao-Alvarellos, S. et al. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion. Endocrinology 150, 4562–4574 (2009).
Perez-Tilve, D. et al. Ghrelin-induced adiposity is independent of orexigenic effects. FASEB J. 25, 2814–2822 (2011).
Andrews, Z. B. et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008).
Gao, S., Casals, N., Keung, W., Moran, T. H. & Lopaschuk, G. D. Differential effects of central ghrelin on fatty acid metabolism in hypothalamic ventral medial and arcuate nuclei. Physiol. Behav. 118, 165–170 (2013).
Al, M. O. et al. Review of novel aspects of the regulation of ghrelin secretion. Curr. Drug Metab. 15, 398–413 (2014).
Sun, Y., Wang, P., Zheng, H. & Smith, R. G. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc. Natl Acad. Sci. USA 101, 4679–4684 (2004).
Guan, X. M. et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res. Mol. Brain Res. 48, 23–29 (1997).
Tannenbaum, G. S., Lapointe, M., Beaudet, A. & Howard, A. D. Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the mediobasal hypothalamus. Endocrinology 139, 4420–4423 (1998).
Willesen, M. G., Kristensen, P. & Romer, J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306–316 (1999).
Nogueiras, R. et al. Regulation of growth hormone secretagogue receptor gene expression in the arcuate nuclei of the rat by leptin and ghrelin. Diabetes 53, 2552–2558 (2004).
Garcia, A., Alvarez, C. V., Smith, R. G. & Dieguez, C. Regulation of pit-1 expression by ghrelin and ghrp-6 through the gh secretagogue receptor. Mol. Endocrinol. 15, 1484–1495 (2001).
van der Lely, A. J., Tschop, M., Heiman, M. L. & Ghigo, E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr. Rev. 25, 426–457 (2004).
Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).
Lage, R. et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 24, 2670–2679 (2010).
Varela, L. et al. Ghrelin and lipid metabolism: key partners in energy balance. J. Mol. Endocrinol. 46, R43–R63 (2011).
López, M., Nogueiras, R., Tena-Sempere, M. & Dieguez, C. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat. Rev. Endocrinol. 12, 421–432 (2016).
Dietrich, M. O. et al. Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J. Neurosci. 30, 11815–11825 (2010).
Velasquez, D. A. et al. The central Sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin. Diabetes 60, 1177–1185 (2011).
Andersson, U. et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004).
Kola, B. et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE 3, e1797 (2008).
Sangiao-Alvarellos, S. et al. Influence of ghrelin and GH deficiency on AMPK and hypothalamic lipid metabolism. J. Neuroendocrinol. 22, 543–556 (2010).
Yavari, A. et al. Chronic activation of γ2 AMPK induces obesity and reduces ß cell function. Cell Metab. 23, 821–836 (2016).
Sierra, A. Y. et al. CPT1C is localized in endoplasmic reticulum of neurons and has carnitine palmitoyltransferase activity. J. Biol. Chem. 283, 6878–6885 (2008).
Ramírez, S. et al. Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin. Diabetes 62, 2329–2337 (2013).
Martins, L. et al. Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin. PLoS ONE 7, e46923 (2012).
Stevanovic, D. et al. Ghrelin-induced food intake and adiposity depend on central mTORC1/S6K1 signaling. Mol. Cell. Endocrinol. 381, 280–290 (2013).
Martinez de Morentin, P. B. et al. Hypothalamic mTOR: the rookie energy sensor. Curr. Mol. Med. 14, 3–21 (2014).
Sakkou, M. et al. A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior. Cell Metab. 5, 450–463 (2007).
Seoane, L. M. et al. Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology 144, 544–551 (2003).
Nogueiras, R. et al. Bsx, a novel hypothalamic factor linking feeding with locomotor activity, is regulated by energy availability. Endocrinology 149, 3009–3015 (2008).
Yang, Y., Atasoy, D., Su, H. H. & Sternson, S. M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003 (2011).
Kohno, D., Gao, H. Z., Muroya, S., Kikuyama, S. & Yada, T. Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52, 948–956 (2003).
Cowley, M. A. et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661 (2003).
Romero-Pico, A. et al. Hypothalamic κ-opioid receptor modulates the orexigenic effect of ghrelin. Neuropsychopharmacology 38, 1296–1307 (2013).
Kola, B. et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J. Biol. Chem. 280, 25196–25201 (2005).
Lim, C. T. et al. Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism. Mol. Cell. Endocrinol. 365, 303–308 (2013).
Kola, B. et al. The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release. FASEB J. 27, 5112–5121 (2013).
Olszewski, P. K., Grace, M. K., Billington, C. J. & Levine, A. S. Hypothalamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity. Peptides 24, 919–923 (2003).
Olszewski, P. K., Billington, C. J., Grace, M. K. & Levine, A. S. α-Melanocyte stimulating hormone and ghrelin: central interaction in feeding control. Peptides 28, 2084–2089 (2007).
Abizaid, A. et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116, 3229–3239 (2006).
Romero-Pico, A. et al. Central manipulation of dopamine receptors attenuates the orexigenic action of ghrelin. Psychopharmacology 229, 275–283 (2013).
Hewson, A. K., Tung, L. Y., Connell, D. W., Tookman, L. & Dickson, S. L. The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. Diabetes 51, 3412–3419 (2002).
Kohno, D. et al. Leptin suppresses ghrelin-induced activation of neuropeptide Y neurons in the arcuate nucleus via phosphatidylinositol 3-kinase- and phosphodiesterase 3-mediated pathway. Endocrinology 148, 2251–2263 (2007).
Scott, V., McDade, D. M. & Luckman, S. M. Rapid changes in the sensitivity of arcuate nucleus neurons to central ghrelin in relation to feeding status. Physiol. Behav. 90, 180–185 (2007).
Briggs, D. I. et al. Calorie-restricted weight loss reverses high-fat diet-induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin-dependent manner. Endocrinology 154, 709–717 (2013).
Perreault, M. et al. Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss. Int. J. Obes. Relat. Metab. Disord. 28, 879–885 (2004).
English, P. J., Ghatei, M. A., Malik, I. A., Bloom, S. R. & Wilding, J. P. Food fails to suppress ghrelin levels in obese humans. J. Clin. Endocrinol. Metab. 87, 2984 (2002).
Uchida, A. et al. Altered ghrelin secretion in mice in response to diet-induced obesity and Roux-en-Y gastric bypass. Mol. Metab. 3, 717–730 (2014).
Mani, B. K., Osborne-Lawrence, S., Vijayaraghavan, P., Hepler, C. & Zigman, J. M. β1-adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals. J. Clin. Invest. 126, 3467–3478 (2016).
Banks, W. A., Burney, B. O. & Robinson, S. M. Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood–brain barrier. Peptides 29, 2061–2065 (2008).
Briggs, D. I., Enriori, P. J., Lemus, M. B., Cowley, M. A. & Andrews, Z. B. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151, 4745–4755 (2010).
Gardiner, J. V. et al. The hyperphagic effect of ghrelin is inhibited in mice by a diet high in fat. Gastroenterology 138, 2468–2476 (2010).
Briggs, D. I. et al. Evidence that diet-induced hyperleptinemia, but not hypothalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice. Endocrinology 155, 2411–2422 (2014).
Steculorum, S. M. et al. Neonatal ghrelin programs development of hypothalamic feeding circuits. J. Clin. Invest. 125, 846–858 (2015).
Collden, G. et al. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Mol. Metab. 4, 15–24 (2014).
Coll, A. P., Farooqi, I. S. & O'Rahilly, S. The hormonal control of food intake. Cell 129, 251–262 (2007).
Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 1350–1355 (2012).
Perello, M. et al. Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. J. Comp. Neurol. 520, 281–294 (2012).
Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–532 (1995).
Hahn, T. M., Breininger, J. F., Baskin, D. G. & Schwartz, M. W. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat. Neurosci. 1, 271–272 (1998).
Elias, C. F. et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).
de Morentin, P. B. & López, M. “Mens sana in corpore sano”: exercise and hypothalamic ER stress. PLoS Biol. 8, e1000464 (2010).
Naznin, F. et al. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. J. Endocrinol. 226, 81–92 (2015).
Martin, T. L. et al. Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J. Biol. Chem. 281, 18933–18941 (2006).
Dagon, Y. et al. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab. 16, 104–112 (2012).
Lockie, S. H., Dinan, T., Lawrence, A. J., Spencer, S. J. & Andrews, Z. B. Diet-induced obesity causes ghrelin resistance in reward processing tasks. Psychoneuroendocrinology 62, 114–120 (2015).
Finger, B. C., Dinan, T. G. & Cryan, J. F. Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task. Psychopharmacology 220, 173–181 (2012).
Wang, W. & Tao, Y. X. Ghrelin receptor mutations and human obesity. Prog. Mol. Biol. Transl Sci. 140, 131–150 (2016).
Pantel, J. et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J. Clin. Invest. 116, 760–768 (2006).
Pantel, J. et al. Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. J. Clin. Endocrinol. Metab. 94, 4334–4341 (2009).
Liu, G., Fortin, J. P., Beinborn, M. & Kopin, A. S. Four missense mutations in the ghrelin receptor result in distinct pharmacological abnormalities. J. Pharmacol. Exp. Ther. 322, 1036–1043 (2007).
Inoue, H. et al. Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature. J. Clin. Endocrinol. Metab. 96, E373–E378 (2011).
Rahmouni, K. Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 64, 215–221 (2014).
H.C. is funded by the US National Institutes of Health (HL127673 and MH109920). M.L.'s research is funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 281854; the ObERStress project: Xunta de Galicia (2015-CP079); MINECO co-funded by the FEDER Program of EU (SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición is an initiative of the Instituto de Salud Carlos III (ISCIII). K.R.'s research is supported by the US National Institutes of Health (HL084207); the American Heart Association (14EIA18860041); the University of Iowa Fraternal Order of Eagles Diabetes Research Center; and the University of Iowa Center for Hypertension Research.
The authors declare no competing financial interests.
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Cui, H., López, M. & Rahmouni, K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol 13, 338–351 (2017). https://doi.org/10.1038/nrendo.2016.222
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