An Overview of Appetite Regulation Mechanisms

Year 2022, Volume: 5 Issue: 2, 178 - 193, 30.11.2022

Kübra Şener , Elif Naz Alver , Şule Coşkun Cevher

https://doi.org/10.34088/kojose.1091078

Cited By: 1

Abstract

Maintaining body weight is momentous in quality of life. Appetite takes an important role in establishing the balance of daily food absorption and spent energy and, accordingly, controlling body weight. There is a complex physiological control regulation in the maintenance of energy balance. The regulation of appetite is carried out by central and peripheral signals. The hypothalamus, brainstem, and reward centers, which are involved in central regulation, provide management of food absorption by integrating signals from the peripheral. Gastrointestinal hormones in the peripheral system regulate the digestion and absorption of nutrients. In the central nervous system, these hormones act as neurotransmitters. The ability to adjust food absorption in response to changes in energy status is an essential component of maintaining energy homeostasis. In cases where energy homeostasis cannot be balanced, it risks human life and causes a decrease in their quality of life. Diseases such as anorexia, which is characterized by low body weight, or obesity, which is characterized by increased body weight, may occur. A full understanding of the mechanism of appetite may offer new treatment opportunities in the elimination of diseases and complications that may develop due to these diseases. In this context, central and peripheral processes in the adjustment of food intake were reviewed in our study.

Keywords

Appetite, Central Regulation, Food Intake, Peripheral Regulation

References

• [1] Fromentin G., Darcel N., Chaumontet C., Marsset-Baglieri A., Nadkarni N., Tomé D., 2012. Peripheral and central mechanisms involved in the control of food intake by dietary amino acids and proteins. Nutrition Research Reviews, 25, pp. 29-39.
• [2] Sandoval D., Cota D., Seeley R.J., 2008. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol, 70, pp. 513-535.
• [3] Boguszewski C.L., Paz-Filho G., Velloso L.A., 2010. Neuroendocrine body weight regulation: integration between fat tissue, gastrointestinal tract, and the brain. Endokrynologia Polska, 61, pp. 194-206.
• [4] Schorr M., Miller K.K., 2017. The endocrine manifestations of anorexia nervosa: mechanisms and management. Nature Reviews Endocrinology, 13, pp. 174-186.
• [5] Goodarzi M.O., 2018. Genetics of obesity: what genetic association studies have taught us about the biology of obesity and its complications. The Lancet Diabetes & Endocrinology, 6, pp. 223-236.
• [6] Stanley S., Wynne K., McGowan B., Bloom S., 2005. Hormonal regulation of food intake. Physiol Rev, 85, pp. 1131-1158.
• [7] Timper K., Brüning J.C., 2017. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech, 10, pp. 679-689.
• [8] Wynne K., Stanley S., McGowan B., Bloom S., 2005. Appetite control. Journal of Endocrinology, 184, pp. 291-318.
• [9] Hetherington A., Ranson S., 1940. Hypothalamic lesions and adiposity in the rat. The Anatomical Record, 78, pp. 149-172.
• [10] Anand B.K., Brobeck J.R., 1951. Localization of a “feeding center” in the hypothalamus of the rat. Proceedings of the Society for Experimental Biology and Medicine, 77, pp. 323-325.
• [11] Rodríguez E.M., Blázquez J.L., Guerra M., 2010. The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid. Peptides, 31, pp. 757-776.
• [12] Myers M., Olson D., 2012. Central nervous system control of metabolism. Nature, 491, pp. 357–363.
• [13] Kastin A.J., Akerstrom V., Pan W., 2002. Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. Journal of Molecular Neuroscience, 18, pp. 7-14.
• [14] Nonaka N., Shioda S., Niehoff M. L., Banks W. A., 2003. Characterization of blood-brain barrier permeability to PYY3-36 in the mouse. Journal of Pharmacology and Experimental Therapeutics, 306(3), pp. 948-953.
• [15] Gropp E., Shanabrough M., Borok E., Xu A.W., Janoschek R., Buch T., Plum L., Balthasar N., Hampel B., Waisman A., 2005. Agouti-related peptide–expressing neurons are mandatory for feeding. Nature neuroscience, 8, pp. 1289-1291.
• [16] Balthasar N., Dalgaard L.T., Lee C.E., Yu J., Funahashi H., Williams T., Ferreira M., Tang V., McGovern R.A., Kenny C.D., 2005. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell, 123, pp. 493-505.
• [17] Woods S.C., Seeley R.J., Cota D., 2008. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu Rev Nutr, 28, pp. 295-311.
• [18] McConn B. R., Gilbert, E. R., Cline, M. A., 2018. Appetite-associated responses to central neuropeptide Y injection in quail. Neuropeptides, 69, pp.9-18.
• [19] Lindner D., Stichel, J., Beck-Sickinger A. G., 2008. Molecular recognition of the NPY hormone family by their receptors. Nutrition, 24, pp. 907-917.
• [20] Williams G., Bing C., Cai X. J., Harrold J. A., King P. J., Liu X. H., 2001. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiology & behavior, 74, pp. 683-701.
• [21] Sanacora G., Kershaw M., Finkelstein J.A., White J.D., 1990. Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation. Endocrinology, 127, pp. 730-737.
• [22] Swart I., Jahng J., Overton J., Houpt T., 2002. Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 283, pp. R1020-R1026.
• [23] Benarroch E. E., 2009. Neuropeptide Y: its multiple effects in the CNS and potential clinical significance. Neurology, 72, pp. 1016-1020.
• [24] Gonçalves J., Martins J., Baptista S., Ambrósio A. F., Silva A. P., 2016. Effects of drugs of abuse on the central neuropeptide Y system. Addiction Biology, 21, pp.755-765.
• [25] Kalra S. P., Kalra P. S., 2004. NPY—an endearing journey in search of a neurochemical on/off switch for appetite, sex and reproduction. Peptides, 25, pp. 465-471.
• [26] Suzuki K., Simpson K.A., Minnion J.S., Shillito J.C., Bloom S.R., 2010. The role of gut hormones and the hypothalamus in appetite regulation. Endocrine Journal, 57, pp. 359-372.
• [27] Krashes M. J., Shah B. P., Koda S., Lowell B. B., 2013. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell metabolism, 18, pp. 588-595.
• [28] Billington C., Briggs J., Grace M., Levine A., 1991. Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 260, pp. R321-R327.
• [29] Egawa M., Yoshimatsu H., Bray G., 1991. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 260, pp. R328-R334.
• [30] Qi Y., Lee N. J., Ip C. K., Enriquez R., Tasan R., Zhang L., Herzog H. 2022. NPY derived from AGRP neurons controls feeding via Y1 and energy expenditure and food foraging behaviour via Y2 signalling. Molecular Metabolism, 59, pp. 101455.
• [31] Mercer A.J., Hentges S.T., Meshul C.K., Low M.J., 2013. Unraveling the central proopiomelanocortin neural circuits. Frontiers in neuroscience, 7, pp. 19.
• [32] Kleinridders A., Könner A.C., Brüning J.C., 2009. CNS-targets in control of energy and glucose homeostasis. Current opinion in pharmacology, 9, pp. 794-804.
• [33] Waterson M.J., Horvath T.L., 2015. Neuronal regulation of energy homeostasis: beyond the hypothalamus and feeding. Cell metabolism, 22, pp. 962-970.
• [34] Roh E., Kim M.-S., 2016. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Experimental & molecular medicine, 48, pp. e216-e216.
• [35] Andermann M. L., Lowell B. B., 2017. Toward a wiring diagram understanding of appetite control. Neuron, 95, pp.757-778.
• [36] Abdalla M.M.I., 2017. Central and peripheral control of food intake. Endocrine Regulations, 51, pp. 52-70.
• [37] Garfield A. S., Li C., Madara J. C., Shah B. P., Webber E., Steger J. S., Lowell B. B. (2015). A neural basis for melanocortin-4 receptor–regulated appetite. Nature neuroscience, 18, pp. 863-871.
• [38] Fan W., Boston B.A., Kesterson R.A., Hruby V.J., Cone R.D., 1997. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature, 385, pp. 165-168.
• [39] Argyropoulos G., Rankinen T., Neufeld D.R., Rice T., Province M.A., Leon A.S., Skinner J.S., Wilmore J.H., Rao D., Bouchard C., 2002. A polymorphism in the human agouti-related protein is associated with late-onset obesity. The Journal of Clinical Endocrinology & Metabolism, 87, pp. 4198-4202.
• [40] Lee Y.S., Challis B.G., Thompson D.A., Yeo G.S., Keogh J.M., Madonna M.E., Wraight V., Sims M., Vatin V., Meyre D., 2006. A POMC variant implicates β-melanocyte-stimulating hormone in the control of human energy balance. Cell metabolism, 3, pp. 135-140.
• [41] Biebermann H., Castañeda T.R., van Landeghem F., von Deimling A., Escher F., Brabant G., Hebebrand J., Hinney A., Tschöp M.H., Grüters A., 2006. A role for β-melanocyte-stimulating hormone in human body-weight regulation. Cell metabolism, 3, pp. 141-146.
• [42] Elias C.F., Lee C., Kelly J., Aschkenasi C., Ahima R.S., Couceyro P.R., Kuhar M.J., Saper C.B., Elmquist J.K., 1998. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron, 21, pp. 1375-1385.
• [43] Couceyro P.R., Koylu E.O., Kuhar M.J., 1997. Further studies on the anatomical distribution of CART by in situ hybridization. Journal of chemical neuroanatomy, 12, pp. 229-241.
• [44] Kristensen P., Judge M.E., Thim L., Ribel U., Christjansen K.N., Wulff B.S., Clausen J.T., Jensen P.B., Madsen O.D., Vrang N., 1998. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature, 393, pp. 72-76.
• [45] Aja S., Sahandy S., Ladenheim E.E., Schwartz G.J., Moran T.H., 2001. Intracerebroventricular CART peptide reduces food intake and alters motor behavior at a hindbrain site. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 281, pp. R1862-R1867.
• [46] Rohner-Jeanrenaud F., Craft L., Bridwell J., Suter T., Tinsley F., Smiley D., Burkhart D., Statnick M., Heiman M., Ravussin E., 2002. Chronic central infusion of cocaine-and amphetamine-regulated transcript (CART 55-102): effects on body weight homeostasis in lean and high-fat-fed obese rats. International Journal of Obesity, 26, pp. 143-149.
• [47] Hou J., Zheng D.Z., Zhou J.Y., Zhou S.W., 2010. Orexigenic effect of cocaine‐and amphetamine‐regulated transcript (CART) after injection into hypothalamic nuclei in streptozotocin‐diabetic rats. Clinical and Experimental Pharmacology and Physiology, 37, pp. 989-995.
• [48] Dhillo W., Small C., Stanley S., Jethwa P., Seal L., Murphy K., Ghatei M., Bloom S., 2002. Hypothalamic interactions between neuropeptide Y, agouti‐related protein, cocaine‐and amphetamine‐regulated transcript and alpha‐melanocyte‐stimulating hormone in vitro in male rats. Journal of neuroendocrinology, 14, pp. 725-730.
• [49] Neary N.M., Goldstone A.P., Bloom S.R., 2004. Appetite regulation: from the gut to the hypothalamus. Clinical endocrinology, 60, pp. 153-160.
• [50] Hamamura M., Leng G., Emson P., Kiyama H., 1991. Electrical activation and c‐fos mRNA expression in rat neurosecretory neurones after systemic administration of cholecystokinin. The Journal of physiology, 444, pp. 51-63.
• [51] Lambert P., Phillips P., Wilding J., Bloom S., Herbert J., 1995. c-fos expression in the paraventricular nucleus of the hypothalamus following intracerebroventricular infusions of neuropeptide Y. Brain research, 670, pp. 59-65.
• [52] Lawrence C.B., Snape A.C., Baudoin F.M.-H., Luckman S.M., 2002. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology, 143, pp. 155-162.
• [53] Edwards C., Abusnana S., Sunter D., Murphy K., Ghatei M., Bloom S., 1999. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. Journal of Endocrinology, 160, pp. R7.
• [54] Van Dijk G., Thiele T.E., Donahey J., Campfield L.A., Smith F.J., Burn P., Bernstein I.L., Woods S.C., Seeley R.J., 1996. Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 271, pp. R1096-R1100.
• [55] Giraudo S.Q., Billington C.J., Levine A.S., 1998. Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain research, 809, pp. 302-306.
• [56] Wirth M.M., Olszewski P.K., Yu C., Levine A.S., Giraudo S.Q., 2001. Paraventricular hypothalamic α-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects. Peptides, 22, pp. 129-134.
• [57] Cowley M.A., Pronchuk N., Fan W., Dinulescu D.M., Colmers W.F., Cone R.D., 1999. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron, 24, pp. 155-163.
• [58] Andersson U., Filipsson K., Abbott C.R., Woods A., Smith K., Bloom S.R., Carling D., Small C.J., 2004. AMP-activated protein kinase plays a role in the control of food intake. Journal of Biological Chemistry, 279, pp. 12005-12008.
• [59] Minokoshi Y., Alquier T., Furukawa N., Kim Y.-B., Lee A., Xue B., Mu J., Foufelle F., Ferré P., Birnbaum M.J., 2004. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature, 428, pp. 569-574.
• [60] Legradi G., Lechan R.M., 1999. Agouti-related protein containing nerve terminals innervate thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology, 140, pp. 3643-3652.
• [61] Fekete C., Sarkar S., Rand W.M., Harney J.W., Emerson C.H., Bianco A.C., Lechan R.M., 2002. Agouti-related protein (AGRP) has a central inhibitory action on the hypothalamic-pituitary-thyroid (HPT) axis; comparisons between the effect of AGRP and neuropeptide Y on energy homeostasis and the HPT axis. Endocrinology, 143, pp. 3846-3853.
• [62] Fekete C., Légrádi G., Mihály E., Huang Q.-H., Tatro J.B., Rand W.M., Emerson C.H., Lechan R.M., 2000. α-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. Journal of Neuroscience, 20, pp. 1550-1558.
• [63] Sarkar S., Lechan R.M., 2003. Central administration of neuropeptide Y reduces α-melanocyte-stimulating hormone-induced cyclic adenosine 5′-monophosphate response element binding protein (CREB) phosphorylation in pro-thyrotropin-releasing hormone neurons and increases CREB phosphorylation in corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology, 144, pp. 281-291.
• [64] Chen P., Williams S.M., Grove K.L., Smith M.S., 2004. Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y expression in the dorsomedial hypothalamus during lactation. Journal of Neuroscience, 24, pp. 5091-5100.
• [65] Mihály E., Fekete C., Légrádi G., Lechan R.M., 2001. Hypothalamic dorsomedial nucleus neurons innervate thyrotropin-releasing hormone-synthesizing neurons in the paraventricular nucleus. Brain research, 891, pp. 20-31.
• [66] Stanley B.G., Chin A., Leibowitz S.F., 1985. Feeding and drinking elicited by central injection of neuropeptide Y: evidence for a hypothalamic site (s) of action. Brain research bulletin, 14, pp. 521-524.
• [67] Kyrkouli S., Stanley B., Seirafi R., Leibowitz S., 1990. Stimulation of feeding by galanin: anatomical localization and behavioral specificity of this peptide's effects in the brain. Peptides, 11, pp. 995-1001.
• [68] Kelly J., Rothstein J., Grossman S.P., 1979. GABA and hypothalamic feeding systems. I. Topographic analysis of the effects of microinjections of muscimol. Physiology & behavior, 23, pp. 1123-1134.
• [69] Bernardis L.L., Bellinger L.L., 1987. The dorsomedial hypothalamic nucleus revisited: 1986 update. Brain Research Reviews, 12, pp. 321-381.
• [70] Marsh D.J., Weingarth D.T., Novi D.E., Chen H.Y., Trumbauer M.E., Chen A.S., Guan X.-M., Jiang M.M., Feng Y., Camacho R.E., 2002. Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proceedings of the National Academy of Sciences, 99, pp. 3240-3245.
• [71] Qu D., Ludwig D.S., Gammeltoft S., Piper M., Pelleymounter M.A., Cullen M.J., Mathes W.F., Przypek J., Kanarek R., Maratos-Flier E., 1996. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature, 380, pp. 243-247.
• [72] Borowsky B., Durkin M.M., Ogozalek K., Marzabadi M.R., DeLeon J., Heurich R., Lichtblau H., Shaposhnik Z., Daniewska I., Blackburn T.P., 2002. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nature medicine, 8, pp. 825-830.
• [73] Shimada M., Tritos N.A., Lowell B.B., Flier J.S., Maratos-Flier E., 1998. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 396, pp. 670-674.
• [74] Stanley B.G., Magdalin W., Seirafi A., Thomas W.J., Leibowitz S.F., 1993. The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system (s). Brain research, 604, pp. 304-317.
• [75] De Lecea L., Kilduff T., Peyron C., Gao X.-B., Foye P., Danielson P., Fukuhara C., Battenberg E., Gautvik V., Bartlett F.n., 1998. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proceedings of the National Academy of Sciences, 95, pp. 322-327.
• [76] Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R.M., Tanaka H., Williams S.C., Richardson J.A., Kozlowski G.P., Wilson S., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92, pp. 573-585.
• [77] Peyron C., Tighe D.K., Van Den Pol A.N., De Lecea L., Heller H.C., Sutcliffe J.G., Kilduff T.S., 1998. Neurons containing hypocretin (orexin) project to multiple neuronal systems. Journal of Neuroscience, 18, pp. 9996-10015.
• [78] Hagan M.M., Rushing P.A., Benoit S.C., Woods S.C., Seeley R.J., 2001. Opioid receptor involvement in the effect of AgRP-(83–132) on food intake and food selection. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 280, pp. R814-R821.
• [79] Takahashi N., Okumura T., Yamada H., Kohgo Y., 1999. Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats. Biochemical and biophysical research communications, 254, pp. 623-627.
• [80] Kirchgessner A.L., Liu M.-t., 1999. Orexin synthesis and response in the gut. Neuron, 24, pp. 941-951.
• [81] Bernardis L.L., Bellinger L.L., 1996. The lateral hypothalamic area revisited: ingestive behavior. Neurosci Biobehav Rev, 20, pp. 189-287.
• [82] Moriguchi T., Sakurai T., Nambu T., Yanagisawa M., Goto K., 1999. Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia. Neuroscience letters, 264, pp. 101-104.
• [83] Cai X.J., Widdowson P.S., Harrold J., Wilson S., Buckingham R.E., Arch J., Tadayyon M., Clapham J.C., Wilding J., Williams G., 1999. Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes, 48, pp. 2132-2137.
• [84] Nowak K.W., Maćkowiak P., Świtońska M.M., Fabiś M., Malendowicz L.K., 1999. Acute orexin effects on insulin secretion in the rat: in vivo and in vitro studies. Life sciences, 66, pp. 449-454.
• [85] Xu B., Goulding E.H., Zang K., Cepoi D., Cone R.D., Jones K.R., Tecott L.H., Reichardt L.F., 2003. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nature neuroscience, 6, pp. 736-742.
• [86] Dhillon H., Zigman J.M., Ye C., Lee C.E., McGovern R.A., Tang V., Kenny C.D., Christiansen L.M., White R.D., Edelstein E.A., 2006. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron, 49, pp. 191-203.
• [87] Piotrowicz Z., Chalimoniuk M., Czuba M., Langfort J., 2020. Rola neurotroficznego czynnika pochodzenia mózgowego w kontroli łaknienia. Postępy Biochemii, 66, pp. 205â 212-205â 212.
• [88] Ricardo J.A., Koh E.T., 1978. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain research, 153, pp. 1-26.
• [89] Ter Horst G., De Boer P., Luiten P., Van Willigen J., 1989. Ascending projections from the solitary tract nucleus to the hypothalamus. A Phaseolus vulgaris lectin tracing study in the rat. Neuroscience, 31, pp. 785-797.
• [90] Schwartz G.J., 2010. Brainstem integrative function in the central nervous system control of food intake. Frontiers in Eating and Weight Regulation, 63, pp. 141-151.
• [91] Kalia M., Sullivan J.M., 1982. Brainstem projections of sensory and motor components of the vagus nerve in the rat. Journal of Comparative Neurology, 211, pp. 248-264.
• [92] Härfstrand A., Fuxe K., Agnati L., Benfenati F., Goldstein M., 1986. Receptor autoradiographical evidence for high densities of 125l‐neuropeptide Y binding sites in the nucleus tractus solitarius of the normal male rat. Acta physiologica scandinavica, 128, pp. 195-200.
• [93] Sawchenko P., Swanson L., Grzanna R., Howe P., Bloom S., Polak J., 1985. Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. Journal of Comparative Neurology, 241, pp. 138-153.
• [94] Williams D.L., Kaplan J.M., Grill H.J., 2000. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology, 141, pp. 1332-1337.
• [95] Turton M., O'shea D., Gunn I., Beak S., Edwards C., Meeran K., Choi S., Taylor G., Heath M., Lambert P., 1996. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature, 379, pp. 69-72.
• [96] De Silva A., Bloom S.R., 2012. Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity. Gut and liver, 6, pp. 10.
• [97] Klok M.D., Jakobsdottir S., Drent M., 2007. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obesity reviews, 8, pp. 21-34.
• [98] Friedman J.M., 2004. Modern science versus the stigma of obesity. Nature medicine, 10, s. 563-569.
• [99] Ahima R.S., Prabakaran D., Mantzoros C., Qu D., Lowell B., Maratos-Flier E., Flier J.S., 1996. Role of leptin in the neuroendocrine response to fasting. Nature, 382, pp. 250-252.
• [100] Halaas J.L., Gajiwala K.S., Maffei M., Cohen S.L., Chait B.T., Rabinowitz D., Lallone R.L., Burley S.K., Friedman J.M., 1995. Weight-reducing effects of the plasma protein encoded by the obese gene. Science, 269, pp. 543-546.
• [101] Chan J.L., Heist K., DePaoli A.M., Veldhuis J.D., Mantzoros C.S., 2003. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. The Journal of clinical investigation, 111, pp. 1409-1421.
• [102] Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J.M., 1994. Positional cloning of the mouse obese gene and its human homologue. Nature, 372, pp. 425-432.
• [103] Bado A., Levasseur S., Attoub S., Kermorgant S., Laigneau J.-P., Bortoluzzi M.-N., Moizo L., Lehy T., Guerre-Millo M., Le Marchand-Brustel Y., 1998. The stomach is a source of leptin. Nature, 394, pp. 790-793.
• [104] Masuzaki H., Ogawa Y., Sagawa N., Hosoda K., Matsumoto T., Mise H., Nishimura H., Yoshimasa Y., Tanaka I., Mori T., 1997. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nature medicine, 3, pp. 1029-1033.
• [105] Tartaglia L.A., Dembski M., Weng X., Deng N., Culpepper J., Devos R., Richards G.J., Campfield L.A., Clark F.T., Deeds J., 1995. Identification and expression cloning of a leptin receptor, OB-R. Cell, 83, pp. 1263-1271.
• [106] Chua Jr S.C., Koutras I.K., Han L., Liu S.-M., Kay J., Young S.J., Chung W.K., Leibel R.L., 1997. Fine structure of the murine leptin receptor gene: splice site suppression is required to form two alternatively spliced transcripts. Genomics, 45, pp. 264-270.
• [107] Tartaglia L.A., 1997. The leptin receptor. Journal of Biological Chemistry, 272, pp. 6093-6096.
• [108] Ge H., Huang L., Pourbahrami T., Li C., 2002. Generation of soluble leptin receptor by ectodomain shedding of membrane-spanning receptors in vitro and in vivo. Journal of Biological Chemistry, 277, pp. 45898-45903.
• [109] Elmquist J.K., Bjørbæk C., Ahima R.S., Flier J.S., Saper C.B., 1998. Distributions of leptin receptor mRNA isoforms in the rat brain. Journal of Comparative Neurology, 395, pp. 535-547.
• [110] Fei H., Okano H.J., Li C., Lee G.-H., Zhao C., Darnell R., Friedman J.M., 1997. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proceedings of the National Academy of Sciences, 94, pp. 7001-7005.
• [111] Håkansson M.-L., Brown H., Ghilardi N., Skoda R.C., Meister B., 1998. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. Journal of Neuroscience, 18, pp. 559-572.
• [112] Mercer J.G., Moar K.M., Hoggard N., 1998. Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. Endocrinology, 139, pp. 29-34.
• [113] Lee G.-H., Proenca R., Montez J., Carroll K., Darvishzadeh J., Lee J., Friedman J., 1996. Abnormal splicing of the leptin receptor in diabetic mice. Nature, 379, pp. 632-635.
• [114] Vaisse C., Halaas J.L., Horvath C.M., Darnell J.E., Stoffel M., Friedman J.M., 1996. Leptin activation of Stat3 in the hypothalamus of wild–type and ob/ob mice but not db/db mice. Nature genetics, 14, pp. 95-97.
• [115] Mori H., Hanada R., Hanada T., Aki D., Mashima R., Nishinakamura H., Torisu T., Chien K.R., Yasukawa H., Yoshimura A., 2004. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature medicine, 10, pp. 739-743.
• [116] Pelleymounter M.A., Cullen M.J., Baker M.B., Hecht R., Winters D., Boone T., Collins F., 1995. Effects of the obese gene product on body weight regulation in ob/ob mice. Science, 269, pp. 540-543.
• [117] Campfield L.A., Smith F.J., Guisez Y., Devos R., Burn P., 1995. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science, 269, pp. 546-549.
• [118] Banks W.A., Kastin A.J., Huang W., Jaspan J.B., Maness L.M., 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides, 17, pp. 305-311.
• [119] Tsao T.S., Lodish H.F., Fruebis J., 2002. ACRP30, a new hormone controlling fat and glucose metabolism. Eur J Pharmacol, 440, pp. 213-221.
• [120] Scherer P.E., Williams S., Fogliano M., Baldini G., Lodish H.F., 1995. A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry, 270, pp. 26746-26749.
• [121] Scherer P. E., 2006. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes, 55, pp. 1537-1545.
• [122] Yang W.-S., Lee W.-J., Funahashi T., Tanaka S., Matsuzawa Y., Chao C.-L., Chen C.-L., Tai T.-Y., Chuang L.-M., 2001. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. The Journal of Clinical Endocrinology & Metabolism, 86, pp. 3815-3819.
• [123] Kadowaki, T., Yamauchi, T., Kubota, N., Hara, K., Ueki, K., Tobe, K., 2006. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. The Journal of clinical investigation, 116, pp. 1784-1792.
• [124] Berg A. H., Combs T. P., Du X., Brownlee M., Scherer P. E., 2001. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature medicine, 7, pp. 947-953.
• [125] Yamauchi T., Kamon J., Waki H., Terauchi Y., Kubota N., Hara K., Kadowaki T., 2001. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature medicine, 7, pp. 941-946.
• [126] Fruebis J., Tsao T. S., Javorschi S., Ebbets-Reed D., Erickson M. R. S., Yen F. T., Lodish H. F., 2001. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proceedings of the National Academy of Sciences, 98, pp. 2005-2010.
• [127] Nawrocki A. R., Rajala M. W., Tomas E., Pajvani U. B., Saha A. K., Trumbauer M. E., Scherer P. E., 2006. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists. Journal of Biological Chemistry, 281, pp. 2654-2660.
• [128] Schwartz M.W., Figlewicz D.P., Baskin D.G., Woods S.C., Porte Jr D., 1992. Insulin in the brain: a hormonal regulator of energy balance. Endocrine reviews, 13, pp. 387-414.
• [129] Porte Jr D., Baskin D.G., Schwartz M.W., 2002. Leptin and insulin action in the central nervous system. Nutrition reviews, 60, pp. S20-S29.
• [130] Dimitriadis G., Mitrou P., Lambadiari V., Maratou E., Raptis S.A., 2011. Insulin effects in muscle and adipose tissue. Diabetes research and clinical practice, 93, pp. 52-59.
• [131] Begg, D. P., Woods, S. C., 2013. The endocrinology of food intake. Nature Reviews Endocrinology, 9, pp. 584-597.
• [132] Air E.L., Strowski M.Z., Benoit S.C., Conarello S.L., Salituro G.M., Guan X.-M., Liu K., Woods S.C., Zhang B.B., 2002. Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity, Nature medicine, 8, pp. 179-183.
• [133] Rhea E. M., Banks W.A., 2019. Role of the blood-brain barrier in central nervous system insulin resistance, Frontiers in neuroscience, 13, pp. 521.
• [134] Woods S.C., Seeley R.J., Baskin D.G., Schwartz M.W., 2003. Insulin and the blood-brain barrier, Current pharmaceutical design, 9, pp. 795.
• [135] Banks W.A., 2004. The source of cerebral insulin. European journal of pharmacology, 490, pp. 5-12.
• [136] Chen W., Cai, W., Hoover B., Kahn C. R., 2022. Insulin action in the brain: cell types, circuits, and diseases. Trends in Neurosciences, 45, pp. 384-400
• [137] Harada N., Inagaki N., 2022. Regulation of food intake by intestinal hormones in brain. Journal of diabetes,13, pp.17-18.
• [138] Bewick G. A., 2012. Bowels control brain: gut hormones and obesity. Biochemia medica, 22, pp. 283-297.
• [139] Arosio M., Ronchi C.L., Gebbia C., Cappiello V., Beck-Peccoz P., Peracchi M., 2003. Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels. The Journal of Clinical Endocrinology & Metabolism, 88, pp. 701-704.
• [140] Katsuura G., Asakawa A., Inui A., 2002. Roles of pancreatic polypeptide in regulation of food intake. Peptides, 23, pp. 323-329.
• [141] Peracchi M., Tagliabue R., Quatrini M., Reschini E., 1999. Plasma pancreatic polypeptide response to secretin. European journal of endocrinology, 141, pp. 47-49.
• [142] Christofides N., Sarson D., Albuquerque R., Adrian T., Ghatei M., Modlin I., Bloom S., 1979. Release of gastrointestinal hormones following an oral water load. Experientia, 35, pp. 1521-1523.
• [143] Parkinson C., Drake W.M., Roberts M.E., Meeran K., Besser G., Trainer P.J., 2002. A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. The Journal of Clinical Endocrinology & Metabolism, 87, pp. 1797-1804.
• [144] Whitcomb D., Taylor I., Vigna S., 1990. Characterization of saturable binding sites for circulating pancreatic polypeptide in rat brain. American Journal of Physiology-Gastrointestinal and Liver Physiology, 259, pp. G687-G691.
• [145] McLaughlin C.L., Baile C.A., Buonomo F.C., 1985. Effect of CCK antibodies on food intake and weight gain in Zucker rats. Physiology & behavior, 34, pp. 277-282.
• [146] Lin S., Boey D., Herzog H., 2004. NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides, 38, pp. 189-200.
• [147] Sam A. H., Gunner D. J., King A., Persaud S. J., Brooks L., Hostomska K., Bewick G.A., 2012. Selective ablation of peptide YY cells in adult mice reveals their role in beta cell survival. Gastroenterology, 143, pp. 459-468.
• [148] Ekblad E., Sundler F., 2002. Distribution of pancreatic polypeptide and peptide YY. Peptides, 23, pp. 251-261.
• [149] Fu-Cheng X., Anini Y., Chariot J., Castex N., Galmiche J.-P., Roze C., 1997. Mechanisms of peptide YY release induced by an intraduodenal meal in rats: neural regulation by proximal gut. Pflügers Archiv, 433, pp. 571-579.
• [150] Allen J., Fitzpatrick M., Yeats J., Darcy K., Adrian T., Bloom S., 1984. Effects of peptide YY and neuropeptide Y on gastric emptying in man. Digestion, 30, pp. 255-262.
• [151] Adrian T., Savage A., Sagor G., Allen J., Bacarese-Hamilton A., Tatemoto K., Polak J., Bloom S., 1985. Effect of peptide YY on gastric, pancreatic, and biliary function in humans. Gastroenterology, 89, pp. 494-499.
• [152] Hoentjen F., Hopman W., Jansen J., 2001. Effect of circulating peptide YY on gallbladder emptying in humans. Scandinavian journal of gastroenterology, 36, pp. 1086-1091.
• [153] Batterham R.L., Cowley M.A., Small C.J., Herzog H., Cohen M.A., Dakin C.L., Wren A.M., Brynes A.E., Low M.J., Ghatei M.A., 2002. Gut hormone PYY 3-36 physiologically inhibits food intake. Nature, 418, pp. 650-654.
• [154] Challis B., Pinnock S., Coll A., Carter R., Dickson S., O’rahilly S., 2003. Acute effects of PYY3–36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochemical and biophysical research communications, 311, pp. 915-919.
• [155] Pittner R., Moore C., Bhavsar S., Gedulin B., Smith P., Jodka C., Parkes D., Paterniti J., Srivastava V., Young A., 2004. Effects of PYY [3–36] in rodent models of diabetes and obesity. International journal of obesity, 28, pp. 963-971.
• [156] Nonaka N., Shioda S., Niehoff M.L., Banks W.A., 2003. Characterization of blood-brain barrier permeability to PYY3-36 in the mouse. Journal of Pharmacology and Experimental Therapeutics, 306, pp. 948-953.
• [157] Broberger C., Landry M., Wong H., Walsh J.N., Hökfelt T., 1997. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin-and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology, 66, pp. 393-408.
• [158] Date Y., Kojima M., Hosoda H., Sawaguchi A., Mondal M.S., Suganuma T., Matsukura S., Kangawa K., Nakazato M., 2000. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology, 141, pp. 4255-4261.
• [159] Sakata I., Nakamura K., Yamazaki M., Matsubara M., Hayashi Y., Kangawa K., Sakai T., 2002. Ghrelin-producing cells exist as two types of cells, closed-and opened-type cells, in the rat gastrointestinal tract. Peptides, 23, pp. 531-536.
• [160] Castaneda T., Tong J., Datta R., Culler M., Tschöp M., 2010. Ghrelin in the regulation of body weight and metabolism. Frontiers in neuroendocrinology, 31, pp. 44-60.
• [161] Murakami N., Hayashida T., Kuroiwa T., Nakahara K., Ida T., Mondal M., Nakazato M., Kojima M., Kangawa K., 2002. Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats. Journal of Endocrinology, 174, pp. 283-288.
• [162] Sun Y., Wang P., Zheng H., Smith R.G., 2004. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proceedings of the National Academy of Sciences, 101, pp. 4679-4684.
• [163] Cowley M.A., Smith R.G., Diano S., Tschöp M., Pronchuk N., Grove K.L., Strasburger C.J., Bidlingmaier M., Esterman M., Heiman M.L., 2003. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron, 37, pp. 649-661.
• [164] Toshinai K., Date Y., Murakami N., Shimada M., Mondal M.S., Shimbara T., Guan J.-L., Wang Q.-P., Funahashi H., Sakurai T., 2003. Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology, 144, pp. 1506-1512.
• [165] Tang-Christensen M., Vrang N., Larsen P., 2001. Glucagon-like peptide containing pathways in the regulation of feeding behaviour. International journal of obesity, 25, pp. S42-S47.
• [166] Holst J.J., 2004. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors. Expert opinion on emerging drugs, 9, pp. 155-166.
• [167] Holst J., 2004. On the physiology of GIP and GLP-1. Hormone and Metabolic Research, 36, pp. 747-754.
• [168] Ghatei M., Uttenthal L., Christofides N., Bryant M., Bloom S., 1983. Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. The Journal of Clinical Endocrinology & Metabolism, 57, pp. 488-495.
• [169] Le Quellec A., Kervran A., Blache P., Ciurana A., Bataille D., 1992. Oxyntomodulin-like immunoreactivity: diurnal profile of a new potential enterogastrone. The Journal of Clinical Endocrinology & Metabolism, 74, pp. 1405-1409.
• [170] Dakin C.L., Gunn I., Small C., Edwards C., Hay D., Smith D., Ghatei M., Bloom S., 2001. Oxyntomodulin inhibits food intake in the rat. Endocrinology, 142, pp. 4244-4250.
• [171] Dakin C.L., Small C.J., Park A.J., Seth A., Ghatei M.A., Bloom S.R., 2002. Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. American Journal of Physiology-Endocrinology and Metabolism, 283, pp. E1173-E1177.
• [172] Dakin C.L., Small C.J., Batterham R.L., Neary N.M., Cohen M.A., Patterson M., Ghatei M.A., Bloom S.R., 2004. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology, 145, pp. 2687-2695.
• [173] Larsson L., Rehfeld J., 1978. Distribution of gastrin and CCK cells in the rat gastrointestinal tract. Histochemistry, 58, pp. 23-31.
• [174] Reeve Jr J.R., Eysselein V.E., Ho F., Chew P., Vigna S.R., Liddle R.A., Evans C., 1994. Natural and synthetic CCK-58. Novel reagents for studying cholecystokinin physiology. Annals of the New York Academy of Sciences, 713, pp. 11-21.
• [175] Warrilow, A., Turner, M., Naumovski, N., & Somerset, S., 2022. Role of cholecystokinin in satiation: A systematic review and meta-analysis. Published online by Cambridge University Press: 14 February 2022, British Journal of Nutrition, pp. 1-25.
• [176] Crawley J.N., Corwin R.L., 1994. Biological actions of cholecystokinin. Peptides, 15, pp. 731-755.
• [177] Wank S.A., Harkins R., Jensen R.T., Shapira H., De Weerth A., Slattery T., 1992. Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. Proceedings of the National Academy of Sciences, 89, pp. 3125-3129.
• [178] Moran T.H., Robinson P.H., Goldrich M.S., McHUGH P.R., 1986. Two brain cholecystokinin receptors: implications for behavioral actions. Brain research, 362, pp. 175-179.
• [179] Wank S.A., Pisegna J.R., De Weerth A., 1992. Brain and gastrointestinal cholecystokinin receptor family: structure and functional expression. Proceedings of the National Academy of Sciences, 89, pp. 8691-8695.