Hormonal Regulation of Feeding Behaviour

The human body is normally capable of matching the day-to-day fluctuations in energy intake with an appropriate amount of energy expenditure. This homeostatic regulation of energy consumption is achieved by many peptides and steroids that circulate in the body, imposing substantial influence on development, appetite, and feeding behaviour. These signalling molecules, or hormones, are largely regulated and secreted from the hypothalamus, pancreas, fat cells, and the gastrointestinal tract.

The actions and mechanisms in which these hormones regulate our appetite and feeding behaviour through signalling pathways involving the leptin-melanocortin pathway in the ventromedial hypothalamus and other downstream signalling effects of leptin are extremely salient to metabolic homeostasis. In addition, gut and endocrine organ derived hormones such as ghrelin, cholecystokinin (CCK) and peptide YY3-36 (PYY3-36) have significant effects on feeding behaviour and appetite.

Recent discoveries have suggested that some of these hormones, markedly leptin and ghrelin, have additional effects on the cognitive aspects of the nervous system such as stress and depressive symptoms. Specifically, leptin and ghrelin have recently been suggested as potential pharmaceutical targets of anti-anxiety and anti-depressant drugs, as these molecules are associated with decreased levels of depressive symptoms and chronic stress in human adults[1] and mouse models[2].

Therefore, the overall effects of hormones on feeding behavior and energy consumption require thorough investigation, with further emphasis on newly discovered cognitive impacts of these hormones on stress and depression.

Image Unavailable
Obesity is in part caused by disturbances in hormonal regulation of energy homeostasis. Image source:[3]

1.1 Leptin as the major regulator of energy intake and expenditure

Leptin was one of the first satiety regulating compounds discovered. The effect of leptin was studied using two naturally occurring mouse models that were massively obese and voracious. These mouse models were later found to be homozygous for single gene mutations- ob/ob, those with mutations in the gene coding for satiety factor leptin, and db/db, those with mutations in the gene coding for leptin receptors.[4] In addition to obesity and hyperphagia, leptin-deficient animals including humans showed symptoms of hypothermia, decreased locomotor acitivity, neuroendocrine and immunological abnormalities – all of which were reversed by external administration of leptin.[5]

Leptin is synthesized by adipocytes of white adipose tissue along with minor secretions from brown adipose tissue, skeletal muscle, mammary epithelial cells, bone marrow, pituitary gland, stomach, placenta, ovaries, and liver.[6] Consequently, the concentration of circulating leptin is proportional to the amount of fat cells in the body.

Leptin was initially suggested to be the key molecule involved in monitoring the balance and transition between well-nourished and starving states, and the absence of starvation-induced normal neuroendocrine abnormalities upon administration of leptin has led to the confirmation of such proposition.[5]

1.1a Hypothalamic leptin-melanocortin pathway

Regulation of Appetite by the Hypothalmic Leptin-Melanocortin Pathway
Image Unavailable
Leptin has a critical role in regulation of appetite through the melanocortin pathway in the hypothalamus.
PVN, paraventricular nucleus; Arc, arcuate nucleus; MC4R, melanocortin 4 receptor;
AgRP, Agouti-related protein; POMC, pro-opiomelanocortin. Image source:[9]

Direct administration of leptin in the central nervous system results in reversal of characteristic phenotypes associated with leptin-deficient ob/ob mice.[5] This suggests the existence of central leptin receptors in the brain that mediate the downstream effects of leptin.

Markedly, two populations of cells in the arcuate nucleus of the hypothalamus have been discovered to be the leptin-responsive neurons in the brain: 1) appetite stimulatory (orexigenic) melanocortin antagonists Agouti-related peptide (AgRP) and neuropeptide Y (NPY), and 2) satiety stimulatory pro-opiomelanocortin (POMC) and cocaine-and amphetamine regulated transcript (CART).[7] NPY/AgRP neurons have stimulatory inputs to the lateral hypothalamus (LH) and inhibitory inputs to the ventromedial hypothalamus (VMH). In contrast, POMC/CART neurons have stimulatory inputs to VMH and inhibitory inputs to LH.[7] Leptin inhibits the NPY/AgRP neurons and stimulates POMC/CART neurons. Thus, deficiency in leptin or leptin receptors, such as observed in ob/ob and db/db mice, may lead to heightened appetite and feeding behaviour which may contribute to obesity.[8] In addition, starvation leads to upregulation of NPY/AgRP expression, which also results in increased appetite and feeding behaviour.[7] Both NPY/AgRP and POMC/CART neurons project to melanocortin 4 receptors (MC4R) expressing neurons in the hypothamalus, where further downstream signals to other sites of appetite regulation are relayed.[9]

1.1b Other downstream signalling pathways of leptin

Melanocortin 4 receptors (MC4R) are critical relay centres within the hypothalamus that send projections to other sites in the brain including structures involved in reward and satiety. MC4Rs are generally involved in the regulation of feeding behaviour, metabolism, male erectile function and sexual behaviour.[10] Mutations in the gene coding for MC4Rs results in individuals with severe hyperphagic obesity, and accounts for 5% of child obesity and 0.5% to 2.5% of adult obesity.[11] Recent studies have discovered the divergence of the melanocortin pathway into two distinct functional roles: 1) control of food intake, and 2) control of energy expenditure. Specifically, when cre-lox selective gene expression technique was used to reexpress MC4Rs in the paraventricular nucleus and the amygdala in naturally MC4R-deficient mice, they were significantly lighter than MC4R-deficient controls- although still heavier than control mice with globally functional MC4Rs.[12] This leads to the conclusion that the paraventicular nucleus and/or the amygdala are crucial for the regulation of energy intake, while other brain areas more involved in the control of energy expenditure.[12]

Recent studies have provided evidence indicating brain-derived neurotrophic factor (BDNF) as another mediator of energy homeostasis. Mice with mutations or deletion in one copy of the Bdnf gene show hyperphagia and obesity[13], and this effect is ameliorated by administration of BDNF.[14] Furthermore, administration of BDNF into MC4R-deficient mice was able to reduce hyperphagic feeding patterns and excessive weight gain, indicating that BDNF and MC4Rs operate under discrete pathways .[9]

1.2 Developmental effects of leptin

Leptin significantly influences neuronal growth and development. In leptin-deficient ob/ob mice, changes in synaptic inputs to the arcuate nucleus are observed. Specifically, deficiency in leptin results in increased excitatory inputs in NPY/AgRP neurons and decreased excitatory inputs to POMC neurons – all of which are reversed by administration of leptin.[15] Evidenced by deficits in hypothalamic innervations found in leptin-deficient mice - markedly in the neuronal projections from the acruate nucleus to the paraventricular nucleus, lateral hypothalamus, and dorsomedial nucleus- leptin functions as a crucial neurotrophic growth factor.[16]

2.1 Gastrointestinal tract hormones

Signaling Pathways of Gut and Endocrine Derived Hormones
Image Unavailable
Hormones derived from the gut and endocrine organs such as pancreas,
adrenal glands, and thyroid relay signals to the brain to affect appetite and feeding behaviour.
CCK, cholecystokinin; GLP1, glucagon-like peptide-1; PYY3-36, peptide YY3-36; OXM, oxyntomodulin.
Image source:[9]

Gastrointestinal tract hormones, or gut hormones, are secreted by the stomach, small intestine, and pancreas and act as neurotransmitters and neuromodulators that mediate energy homeostasis. Some of the major hormones found in the gut are cholecystokinin (CCK), peptide YY3-36 (PYY3-36), and ghrelin.

2.1a Cholecystokinin, PYY3-36, Ghrelin

Cholecystokinin (CCK) is secreted postprandially by enteroendocrine cells of the duodenum and jejunum and has long been known as one of the gut hormones most significantly implicated as a satiety signal.[17] CCK relays signals to appetite centres in the brain, namely, the nucleus of the solitary tract (NTS). Administration of CCK activates POMC neurons in the NTS in a MC4R-dependent pathway. However, CCK fails to inhibit food intake in mice lacking functional MC4Rs[18], emphasizing the role of the melanocortin receptor system in mediating gut-induced satiety responses.

Peptide YY3-36 (PYY3-36) is secreted postprandially by endocrine L cells of the gut. Interestingly, direct PYY3-36 administration into the cerebrospinal fluid of animals induces enhanced appetite and increased food intake, whereas peripheral administration of PYY3-36 results in the opposite effect – reduced food intake.[17] Unlike leptin or CCK, PYY3-36 appears to work in a melanocortin-system-independent pathway, evidenced by continued anorexigenic effects of PYY3-36 even when the melanocortin system is disrupted.[19] Deficiency in PYY3-36 is characterized as another contributor of obesity as overweight human subjects show low level of postprandial PYY3-36 release.[20]

Ghrelin is secreted in high levels during fasted states by the oxyntic glands of the stomach and has long been known as the “hunger hormone” since increased circulating ghrelin concentration stimulates appetite.[21] In a recent study, inhibition of ghrelin by producing neutralizing antibodies through pre-inoculated vaccination of ghrelin has led to a decreased rate of weight gain, emphasizing the significant effect of ghrelin as a regulator of appetite and body weight.[22] Ghrelin is also produced in the brain, particularly in the dorsal, ventral, paraventricular, and arcuate neclei of the hypothalamus.[23] Ghrelin acts as a mediator of adipocyte metabolism in the central nervous system.[24] This is evidenced by increased lipogenesis along with a reduction in energy expenditure following chronic infusion of ghrelin into the CNS.[24] Thus, ghrelin is most likely a signal that prepares the body for storage of in-coming nutrients by triggering the metabolic pathway for lipogenesis.

2.2 Pancreatic hormones

2.2a Insulin

Despite its broad distribution of receptors in areas such as the hippocampus, olfactory bulb, cerebral cortex, and the arcuate nucleus within the hypothalamus, insulin has relatively minimal effects on body weight and food intake. Female mice with loss-of-function mutations in the gene coding for insulin receptors in the central nervous system were only 10%-15% heavier than control mice.[25] Interestingly, this effect was not found in male mice.[25] However, recent studies have shown mixed results on the role of insulin as a mediator of energy homeostasis in the CNS. Therefore, administration of insulin into the CNS undoubtedly has appetite-suppressing activity, although the mechanism underlying such phenomenon is still largely uncertain. 

3.1 Cognitive effects of feeding hormones

3.1a Leptin and ghrelin as anti-depressive pharmaceutical targets

Image Unavailable
Depression is an altered state of mood that may severely impair
a person's behaviour, thoughts, world view, feelings, and physical well-being.
Leptin and ghrelin have recently been suggested as potential pharmaceutial
targets for treatment of depression.
Image source:[26]

A recent study has implicated leptin as not only the essential molecule of metabolic homeostasis, but also an important molecule associated with depressive symptoms in adult women across a spectrum of various weight and body fat compositions.[1] Leptin is as an anorexigenic hormone with markedly low levels of secretion in women with low body weight. Therefore, women with anorexia nervosa were believed to be at an increased risk of depression and anxiety due to the deficiency in leptin expression. Upon examination of correlational relationship between leptin and ghrelin levels and symptoms of depression and anxiety in women across various body weight, inverse relationships between leptin levels and scores from scales of depressive symptoms (Hamilton Rating Scale for Depression; HAM-D, Hamilton Rating Scale for Anxiety; HAM-A, Perceived Stress Scale) were found.[1] More importantly, this negative relationship was found to be significant even after controlling for body fat or weight, indicating that leptin levels may have significant effects on modulating mood regardless of body weight.[1] In addition, increased ghrelin levels were associated with increased degree of perceived stress, although this effect was not significant after controlling for body fat or weight. Therefore, leptin has recently been suggested as a possible candidate molecule for treatment of depressive symptoms. However, the administration of leptin as a potential treatment option for depression and anxiety is still at an early stage, and further investigation involving leptin as the pharmaceutical target of mood regulation is required. 

In addition to leptin, ghrelin was also recently implicated as a molecule that defends against depressive symptoms of chronic stress. Mice with subcutaneous injections of ghrelin or caloric restriction which increases circulating ghrelin levels produced anti-depressant and anti-anxiety responses in forced swim test and elevated plus maze.[2] In addition, increased chronic social defeat stress- a recent model of depression in animal models- induced increased ghrelin levels as a defensive response against stress.[2] Moreover, mice with knockouts in the gene coding for growth hormone secretagogue receptors- the endogenous receptor for ghrelin- showed increased deficits arising from chronic defeat.[2] These findings demonstrate a newly discovered role of ghrelin, which may function as an effective molecule against depressive symptoms of chronic stress.  However, the mechanism underlying stress-induced increase in circulating ghrelin level is unclear, and further investigation with emphasis in psychopathological conditions known to alter ghrelin levels, such as anorexia nervosa, is required.

See also

1. Lawson, E. A., Miller, K. K., Blum, J. I., Meenaghan, E., Misra, M., Eddy, K. T., Herzog, D. B., & Klibanski, A. (2012). Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat. Clinical Endocrinology, 76(4), 520-525.
2. Lutter, M., Sakata, I., Osborne-Lawrence, S., Rovinsky, S.A., Anderson, J.G., Jung, S., Birnsbaum, S., Yanagisawa, M., Elmquist, J.K., Nestler, E.J., Zignman, J.M. (2008). The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nature Neuroscience, 11(7), 752-753.
3. [Obesity Silhouette]. Retrievd March 25, 2013, from: http://fittipdaily.com/wp-content/uploads/2010/06/USA-Obesity-Rate.jpg
4. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.
5. Friedman, J.M., and Halaas, J.L. (1998). Leptin and the regulation of body weight in mammals. Nature 395, 763-770.
6. Margetic, S., Gazzola, C., Pegg, G. G., Hill, R. A. (2002). Leptin: a review of its peripheral actions and interactions. Int. J. Obes. Relat. Metab. Disord. 26 (11): 1407–1433.
7. Cone, R.D. (2005). Anatomy and regulation of the central melanocortin system. Nature Neuroscience 8, 571–578.
8. Flier, J.S. (2004). Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350.
9. Coll, A.P., Farooqi, I.S., O'Rahilly, S. (2007). The hormonal control of food intake. Cell 129, 251-262.
10. Van der Ploeg LH, Martin WJ, Howard AD, Nargund RP, Austin CP, Guan X, Drisko J, Cashen D, Sebhat I, Patchett AA, Figueroa DJ, DiLella AG, Connolly BM, Weinberg DH, Tan CP, Palyha OC, Pong SS, MacNeil T, Rosenblum C, Vongs A, Tang R, Yu H, Sailer AW, Fong TM, Huang C, Tota MR, Chang RS, Stearns R, Tamvakopoulos C, Christ G, Drazen DL, Spar BD, Nelson RJ, MacIntyre DE. (2002). A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci USA 99 (17): 11381–11386.
11. Hinney, A., Bettecken, T., Tarnow, P., Brumm, H., Reichwald, K., Lichtner, P., Scherag, A., Nguyen, T.T., Schlumberger, P., Rief, W., et al. (2006). Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J. Clin. Endocrinol. Metab. 91, 1761–1769.
12. Balthasar, N., Dalgaard, L.T., Lee, C.E., Yu, J., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R.A., Kenny, C.D., et al. (2005). Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505.
13. Rios, M., Fan, G., Fekete, C., Kelly, J., Bates, B., Kuehn, R., Lechan, R.M., and Jaenisch, R. (2001). Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748–1757.
14. Nakagawa, T., Tsuchida, A., Itakura, Y., Nonomura, T., Ono, M., Hirota, F., Inoue, T., Nakayama, C., Taiji, M., and Noguchi, H. (2000). Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice. Diabetes 49, 436–444.
15. Pinto, S., Roseberry, A.G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J.M., and Horvath, T.L. (2004). Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115.
16. Bouret, S.G., Draper, S.J., and Simerly, R.B. (2004). Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110.
17. Chaudhri, O., Small, C., and Bloom, S. (2006). Gastrointestinal hormones regulating appetite. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1187–1209.
18. Fan, W., Ellacott, K.L., Halatchev, I.G., Takahashi, K., Yu, P., and Cone, R.D. (2004). Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat. Neurosci. 7, 335–336.
19. Coll, A.P., Farooqi, I.S., Challis, B.G., Yeo, G.S., and O’Rahilly, S. (2004). Proopiomelanocortin and energy balance: insights from human and murine genetics. J. Clin. Endocrinol. Metab. 89, 2557–2562.
20. le Roux, C.W., Aylwin, S.J., Batterham, R.L., Borg, C.M., Coyle, F., Prasad, V., Shurey, S., Ghatei, M.A., Patel, A.G., and Bloom, S.R. (2006). Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann. Surg. 243, 108–114.
21. Williams, D.L., and Cummings, D.E. (2005). Regulation of ghrelin in physiologic and pathophysiologic states. J. Nutr. 135, 1320–1325.
22. Zorrilla, E.P., Iwasaki, S., Moss, J.A., Chang, J., Otsuji, J., Inoue, K., Meijler, M.M., and Janda, K.D. (2006). From the cover: Vaccination against weight gain. Proc. Natl. Acad. Sci. USA 103, 13226–13231.
23. Cowley, M.A., Smith, R.G., Diano, S., Tschop, M., Pronchuk, N., Grove, K.L., Strasburger, C.J., Bidlingmaier, M., Esterman, M., Heiman, M.L., et al. (2003). The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661.
24. Theander-Carrillo, C., Wiedmer, P., Cettour-Rose, P., Nogueiras, R., Perez-Tilve, D., Pfluger, P., Castaneda, T.R., Muzzin, P., Schurmann, A., Szanto, I., et al. (2006). Ghrelin action in the brain controls adipocyte metabolism. J. Clin. Invest. 116, 1983–1993.
25. Bruning, J.C., Gautam, D., Burks, D.J., Gillette, J., Schubert, M., Orban, P.C., Klein, R., Krone, W., Muller-Wieland, D., and Kahn, C.R. (2000). Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125.
26. [Depression]. Retrieved April 1, 2013, from http://micah.sparacio.org/05/16/2011/10-ways-to-fight-depression/

Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License