ed

iew
Endocrine Systems
by
Vivien Cheng
Dr. Paul Cottrell

ev
John Mark Johnson
Amrit Sanal

r
October 18, 2018

er
pe
ot
tn
rin
ep
Pr

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 1. Introduction

ed
The endocrine system assumes a primary role for maintaining energy homeostasis within
the body. In coordination with the nervous system, the endocrine system is responsible for
regulating hormonal responses to control the use and storage of energy molecules in order to
meet the physiological demands of the body and ensure proper cellular functioning. These

iew
actions are essential for human survival as they allocate the energy necessary to operate in ever
changing environments: supplying the brain with enough glucose to think and perceive, to digest
nutrients, to ready the body to external threats (i.e. fight-or-flight), to reproduce, etc. The goal of
this paper is to discuss a few of the main components of the endocrine system that are crucial for
homeostasis of energy metabolism: insulin, adipose tissue, as well as the roles of gastrointestinal
and neuropeptide hormones. In this discussion, we will review the mechanisms behind each

ev
component and explore how they affect overall energy metabolism. Furthermore, we will delve
into the effects of exercise on the endocrine system and review the mechanisms influencing
hormone levels. Finally, we will discuss recent research that presents a new outlook on exercise
by way of an evolutionary renovation of metabolic mechanisms that makes humans distinct from

r
our ape ancestors.

2. Insulin
er
Insulin is one of the most important hormones in human physiology. Beta-cells of the
pancreatic islets of Langerhans act as glucose sensors, adjusting insulin output to the prevailing
pe
blood glucose level. Insulin is released as the beta cells recognize that there are higher levels of
glucose in the bloodstream, and then goes on to act to bring blood glucose levels back within the
normal range. Insulin does this in two ways, by increasing the uptake of glucose into skeletal
muscle and by stimulating the production of glycogen in the liver. Insulin stimulates glucose
uptake in skeletal muscle by promoting the membrane translocation of GLUT4, the major
ot

glucose transporter in skeletal muscle [1]. In the liver, insulin acts to modulate the hepatic output
of glucose [...] by limiting the production and secretion of glucose from the liver [through]
inhibition of glucagon secretion, reduction of levels of free fatty acids, reduction of
gluconeogenic precursors, and changes in neural signaling relayed to the liver [2]. Insulin
tn

activates the IR in the liver, [which leads] to the activation of PI3K and ultimately Akt2. The
activation of Akt2 promotes glycogen synthesis and inhibits gluconeogenesis and glucose
production. [1][3]. Insulin thereby keeps the glucose levels in the blood within homeostatic
levels, which in turn decreases the metabolic rate so that there will be more stores of glucose for
the future.
rin

Insulin secretion, as mentioned before is controlled by the beta cells of the islet of
Langerhans. Insulin secretion is thought to be stimulated by four different pathways. One way is
through glucose sensing and insulin secretion. How glucose is sensed by the cell is still an area
of study that has no conclusive answer, but what’s generally agreed upon is that the glucose
ep

sensing step is within the actions of metabolism within the beta cell. The secretion of insulin is
induced also by actions of metabolism. The generation of ATP in the beta cell leads to the
closure of ATP-sensitive K+ (KATP) channels which leads to depolarization of the membrane.
This depolarization opens voltage gated Ca 2+ channels, which induces insulin granule
exocytosis [4]. The second way that insulin secretion is stimulated is through incretins. Incretins
Pr

are hormones of the GI tract that amplifies the insulin response to glucose. The major incretins
include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 The actions of incretins provide a feedforward component to glucose regulation during the

ed
ingestion of a meal [5]. The third stimulus of insulin secretion is through amino acid metabolism.
Several amino acids are known to elicit positive and/or negative effects on β-cell insulin release
in vitro and in vivo. [6] Amino acids tend to influence secretion of insulin similarly to how
glucose stimulate insulin secretion. The fourth way insulin secretion is stimulated is through
autonomic neuronal stimulation, which depolarizes the membrane during situations of stress.

iew
Epinephrine, cortisol and growth hormone are all hormones that are released during
hypoglycemia and other stress situations. These hormones all have insulin antagonistic effects in
the liver and other peripheral tissues. Epinephrine is a fast acting antagonist to insulin, whereas
cortisol and growth hormone are for more prolonged situations [7]. These hormones become
physiologically important when the body is under stressful conditions. Epinephrine acts in the
liver to promote glycogen decomposition into glucose while cortisol and growth hormone act to

ev
break down fats and proteins into glucose for long term energy usage. In a stressful situation, the
body needs to have more energy at hand, and these hormones effectively counter the effect of
insulin to provide the body with the energy it needs. The incretins provide a similar, but opposite
effect as these other hormones. Incretins provide a feedforward, amplifying effect to insulin, both
preparing the body for an intake of glucose, and making the insulin response more widespread

r
and effective on glucose metabolism. The incretins also provide a check to the stress response of
epinephrine, cortisol and GH, making it sure that there are still some energy reserves for the
body.
er
The insulin receptor belongs to the receptor tyrosine kinase superfamily. Insulin binds to
two distinct sites on each subunit of the receptor, crosslinking the two receptor halves to create
high affinity [8]. The tyrosine kinases that are attached to the insulin receptor work to
pe
phosphorylate and activate certain proteins which eventually lead to the cascade of effects which
lead to glucose uptake by the cell or glycogen synthesis.

1. Zhang, J. and Liu, F. (2014), Tissue‐specific insulin signaling in the regulation of metabolism
and aging. IUBMB Life, 66: 485-495. doi:10.1002/iub.1293
ot

2. Sharma, M. D., Garber, A. J., and Farmer, J. A. (2008) Role of insulin signaling in
maintaining energy homeostasis. Endocr. Pract. 14, 373–380.
3. Zhang, J. and Liu, F. (2014), Tissue‐specific insulin signaling in the regulation of metabolism
tn

and aging. IUBMB Life, 66: 485-495. doi:10.1002/iub.1293

4. MacDonald P.E., Joseph J.W., Rorsman P. Glucose-sensing mechanisms in pancreatic β-
cells. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005;360:2211–2225. doi:
10.1098/rstb.2005.1762.
rin

5. Widmaier, E. P., Raff, H., & Strang, K. T. (2016). Vanders human physiology: The
mechanisms of body function(14th ed.). New York, NY: McGraw-Hill Education.
6. Keane, K. and Newsholme, P. (2014) Metabolic regulation of insulin secretion. Vitam.
Horm. 95, 1–33
ep

7. Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J Inter Med Suppl
1991; 735:41–47.
8. De Groot LJ, Chrousos G, Dungan K, et al., editors. South Dartmouth (MA): MDText.com,
Inc.; 2000-.
Pr

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 3. Adipose Tissue

ed
The cells that secrete leptin and adiponectin are adipocytes. Adipocytes can be found in
white adipose tissue (WAT), brown adipose tissue (BAT), and bone marrow adipose tissue
(MAT). Leptin regulates energy balance by inhibiting hunger through opposition to the actions
of the hormone ghrelin. Adiponectin are involved in regulating glucose levels and fatty acid

iew
breakdown. The leptin receptor is a transmembrane-domain receptor that in hypothalamic
neurons regulate energy homeostasis by activating the STAT3 pathway [1]. The adiponectin
receptors are AdipoR1 and AdipoR2, which are structurally and functionally distinct from G-
protein-coupled receptors [2]. Adiponectin receptors activates the transduction pathway of
AMP-activated protein kinase for energy balance regulation [2].
To maintain long-term energy homeostasis leptin expression and secretion are elevated

ev
during energy absorption [1]. When energy intake exceeds energy expenditures fat deposition
results, which releases higher levels of leptin into the plasma. Leptin then signals the
hypothalamus to inhibit hunger through the neurotransmitter neuropeptide Y and suppression of
ghrelin hormones. This inhibition of hunger signal from leptin lowers energy intake and

r
increases metabolic rate. This negative feedback loop in extremely important in long-term
maintenance of the energy intake and energy expenditure balance. The short-term effects of
higher plasma levels of leptin are to suppress hunger, which helps to control insulin secretion
er
during absorption episodes—reducing glucose uptake by cells.
To maintain long-term energy homeostasis adiponectin is secreted from adipocytes,
which is also known to have antidiabetic, antiatherogenic, anti-inflammatory, and angiogenic
pe
properties [2]. A short-term effect of adiponectin secretion is the effects on muscle tissue,
whereby it stimulates glucose transport by increasing GLUT4 translocation—leading to
increased energy expenditures [2]. Another short-term effect of adiponectin secretion into
plasma is to lower the production of glucose from hepatic cells [3]. In normal individuals to
maintain glucose and fatty acid levels adiponectin is a negative feedback on glucose production
and a positive feedback on fatty acid oxidation.
ot

Leptin and adiponectin effects the reproductive axis as well. Leptin has roles in puberty
and pregnancy. It has been found that leptin deficient individuals have reduced puberty
development unless treated with external sources of leptin via direct and indirect regulation of
GnRH [4]. Lower GnRH due to lower leptin levels leads to reproductive and sexual
tn

development issues. Interestingly, it has been shown that leptin can induce ovulation in GnRH
deficient mice [4]. Pregnant women secret elevated levels of leptin for the placenta into maternal
plasma circulation resulting in leptin resistance in pregnancy—allowing a new setpoint for body
weight and increased food intake levels to help with the fetal growth [4]. Adiponectin in plasma
rin

positively correlates with the number of oocytes retrieved in FSH treatment for superovulation
[2]. Fetal-maternal interface is also important to regulate, which is accomplished by adiponectin
controlling endometrial stromal cells [5]. The glycogen metabolism of endometrial stromal cells
is regulated by adiponectin through (a) increasing glucose transporter 1 expression, (b) inhibiting
glucose catabolism via decrease in lactate and ATP production, (c) increasing glycogen
ep

synthesis, (d) promoting glycogen accumulation, and (e) enhancing glycogen secretion [5].
Other studies have found that adiponectin as a tissue regenerating hormone, whereby
globular adiponectin increases proliferation, migration and myogenic properties of satellite cells
and mesoangioblasts [3]. Adiponectin secretion from MAT has special significance because
increases in adiponectin during caloric restriction has been found to be produced in MAT [6].
Pr

Ovarian dysfunction in mice has been discovered with adiponectin deficiency [7]. Evidence

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 shows negative effects of adiponectin on GnRH secretion from the hypothalamus, LH and FSH

ed
secretion and testosterone in obese men [8].
Obesity and metabolic syndrome have been linked to hypothalamic-pituitary-adrenal axis
dysfunction and local metabolism of glucocorticoids in adipose tissue [9]. In human and rat
studies leptin inhibited ACTH-stimulated cortisol production but had no effect on basal cortisol
production which effects metabolic pathways [9]. Leptin has a negative feedback loop on the

iew
hypothalamic-pituitary-adrenal axis, since leptin deficient mice have exhibited increased CRH,
ACTH and adrenal cortex hormones. Adiponectin receptors are present in human adrenals and
that glucocorticoids and ACTH are known to decrease adiponectin production in WAT [9]. In
adrenal neoplasia, local secretion of leptin and adiponectin was found [10]. This link with
adrenal neoplasia, leptin and adiponectin can be used as a biomarker for adrenal neoplasia
development.

ev
1. Menzbert, H., & Morrison, C. D. (2015). Structure, production and signaling of leptin.
Metabolism, 64(1). 13-23. doi:10.1016/j.metabol.2014.09.010
2. Dos Santos, E., Pecquery, R., de Mazancourt, P., & Dieudonné, M. (2012). Adiponectin and

r
Reproduction. Vitamins and Hormones, 90.187-209. http://dx.doi.org/10.1016/B978-0-12-
398313-8.00008-7

er
3. Fiaschi, T., Magherini, F., Gamberi, T., Modesti, P.A., & Modesti, A. (2014). Adiponectin as
a tissue regenerating hormone: more than a metabolic function. Cellular and Molecular Life
Sciences, 71. 1917-1925. doi:10.1007/s00018-013-1537-4
4. Chehab, F.F. (2014). Leptin and reproduction: past milestones, present undertakings and
pe
future endeavors. Journal of Endocrinology, 223,(1). T37-T48. doi:10.1530/JOE-14-0413
5. Duval, F., Dos Santos, E., Maury, B., Serazin, V., Fathallah, K., Vialard, F., & Dieudonné,
M. (2018). Adiponectin regulates glycogen metabolism at the human fetal-maternal interface.
Journal of Molecular Endocrinology, 61,(3). 139-152. https://doi.org/10.1530/JME-18-0013
6. Cawthorn, W.P., Scheller, E.L., Learman, B.S., Parlee, S.D., Simon, B.R., Mori, H., …
ot

MacDougald, O.A. (2014). Bone marrow adipose tissue is an endocrine organ that contributes to
increased circulating adiponectin during caloric restriction. Cell Metabolism, 20. 368-375.
http://dx.doi.org/10/1016/j.cmet.2014.06.003
tn

7. Cheng, L., Shi, H., Jin, Y., Li, X., Pan, J., Lai, Y., … Li, F. (2016). Adiponectin deficiency
leads to female subfertility and ovarian dysfunctions in mice. Endocrinology, 157(12). 4875-
4887. doi:10.1210/en.2015-2080
8. Martin, L.J. (2014). Implications of adiponectin in linking metabolism to testicular function.
rin

Endocrine, 46. 16-28. doi:10.1007/s12020-013-0102-0

9. Kargi, A.Y., & Iacobellis, G. (2014). Adipose tissue and adrenal glands: novel
pathophysiological mechanisms and clinical applications. International Journal of
Endocrinology, 2014. 1-8. http://dx.doi.org/10.1155/2014/614074
ep

10. Letizia, C., Petramala, L., Rosaria, C., Di Gioia, T., Chiappetta, C., Zinnamosca, L, …
Iacobellis, G. (2015). Leptin and adiponectin mRNA expression from the adipose tissue
surrounding the adrenal neoplasia. The Journal of Clinical Endocrinology & Metabolism, 100(1).
E101-E104. doi:10.1210/jc.2014-2274
Pr

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 4. Gastrointestinal and Neuropeptide Hormones

ed
At the core of homeostasis is the
balance between catabolism, anabolism and
storage of biomolecules that must be
replenished from outside nutrient sources.

iew
Thus, hormones involved in feeding
behavior and gastrointestinal systems such
as Neuropeptide Y (NPY), Ghrelin and
Agouti-related peptide (AGRP) become
important regulators in energy balance. As
seen in the following diagram taken from

ev
González-Muniesa, Pedro, et al. 2017
article “Obesity”, these three hormonal
signals feed and act in conjunction with one
another to regulate nutrient uptake [1]. We

r
will discuss them individually below:
Ghrelin is a 28-amino acid peptide
secreted from the gastrointestinal endocrine
cells, concentrated in the stomach [2].
Ghrelin has been linked to the regulation of er
many homeostatic processes including heat production, insulin secretion, weight gain, and most
pe
famously, hunger. Ghrelin levels have found to be associated with food cues including visual,
olfactory and ingestion signals [3]. One of the proposed mechanisms for Ghrelin signaling is as
ligand to the Growth Hormone secretagogue (GHS) receptor, becoming a potent acute signal for
Growth Hormone (GH) release [2]. In fact this mechanism not only allows Ghrelin regulation of
food intake and the GI tract, but also an equally important role of glucose homeostasis and the
pancreas. Studies have shown that pancreatic Ghrelin can rescue hypoglycemic states through
ot

GH release mediation; Ghrelin utilizes GH’s function to uptake energy and nutrients to process
food from feeding [4]. Current research is interested in the mechanism of how Ghrelin influences
the pancreas; some indicate a direct influence of Ghrelin on beta-cells while others indicate that
ghrelin indirectly inhibits insulin through stimulation of somatostatin release [5].
tn

While Ghrelin pathways are still unclear, many papers have indicated the involvement of
NPY, a 36-residue long peptide that functions in multiple systems throughout the body including
cardiovascular, gastrointestinal, neuroendocrine, and sympathetic systems. Research suggests
that NPY is one of the downstream signals triggered by Ghrelin to carry out hunger activation.
rin

NPY is synthesized and released from both sympathetic neurons and the adrenal medulla. The
biochemical explanation to NPY’s diverse functionality is its family of G-protein coupled
receptors that enhance signaling via signal cascades starting with cAMP/PKA activation. These
G-protein receptors are differentially localized throughout the body, allowing NPY to perform
specified functionalities for each system. For example, the NPY Y5 receptor mainly effects
ep

feeding regulation whereas the NPY Y2 receptor has a broader range of effects including
gastrointestinal motility and blood pressure regulation [6]. The research indicates that one
pathway NPY regulates homeostasis is by driving energy conservation in Brown Adipose Tissue
as well as peripheral mastication in motor systems; in effect, NPY tells our bodies to save
nutrients while preparing to feed and replenish new nutrients. This pathway is driven through
Pr

stimulation of NPY’s release in the paraventricular hypothalamic nucleus (PVH) and is inhibited
by the sensation of food [7].

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 Another factor of Ghrelin’s hunger signaling is the Agouti-related protein (AGRP); at

ed
131 amino acids long, AGRP is larger than Ghrelin and NPY and is expressed in the
hypothalamic arcuate nucleus and adrenal medulla. AGRP is mechanistically antagonistic for
melanocortin receptors MC3-R and MC4-R and all three molecules have been implicated in
feeding [8]. In fact, AGRP is frequently mentioned in conjunction with NPY due to its exclusive
co-expression in NPY arcuate nucleus neurons. Interestingly, the arcuate nucleus is also home to

iew
receptors for other metabolic factors such as insulin and growth hormone indicating a sort of
homeostatic hub. Recent studies suggest that AGRP’s functionality is either separate or
downstream of NPY’s pathway. Moreover, while AGRP has been found to influence resting
metabolic rate and long-term appetite it does not seem to influence changes in fat as NPY does
[9]. This indicates that while AGRP and NPY are both downstream of Ghrelin, the signaling
pathway is not the amplification of one task, rather an incredibly diverse set of task combinations

ev
that could be independent of each other.
Physiologically, this array of differentiated functions for hunger hormones and their
receptors allow for different organs to perform specific tasks in the feeding, nutrient digestion
and energy absorption process. Speculatively, this also allows for a safety net in case one
regulatory hormone is not functional e.g. GH triggered by Ghrelin can rescue hypoglycemic

r
states [4]. Finally, it also allows for nutrient processing to trigger other necessary systems e.g.
NPY’s family of receptors allows simultaneous regulation of the GI tract and blood pressure,

er
both important in the digestion and transport of nutrients [6].

1. González-Muniesa, Pedro, et al. (2017, June 15). Figure 6: Control of hunger and satiety.
pe
[Digital image]. Retrieved from https://www.nature.com/articles/nrdp201734#f6
2. Kojima M., Hosoda H., Matsuo H. and Kangawa K. (2001) Ghrelin: discovery of the natural
endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol. Metab.
12, 118–122 10.1016/S1043-2760(00)00362-3
3. Malik S., McGlone F., Bedrossian D. and Dagher A. (2008) Ghrelin modulates brain activity
in areas that control appetitive behavior. Cell Metab. 7, 400–409 10.1016/j.cmet.2008.03.007
ot

4. Zhao T‐J, Liang G, Li RL, et al. Ghrelin O‐acyltransferase (GOAT) is essential for growth
hormone‐mediated survival of calorie‐restricted mice. Proc Natl Acad Sci U S A.
2010;107(16):7467‐7472.
tn

5. DiGruccio MR, Mawla AM, Donaldson CJ, et al. Comprehensive alpha, beta and delta cell
transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin
release from pancreatic islets. Mol Metab. 2016;5(7):449‐458.
6. Li, L., Najafi, A. H., Kitlinska, J. B., Neville, R., Laredo, J., Epstein, S. E., et al. (2011). Of
rin

mice and men: neuropeptide Y and its receptors are associated with atherosclerotic lesion burden
and vulnerability. J. Cardiovasc. Transl. Res. 4, 351–362. doi: 10.1007/s12265-011-9271-5
7. Nakamura, Y., Yanagawa, Y., Morrison, S. F., & Nakamura, K. (2017). Medullary Reticular
Neurons Mediate Neuropeptide Y-Induced Metabolic Inhibition and Mastication. Cell
ep

Metabolism, 322-334. doi:10.1016/j.cmet.2016.12.002

8. 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,165-168.
doi:10.1038/385165a0
Pr

9. Broberger, Christian et al. “The Neuropeptide Y/agouti Gene-Related Protein (AGRP) Brain
Circuitry in Normal, Anorectic, and Monosodium Glutamate-Treated Mice.” Proceedings of the

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 National Academy of Sciences of the United States of America 95.25 (1998): 15043–15048.

ed
Print.

5. Exercise

iew
Exercise produces a number of beneficial health factors and is associated with reduced
risk for disease, such as type 2 diabetes, coronary heart disease, and stroke [2,3]. The effects of
exercise are accomplished through modulation of endocrine physiology. The stress placed on the
body during exercise produces an abrupt shift from homeostasis [5]. This shift causes a number
physiological changes including: increased growth hormone, increased cortisol secretion,
increased levels of testosterone, and increased cytokine release allowing the body to adapt to the

ev
increasing metabolic demands [5,9].
According to the exploratory HERM model (Hormonal Exercise Response Model), the
physiological changes brought about by exercise occur in three phases starting with immediate
neural signaling from the sympathetic nervous system [5]. Signaling from the sympathetic
nervous system activates the adrenal medulla, which secretes catecholamines (i.e. epinephrine

r
and norepinephrine). The increased circulation of epinephrine and/or the sympathetic neural
signaling inhibits the secretion of insulin, which causes the body to adapt in order to provide

er
enough glucose to for cells to properly function [10]. Although the mechanism has yet to be
completely defined, studies suggest that the body adapts by synthesizing more glucose
transporters as well as directing other intracellular glucose transporters to the plasma membrane
thus allowing more glucose to enter the cell with decreased levels of insulin [10].
pe
In the second phase of hormonal response to exercise, the hypothalamus releases a
number of hormones including: corticotropin releasing hormone (CRH), growth hormone
releasing hormone (GHRH), and gonadotropin releasing hormone (GnRH) [5]. CRH signals the
pituitary to release ACTH, which is then carried through the bloodstream to the adrenal cortex
where it stimulates the secretion of cortisol. Increased cortisol produces the net result of
increased plasma concentrations of amino acids, glucose, and free fatty acids, which are all
ot

necessary for sufficient nutrients during bouts of exercise. Similarly, the secretion of GHRH
from the hypothalamus stimulates the pituitary to secrete growth hormone. Increased growth
hormones primary effects are: stimulating growth and increased protein synthesis and the
tn

secondary effects are aimed at carbohydrate and lipid metabolism similar to the effects of
cortisol [5,10]. Specifically, a greater concentration of growth hormone increases
gluconeogenesis and lipolysis while inhibiting insulin to produce increased plasma
concentrations of glucose necessary during strenuous exercise [10]. Finally, increased levels of
GnRH secreted by the hypothalamus signals the pituitary to secrete FSH and LH. In men, LH
rin

stimulates the testes to make testosterone. Therefore, in response to exercise men produce
increased testosterone mainly through the hypothalamic-pituitary-testes pathway [9]. However,
to a lesser degree, the release of testosterone during exercise may be achieved through other
mechanisms [9]. For example, spillover from the activation of the adrenal cortex (e.g. for
secretion of cortisol) also leads to the secretion of sex hormones [9]. Moreover, testosterone is
ep

also produced in small amounts in the ovaries of females. Spillover effects and the conversion of
testosterone to estradiol in the ovaries are the primary mechanisms for increasing testosterone in
women and in prepubescent males- this explains why women and prepubescent males do not
show a large increase in testosterone in response to exercise [9]. In summary, there is an increase
Pr

in growth hormone, cortisol, and testosterone in response to exercise that are all produced
through endocrine responses to exercise.

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 The third phase of the hormonal response to exercise is marked by the modulating

ed
influence of circulating hormones [5]. Feedback systems begin modulating hormone levels and
controlling for the amount of energy necessary to maintain function during ongoing exercise.
Importantly, during this phase contracting skeletal muscles release myokines (i.e. a subset of
cytokines) which cause autocrine, endocrine, and paracrine responses in target tissues [5,10]. A
specific myokine, IL-6, is primarily involved in energy mobilization providing fuel for local and

iew
systemic use. Studies have also found that IL-6 is involved in other metabolic processes such as
regulating muscle stem cell- mediated hypertrophy [7]. The activity of myokines, in response to
muscle contraction, provides evidence for muscle maintaining a major endocrine role and a
modulator of energy mobilization.
Exercise also maintains influence on energy and metabolism through appetite. Research
suggests that exercise has a negative effect on appetite by inhibiting the hormone ghrelin- a

ev
hormone that stimulates hunger [1,8]. Moreover, studies have shown that exercise increases
sensitivity to insulin thus requiring less concentration of insulin to transport glucose into cells for
energy [4]. These findings suggest that exercise must maintain a modulatory role on metabolism
and appetite. However, research from Pontzer (2017) has questioned the effect of exercise on
metabolic rate [6]. His research has shown that active individuals burn the same amount of

r
calories per day as individuals who live less active lives [6]. This appears counterintuitive, as it
would seem those who are more active burn more calories but as Pontzer (2017) goes on to

er
explain: metabolism in humans has been maximized by evolution [6]. Compared to our ape
ancestors, humans have evolved to possess a higher metabolism that affords advantages such as
allocating enough nutrients to feed our larger brains [6]. Pontzer (2017) argues convincingly that
exercise doesn’t change a person’s metabolic rate, rather exercise causes adaptation of metabolic
pe
mechanisms to operate more efficiently (e.g. increased insulin sensitivity) and that weight
control largely depends on an individual’s diet as a person’s metabolic rate is, more or less, fixed
[6].

1. Broom, D. R., Batterham, R. L., King, J. A., & Stensel, D. J. (2009). Influence of resistance
ot

and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy
males. American Journal of Physiology-Regulatory, Integrative and Comparative
Physiology,296(1). doi:10.1152/ajpregu.90706.2008
tn

2. Fentem, P. H. (1994). ABC of Sports Medicine: Benefits of exercise in health and disease.
Bmj,308(6939), 1291-1295. doi:10.1136/bmj.308.6939.1291
3. Garber, C. E., Blissmer, B., Deschenes, M. R., Franklin, B. A., Lamonte, M. J., Lee, I., . . .
Swain, D. P. (2011). Quantity and Quality of Exercise for Developing and Maintaining
rin

Cardiorespiratory, Musculoskeletal, and Neuromotor Fitness in Apparently Healthy Adults.

Medicine & Science in Sports & Exercise,43(7), 1334-1359. doi:10.1249/mss.0b013e318213fefb
4. Goodyear, P. L., & Kahn, M. B. (1998). Exercise, Glucose Transport, And Insulin
Sensitivity. Annual Review of Medicine,49(1), 235-261. doi:10.1146/annurev.med.49.1.235
ep

5. Hackney, A. C., & Lane, A. R. (2015). Exercise and the Regulation of Endocrine Hormones.
Progress in Molecular Biology and Translational Science Molecular and Cellular Regulation of
Adaptation to Exercise,293-311. doi:10.1016/bs.pmbts.2015.07.001
6. Pontzer, H. (2017). The Exercise Paradox. Scientific American,316(2), 26-31.
Pr

doi:10.1038/scientificamerican0217-26

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237
 7. Serrano, A. L., Baeza-Raja, B., Perdiguero, E., Jardí, M., & Muñoz-Cánoves, P. (2008).

ed
Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle Hypertrophy.
Cell Metabolism,7(1), 33-44. doi:10.1016/j.cmet.2007.11.011
8. Vatansever-Ozen, S., Tiryaki-Sonmez, G., Bugdayci, G., & Ozen, G. (2011). The Effects of
Exercise on Food Intake and Hunger: Relationship with Acylated Ghrelin and Leptin. Journal of

iew
Sports Science & Medicine, 10(2), 283–291.
9. Vingren, J. L., Kraemer, W. J., Ratamess, N. A., Anderson, J. M., Volek, J. S., & Maresh, C.
M. (2010). Testosterone Physiology in Resistance Exercise and Training. Sports
Medicine,40(12), 1037-1053. doi:10.2165/11536910-000000000-00000
10. Widmaier, E. P., Raff, H., & Strang, K. T. (2016). Vanders human physiology: The
mechanisms of body function(14th ed.). New York, NY: McGraw-Hill Education.

ev
6. Conclusion

r
In this paper, we reviewed just a subset of the complex endocrine system and its vital role
in homeostasis: First, Insulin is an important hormone that regulates glucose levels in the
bloodstream through the pancreatic beta-cells secretion. Four different pathways were discussed

er
on how insulin secretion is stimulated. Insulin antagonists such as epinephrine, cortisol and
growth hormones were also discussed in relation to hypoglycemia and stress. Second, Adipose
tissue secretes leptin and adiponectin via adipocytes to help control energy balance, regulate
glucose levels and fatty acid breakdown. Leptin and adiponectin affects the reproductive axis as
pe
well, whereby Leptin has roles in puberty and pregnancy. Third, Ghrelin, NPY and AGRP are
important regulatory hormones linked to: (a) GI metabolism, (b) insulin secretion, (b) blood
pressure, and (d) hunger triggering. Finally, exercise has complex endocrine effects; we discuss
the HERM model, e.g. exercise induced physiological changes that occur in three phases. We
suggest that exercise can inhibit the ghrelin hormone, thus having negative effects on appetite.
ot

Through this paper we see that human behaviors such as exercise, organs such as adipose,
and hormones such as Ghrelin collaborate to maintain homeostasis. For example, exercise
heightens efficiency of food metabolism whose intake is triggered by Ghrelin. These nutrients
are processed in pathways involving NPY, AGRP, and Insulin signaling to be stored in Adipose
tn

tissues that signals a well-nourished body suitable for development or pregnancy. Speculatively,
this correlates homeostasis with higher evolutionary fitness. Our review shows that future
research directions revolve around treatments of obesity and diabetes. For example, Insulin is
now a key indicator in clinical research on effects of exercise and hormones on obesity reversal
i.e providing GH or ghrelin to balance serum insulin/sugar levels. As our understanding of the
rin

endocrine system increases, we expect future research to continue development of new

generation therapy and to test efficacy of treatment in expanded diabetic patient populations.
ep
Pr

This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3309237