Dr. Paul Cottrell
John Mark Johnson
Human Endocrine Physiology
October 18, 2018
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 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 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 our ape ancestors.
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 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 glucose transporter in skeletal muscle . 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 . Insulin 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. . 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.
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 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 . The second way that insulin secretion is stimulated is through incretins. Incretins 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). The actions of incretins provide a feedforward component to glucose regulation during the ingestion of a meal . 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-cellinsulin release in vitro and in vivo.  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.
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 . 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 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 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.
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 . The tyrosine kinases that are attached to the insulin receptor work to phosphorylate and activate certain proteins which eventually lead to the cascade of effects which lead to glucose uptake by the cell or glycogen synthesis.
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3. Adipose Tissue
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 breakdown. The leptin receptor is a transmembrane-domain receptor that in hypothalamic neurons regulate energy homeostasis by activating the STAT3 pathway . The adiponectin receptors are AdipoR1 and AdipoR2, which are structurally and functionally distinct from G-protein-coupled receptors . Adiponectin receptors activates the transduction pathway of AMP-activated protein kinase for energy balance regulation .
To maintain long-term energy homeostasis leptin expression and secretion are elevated during energy absorption . 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 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 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 properties . 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 . Another short-term effect of adiponectin secretion into plasma is to lower the production of glucose from hepatic cells . 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.
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 . Lower GnRH due to lower leptin levels leads to reproductive and sexual development issues. Interestingly, it has been shown that leptin can induce ovulation in GnRH deficient mice . 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 . Adiponectin in plasma positively correlates with the number of oocytes retrieved in FSH treatment for superovulation . Fetal-maternal interface is also important to regulate, which is accomplished by adiponectin controlling endometrial stromal cells . 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 synthesis, (d) promoting glycogen accumulation, and (e) enhancing glycogen secretion .
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 . Adiponectin secretion from MAT has special significance because increases in adiponectin during caloric restriction has been found to be produced in MAT . Ovarian dysfunction in mice has been discovered with adiponectin deficiency . Evidence shows negative effects of adiponectin on GnRH secretion from the hypothalamus, LH and FSH secretion and testosterone in obese men .
Obesity and metabolic syndrome have been linked to hypothalamic-pituitary-adrenal axis dysfunction and local metabolism of glucocorticoids in adipose tissue . In human and rat studies leptin inhibited ACTH-stimulated cortisol production but had no effect on basal cortisol production which effects metabolic pathways . Leptin has a negative feedback loop on the 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 . In adrenal neoplasia, local secretion of leptin and adiponectin was found . This link with adrenal neoplasia, leptin and adiponectin can be used as a biomarker for adrenal neoplasia development.
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4. Gastrointestinal and Neuropeptide Hormones
At the core of homeostasis is the balance between catabolism, anabolism and storage of biomolecules that must be replenished from outside nutrient sources. 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 González-Muniesa, Pedro, et al. 2017 article “Obesity”, these three hormonal signals feed and act in conjunction with one another to regulate nutrient uptake . We will discuss them individually below:
Ghrelin is a 28-amino acid peptide secreted from the gastrointestinal endocrine cells, concentrated in the stomach . Ghrelin has been linked to the regulation of many homeostatic processes including heat production, insulin secretion, weight gain, and most famously, hunger. Ghrelin levels have found to be associated with food cues including visual, olfactory and ingestion signals . 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 . 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 GH release mediation; Ghrelin utilizes GH’s function to uptake energy and nutrients to process food from feeding . 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 .
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. 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 feeding regulation whereas the NPY Y2 receptor has a broader range of effects including gastrointestinal motility and blood pressure regulation . 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 stimulation of NPY’s release in the paraventricular hypothalamic nucleus (PVH) and is inhibited by the sensation of food .
Another factor of Ghrelin’s hunger signaling is the Agouti-related protein (AGRP); at 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 . 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 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 . 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 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 states . 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, both important in the digestion and transport of nutrients .
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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 . 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 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 . Signaling from the sympathetic nervous system activates the adrenal medulla, which secretes catecholamines (i.e. epinephrine 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 enough glucose to for cells to properly function . 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 .
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) . 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 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 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 . Finally, increased levels of GnRH secreted by the hypothalamus signals the pituitary to secrete FSH and LH. In men, LH stimulates the testes to make testosterone. Therefore, in response to exercise men produce increased testosterone mainly through the hypothalamic-pituitary-testes pathway . However, to a lesser degree, the release of testosterone during exercise may be achieved through other mechanisms . For example, spillover from the activation of the adrenal cortex (e.g. for secretion of cortisol) also leads to the secretion of sex hormones . Moreover, testosterone is 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 . In summary, there is an increase in growth hormone, cortisol, and testosterone in response to exercise that are all produced through endocrine responses to exercise.
The third phase of the hormonal response to exercise is marked by the modulating influence of circulating hormones . 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 systemic use. Studies have also found that IL-6 is involved in other metabolic processes such as regulating muscle stem cell- mediated hypertrophy . 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 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 . 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 . His research has shown that active individuals burn the same amount of calories per day as individuals who live less active lives . This appears counterintuitive, as it would seem those who are more active burn more calories but as Pontzer (2017) goes on to explain: metabolism in humans has been maximized by evolution . 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 . Pontzer (2017) argues convincingly that exercise doesn’t change a person’s metabolic rate, rather exercise causes adaptation of metabolic 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 .
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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 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 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.
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 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 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.