Weight Control by Fatimat Adigun-Bello, Dr. Paul Cottrell, Victoria Virgulak and Vivian Okonta.


The word balance is a complicated term in the human life. It is often heard relating to everyday tasks, but often forgotten is the most important balance that of which is found within the human body. One pivotal marker of an individual having balance is having full control of body weight. It is a significant challenge to maintain an ideal fitness and weight. 

The human body has a complex set of hormones and signaling systems that monitor and adjust to retain balance. The systems, if properly maintained, work in harmony. However, if there is a slight issue, the systems can turn on the human body and cause damage. Insulin is able to work in the body as a positive and a negative asset. If properly managed, insulin can assist in weight loss by metabolizing glucose and reducing the need for fat synthesis, however if improperly managed, poor diet can lead to rising levels of insulin and eventually result in weight gain and type II diabetes. To sustain the body’s energy, two important hormones work in opposition of each other - leptin and adiponectin. Leptin suppresses appetite and increases metabolic rate while adiponectin increases appetite and decreases metabolic rate. These hormones exert their actions via other hormones and neuropeptides. Others include ghrelin, neuropeptide Y (NPY) and agouti-related peptide (AgRP) which work together to increase energy intake and promote weight gain. With weight loss, hormones such as ghrelin will increase to guard against continued weight loss. There are several other hormones involved in body weight control that are activated with exercise including testosterone, cortisol, and growth hormone. The duration and intensity of the exercise affects them differently. For example, after an intensive exercise, the body upkeeps the balance by repairing and building muscles via these hormones. 

While there are large strides being made in research on the correct way to balance weight in the human body, there is still research to be done to help combat worldwide obesity and obesity related diseases. There are questions left to be answered, however basic understanding of all the systems and its hormones can progress everyone on the correct path for balance. 


The regulation of body weight and energy homeostasis is controlled by different endocrine systems and metabolic pathways, and food intake is controlled by the CNS through neuroendocrine and neurotransmitter circuits. The involvement of Insulin signaling is mostly done by regulation of energy homeostasis and body weight through its effect on lipid and glucose metabolism [1]. Insulin promotes the storage of glucose and fat and has metabolic effects that determine body weight as an anabolic hormone. 

There are physiological actions of insulin that could have effects on body weight or weight loss in an individual which include the metabolism of macronutrients, cellular growth, stimulation of glucose transport, triglyceride synthesis and inhibiting lipolysis, upregulation of LPL and inhibition of adipocytes HSL through blockage of its phosphorylation [2]. 

In healthy individuals, insulin secretion is exact in meeting the metabolic demand. It binds to a receptor on the plasma membrane and induces secondary messengers in the body. The pancreatic beta cells from the islet of langerhans are stimulated by high levels of plasma glucose and are able to sense change in plasma glucose concentration and act by releasing corresponding amounts of insulin into the blood. Insulin then stimulate cells of the body to uptake glucose. In addition, there are other kinds of hormones that modulate insulin secretion by affecting the timing of its release, one type of hormone is incretins. Incretin is released in the GI tract in response to food intake. Another is GLP (glucagon like peptide 1), a major type of incretin, which provides a feedforward component and further induces the secretion of insulin to glucose overload after taking a meal [4]. In addition, fenestration also modulates insulin secretion and allows for the rapid diffusion into the blood [3]. 

Glucose is the primary stimulus for insulin release, due to its fact that it can accumulate immediately after ingestion of food [3]. Other macromolecules are able to cause secretion of insulin but not in large amounts as glucose. In addition, studies have shown different patterns of food intake within 24 hours of the day or longer which have resulted in decrease or increase of insulin secretion and the effect it has. A study tested glucose and insulin excursions in the response to different meal frequencies and macronutrient composition. The study was done with healthy individuals who ate 6 frequent carbohydrate meals in 12 hours, which resulted in high blood glucose levels over the course of the day, while another group ate 3 carb meals a day and had less blood glucose levels, but both individual groups had no difference in insulin response. They came to a conclusion that different eating patterns during the day may increase blood glucose levels in a course of 24 hours, but there will be no difference in insulin response within 24 hours [5]. Although they were able to see a difference in insulin response over the course of 24 hours, they did not have the same response with different meal frequencies in individuals who had only a protein diet. There was a decrease in insulin response than those individuals. 

There has been the association of obesity and type 2 diabetes for some decades now and the main reason for this link is due to obesity giving rise to insulin resistance (SI) [6]. There is a decrease in the Adipo R expression levels, thereby enhancing insulin resistance in individuals who are obese [2]. Exercise has also been a topic that has been discussed as a way to help reduce obesity and improve glucose homeostasis in individuals. Although, this may seem attractive, this concept is still under intensive research and different strategies are being done in order to get a better understanding of how exercise can be beneficial in obesity. It was concluded that acute exercise enhances glucose uptake but insulin resistance (SI) often sets back to its baseline within a couple of days after the physical activity, leaving the effectiveness of exercise in question [6]. 

On the other hand, some studies have provided evidence that regular intensive physical activity reduces the risk of insulin resistance and type 2 diabetes [7]. Insulin resistance can improve with individuals who comply with exercise on a daily and aerobic exercise interventions can also play a positive part. Individuals with obesity or type 2 diabetes, could benefit on adjusting their lifestyles with proper nutrition and exercise that could favour weight maintenance or loss. In regards to the study previously discussed, a proper nutritional meal that contains more of protein and fat could help with weight maintenance, as it is shown that high protein diets reduce insulin response due to low blood glucose. This adjustment accompanied with physical activity, such as; resistance exercise could improve glycaemic regulations [7] and lead to weight maintenance or loss. 

In conclusion, the study of weight maintenance or loss in obesity has been an ongoing study and having these life nutritional adjustment accompanied with exercise, seem to make a difference in glycaemic regulations. In future studies, Could it be possible to make a change in the decrease in Adipo R expression levels, cause an increase in adiponectin level and decrease insulin resistance in obese individuals? This could stimulate insulin sensitivity which could be beneficial alongside exercise in obese individuals and help with insulin resistance which seems to be the hurdle in obesity and type 2 diabetes. Also, instead of engaging in acute exercise, could the intensity of exercise be longer in time? To make sure SI does not reset back to its baseline as previously discussed. These questionable strategies could benefit weight maintenance over time and create a healthy immune glycemic system. 


1. Dokken, B., & Tsao, T. (2018). The Physiology of Body Weight Regulation: Are We Too Efficient for Our Own Good?. 

2. Singla, P. (2010). Metabolic effects of obesity: A review. World Journal Of Diabetes, 1(3), 76. doi: 10.4239/wjd.v1.i3.76. 

3. Fu, Z., R. Gilbert, E., & Liu, D. (2013). Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes. Current Diabetes Reviews, 9(1), 25-53. doi: 10.2174/157339913804143225. 

4. Kim, W. and Egan, J.M. (2009). The Role of Incretins in Glucose Homeostasis and Diabetes Treatment. Pharmacology Review. 

5. Holmstrup, M., Owens, C., Fairchild, T., & Kanaley, J. (2010). Effect of meal frequency on glucose and insulin excursions over the course of a day. E-SPEN, The European E-Journal Of Clinical Nutrition And Metabolism, 5(6), e277-e280. doi: 10.1016/j.eclnm.2010.10.001. 

6. Kahn, B., & flier, j. (2000). Obesity and insulin resistance. The Journal Of Clinical Investigation, 106(4), 473-481. doi: 10.1172/JCI10842. 

7.  Bird, S., & Hawley, J. (2017). Update on the effects of physical activity on insulin sensitivity in humans. BMJ Open Sport & Exercise Medicine, 2(1), e000143. doi: 10.1136/bmjsem-2016-000143. 

Leptin and Adiponectin

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. 

To maintain long-term energy homeostasis leptin expression and secretion are elevated 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 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 [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. 

Obesity and metabolic syndrome have been linked to hypothalamic-pituitary-adrenal axis dysfunction and local metabolism of glucocorticoids in adipose tissue [4]. Adiponectin receptors are present in human adrenals and that glucocorticoids and ACTH are known to decrease adiponectin production in white adipose tissue [4]. 

There is an inverse relationship with adiponectin production and amount of adipose tissue, whereas there is a positive correlation with leptin production and the amount of adipose tissue. These relationships allow for setting a lower bound and upper bound in weight fluctuation, e.g. leptin sets upper bound and adiponectin sets lower bound. Unfortunately resetting boundaries upward is easier for most people than to resetting a downward direction. These resetting phenomena might be evolutionary to maintain energy balance biased to the higher weight setpoint. This prevents overweight individuals from losing weight on a permanent basis. It has been found that leptin-infused mice do not subsequently defend a higher body weight after infusion [5]. 

To promote weight loss, it is hypothesized lipolysis would need to be increased. This increase in lipolysis could be through increased cortisol levels, anti-inflammatory signaling, increased leptin and lower adiponectin signaling. Since the body has reset points for leptin and adiponectin based on the amount of adipose tissue and CNS sensitivity to leptin, a long-term lifestyle change would be needed to properly reset upper and lower bound limits of energy balance. One possible lifestyle change that would affect the endocrine system related to leptin and adiponectin would be a slow reduction in caloric intake. By phasing caloric restriction slowly, the glucose levels are lower leading to lipolysis and gluconeogenesis long-term. This will in turn lead to reduced fat cells over a sustained timeframe and a chance for the CNS to up-regulate leptin sensitivity. Also, to increase energy expenditures during the calorie restriction phase a mild exercise regime would maintain IL-6 plasma levels, inhibiting protein breakdown and maintaining musculature. The mild exercise regime should decrease after the weight target has been reached and maintained for one year. This deduction in exercise and maintained caloric levels further establishes the reset point for energy balance. 

To promote weight gain, it is hypothesized one would need to reset the upper bounds of
leptin. This is accomplished through extensive exercise to increase muscle mass and a phased-in caloric increase. Positive energy balance will activate insulin to store the excess of glucose into cells for storage. This will also overtime lead to lower sensitivity to leptin in the CNS to reduce hunger inhibition. After the weight target has been reached exercise regime should be mild to keep musculature and caloric intake should be slightly reduced to reinforce the upper bound reset point for energy balance. 

Additional research in long-term resetting upper and lower bound energy balance limits are required to further formulate lifestyle recommendations for sustained weight loss and gain. Two follow- up research questions are: (a) How the CNS sensitivity for leptin changes long-term in anorexia nervosa patients with a slow increased caloric intake regime, and (b) How the CNS sensitivity for leptin changes long-term in obese patients with a slow decrease in caloric intake regime? 


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

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. 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 

5. Ravussin, Y., LeDuc, C. A., Watanabe, K., Mueller, B. R., Skowronski, A., Rosenbaum, M., & Leibel, R. L. (2014). Effects of chronic leptin infusion on subsequent body weight and composition in mice: can body weight set point be reset? Molecular Metabolism 3, 432-
440. http://dx.doi.org/10.10.16/j.molmet.2014.02.003 

Neutopeptide Y, Gherkin and Agouti-related Peptide

Ghrelin, neuropeptide Y (NPY) and agouti-related peptide (AgRP) work together to increase energy intake and reduce energy expenditure which can ultimately result in weight gain (1,2). Ghrelin is primarily secreted by enteroendocrine cells in the stomach and other areas in the body such as the hypothalamus and pancreas. In response to hunger, when the stomach is empty and glucose levels are low, ghrelin is secreted in high amounts. Ghrelin activates growth hormone secretagogue receptors (GHSR) in the ARC nucleus to increase the synthesis and release of NPY and AgRP. These neuropeptides then increase appetite. In addition, ghrelin stimulates stomach motility, acid secretion and growth hormone secretion. Together, ghrelin and NPY increase lipogenesis and gluconeogenesis. On its own, NPY suppresses sympathetic nervous system (SNS) activity and decreases metabolic rate via suppression of the hypothalamic-pituitary-thyroid axis. These actions combined move the body towards a positive energy balance. (1–3) 

Normally, ghrelin levels rise during periods of fasting and fall soon after a meal is consumed but genetic mutations can also play a role in its secretion and activity (3). Ghrelin is a polypeptide in which several polymorphisms can exist predisposing an individual to have higher or lower total ghrelin levels. For example, the Arg51Gln is a single nucleotide polymorphism (SNP) that interrupts the normal production of a mature ghrelin peptide. Studies have shown that those with the Arg51Gln mutation have lower total levels of circulating ghrelin. (3,4) Genetics also play a role in the dysfunctional secretion of ghrelin in individuals with Prader-Willi Syndrome but the exact mutation is not yet known. This genetic disorder is characterized by hypotonia and poor feeding at birth followed by hyperphagia and excessive weight gain. When looking at a group of PWS individuals, ghrelin levels are constantly high throughout their lifetime and suspected to be the cause for hyperphagia (5). Lastly, several studies have been done looking at the ghrelin levels of individuals with eating disorders such as anorexia nervosa (AN). Individuals with AN have been found to have higher levels of fasting ghrelin compared to healthy normal weight controls (3). However, more research needs to be done to determine whether there are genetic factors at play or if the altered ghrelin levels are a result of prolonged starvation and the underweight status of those with AN. 

Several lifestyle patterns have been suggested to decrease the secretion of these hormones and promote weight loss. Schmid et al. suggest that adequate sleep can lead to lower levels of ghrelin. Additionally, high protein and keto diets lead to lower levels of post-meal and total circulating ghrelin levels. Blom et al. showed that individuals who had a high protein meal suppressed ghrelin levels stronger than those that had a high carbohydrate meal. This greater suppression of ghrelin reduced appetite and energy intake during the next meal (6). An individual may also opt to use a keto or high fat, low carb diet to attenuate the increase in ghrelin that comes with weight loss. The increase in ghrelin that comes with weight loss is the body’s effort to maintain homeostatic weight by intensifying triggers for food intake. Thus, in order to keep the weight off, individuals may adapt ways to minimize the normal elevation of ghrelin that comes with weight loss. Findings from a study by Sumi et al. found that participants who lost weight on a keto diet did not have as a significant increase in fasting plasma ghrelin compared to participants on a high carb, low fat diet. Fat has also been hypothesized to better signal to the hypothalamus that there is enough food around and decrease the expression of NPY (7). Furthermore, specific types and doses of exercise can have different effects on ghrelin levels. Fasting ghrelin levels are shown to decrease more with moderate-dose (14 kcal/kg per week) exercise as opposed to low-dose (8 kcal/kg per week) (8). Therefore, a high protein or high fat diet combined with proper sleep and moderate dose exercise may promote weight loss and maintenance. 

On the contrary, any lifestyle patterns that would increase the secretion or action of these hormones may also promote weight gain. Just one night of sleep restricted to 4 hours leads to increased total ghrelin levels and appetite (9). Meals containing high fructose content decrease ghrelin levels to a lesser degree (10). Therefore, poor sleep, low dose exercise and diet consisting of high carbohydrates and fructose can increase ghrelin secretion and action via NPY and AgRP ultimately resulting in increased appetite, food intake and weight gain. 

There are still a myriad of unanswered questions pertaining to how the manipulation of ghrelin, NPY and AgRP can effectively promote weight gain and loss. The recommendations described are mostly based on data involving persons that are of normal weight. Is it possible for those that are already overweight or obese to adapt these lifestyle patterns and exert similar effects on these hormones? Furthermore, these data describe lifestyle changes adapted for short periods of time. More research is needed to determine if the effects on ghrelin can be maintained long-term. Are the changes in ghrelin in response to the adapted lifestyle patterns just temporary? 

1. Ibrahim Abdalla MM. Ghrelin – Physiological Functions and Regulation. Eur Endocrinol. 2015 Aug;11(2):90–5. 

2. Delporte C. Structure and Physiological Actions of Ghrelin [Internet]. Scientifica. 2013 [cited 2018 Oct 18]. Available from: https://www.hindawi.com/journals/scientifica/2013/518909/ 

3. Ando T. Chapter Four - Ghrelin Gene Variants and Eating Disorders. In: Litwack G, editor. Vitamins & Hormones [Internet]. Academic Press; 2013 [cited 2018 Dec 2]. p. 107–23. (Anorexia; vol. 92). Available from: http://www.sciencedirect.com/science/article/pii/B9780124104730000040 

4. Ukkola O, Ravussin E, Jacobson P, Pérusse L, Rankinen T, Tschöp M, et al. Role of Ghrelin Polymorphisms in Obesity Based on Three Different Studies. Obes Res. 2002 Aug 1;10(8):782–91. 

5. Atalayer D, Gibson C, Konopacka A, Geliebter A. Ghrelin and Eating Disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:70–82. 

6. Blom WA, Lluch A, Stafleu A, Vinoy S, Holst JJ, Schaafsma G, et al. Effect of a high-protein breakfast on the postprandial ghrelin response. Am J Clin Nutr. 2006 Feb 1;83(2):211–20. 

7. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. Ketosis and appetite-mediating nutrients and hormones after weight loss. Eur J Clin Nutr. 2013 Jul;67(7):759–64. 

8. Bowyer KP, Carson JA, Davis JM, Wang X. The influence of exercise training dose on fasting acylated ghrelin concentration in older women. J Behav Med [Internet]. 2018 Nov 17 [cited 2018 Nov 29]; Available from: https://doi.org/10.1007/s10865-018-9990-z 

9. Schmid SM, Hallschmid M, Jauch‐Chara K, Born J, Schultes B. A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J Sleep Res. 2008 Sep 1;17(3):331–4. 

10. Teff KL, Elliott SS, Tschöp M, Kieffer TJ, Rader D, Heiman M, et al. Dietary Fructose Reduces Circulating Insulin and Leptin, Attenuates Postprandial Suppression of Ghrelin, and Increases Triglycerides in Women. J Clin Endocrinol Metab. 2004 Jun 1;89(6):2963–72. 


The human body is a complex mechanism that has an intricate system of hormones maintaining and monitoring to upkeep a healthy system. The science behind maintaining a healthy body has been debated and updated over the course of history, from dictating what to eat or how to exercise. Hormones such as neuropeptide Y, ghrelin and agouti-related peptide control appetite that in return control food intakes, which affects weight gain or loss. Besides food intake, exercise plays an important role in sustaining a healthy human body. Exercise produces hormones such as testosterone, cortisol, and growth hormone and yields myokines secretion, which assists in muscle building and recovery. The human body has to maintain a balance with exercise, which causes metabolic changes. The essential focus is preserving a fit and healthy body by triggering the intricate system of hormones working cohesively 

Exercise in the body triggers three important hormones, testosterone, cortisol, and growth hormone. Testosterone is increased in the body during and after workouts, which helps with muscle repair. When there is a moderate to high intensity exercise, it has been shown that there is a great elevation in testosterone [3]. Cortisol provides energy while the body is in exercise status and also assists in anti-inflammatory response. Cortisol levels are highly elevated like testosterone when there is high intensity workout and 24 hours after [3]. Low intensity workouts do not “result in significant increases in circulating cortisol levels” [2]. There is strong research supporting that like testosterone and cortisol, growth hormone’s response is produced by high intensity workouts. There is research that shows that the sex of the human plays a key factor. In young women, growth hormone response occurs due to the intensity, while for young men the growth hormone response occurs due to the duration [7]. Humans that are older or unfit have shown that growth hormone secretion is decreased. Exercise is a good indicator to stimulate growth hormone in the body [8].  The intensity and duration of exercise is quite important to the human body for the stimulation of hormones. 

While triggering exercise hormones, a workout also triggers appetite hormones, ghrelin is suppressed during workout and increased after a workout. Leptin is increased during exercise to decrease appetite, after exercise, it decreases to up the food intake. 

Hormones are not the only mechanism that is activated during exercise in the body; myokines are secreted in the muscles. The myokines regulate anti- inflammation in the body after exercise. There are different types of myokines that present themselves around in the body after period a of exercise. Some myokines are considered as a exercise factor like, ANGPTL4, CCL2, and many more, however, there is more research needed to see the effects on the body. There is little data available for each individual myokine that investigates the effects of duration and intensity of exercise in the human body. For example, IL-6 has been showing to be present in high levels during a short form of exercise, however during moderate exercise the concertation plummets [1].  Each myokine has a potential to influence the human body in different ways during and after exercise, while myokines play a role in the body metabolism is also effected from exercise. 

Metabolism is modified during continuous exercise. Professor Herman Pontzer’s research describes that no matter the physical activity of all humans, they all expend the same amount of calories. The common belief is that the greater the physical activity done, the greater benefit is found to the human body, however the belief is not accurate and proves to have negative effects [6].  Current health suggestions should be reformatted to adapt Pontzer’s research, “expenditure and the complex effects of physical activity on metabolic physiology. to better reflect the constrained nature of total energy” [4]. The idea of  maintaining a healthy body is to work smarter, not harder.

A person who is motivated or less motivated to workout, both should be able to workout with a similar regime, given that they are the same sex such as women. They should follow a schedule of  exercising a few times a week to activate exercise hormones by working out high intensity workouts to maintain healthy body weight. However, it would all depend on their starting shape, there is still researched needed to determine, would a better understanding of myokines change an exercise regime or would additional growth hormone supplements promote weight loss or weight maintenance? 


1. Catoire, M., & Kersten, S. (2015, May). The search for exercise factors in humans. Retrieved from 


2. Hill, E. E., Zack, E., Battaglini, C., Viru, M., Viru, A., & Hackney, A. C. (2008, July). Exercise and 

circulating cortisol levels: The intensity threshold effect. Retrieved from 


3. Kraemer, W. J., & Ratamess, N. A. (n.d.). Hormonal responses and adaptations to resistance exercise 

and training. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15831061 

4. Pontzer, H., Durazo-Arvizu, R., Dugas, L. R., Plange-Rhule, J., Bovet, P., Forrester, T. E., Luke, A. 

(2016, February 08). Constrained Total Energy Expenditure and Metabolic Adaptation to Physical 

Activity in Adult Humans. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26832439 

5. Sholi, G. A., Ghanbarzadeh, M., Habibi, A., & Ranjbar, R. (1970, January 01). The Effects of 

Combined Exercises Intensity (Aerobics-Resistance) on Plasma Cortisol and Testosterone Levels in 

Active Males. Retrieved from https://www.semanticscholar.org/paper/The-Effects-of-Combined- 


6. Thomas, D. M., & Heymsfield, S. B. (2016, February 08). Exercise: Is More Always Better? 

Retrieved from https://www.sciencedirect.com/science/article/pii/S0960982215015572#bib3 

7. Wideman, L., Consitt, L., Patrie, J., Swearingin, B., Bloomer, R., Davis, P., & Weltman, A. (2006, 

December). The impact of sex and exercise duration on growth hormone secretion. Retrieved from 


8. Wideman, L., Weltman, J. Y., Hartman, M. L., Veldhuis, J. D., & Weltman, A. (2012, October 23). 

Growth Hormone Release During Acute and Chronic Aerobic and Resistance Exercise. Retrieved from 



Weight management involves complex process in the endocrine system. In this paper we explore the effects of many systems: (a) insulin, (b) leptin and adiponectin, (c) neuropeptide Y, (d) ghrelin, (e) agouti-related peptide, and (f) exercise. 

In terms of insulin, weight management can be achieved through having a high protein diet, which will cause less insulin response in the system along with regular intensive physical activity to help reduce the risk of insulin resistance and type 2 diabetes in obese individuals. Physical activity should be done in longer durations than acute, as to keep a steady weight if one decides to stop exercising or slow down and to also balance the baseline of insulin sensitivity in obesity. 

Within the leptin and adiponectin paradigm weight management is possible. One possible lifestyle change that would affect the endocrine system related to leptin and adiponectin would be a slow reduction in caloric intake. By phasing caloric restriction slowly, the glucose levels are lower leading to lipolysis and gluconeogenesis long-term. This will in turn lead to reduced fat cells over a sustained timeframe and a chance for the CNS to up-regulate leptin sensitivity. Also, to increase energy expenditures during the calorie restriction phase a mild exercise regime would inhibit protein breakdown and maintaining musculature. The mild exercise regime should decrease after the weight target has been reached and maintained for one year. 

Within the neuropeptide Y, ghrelin and agouti-related peptide paradigm weight loss can be achieved through moderate exercise that expends 14 kcal/kg/wk. Consumption of a high protein, high fat and low carbohydrate diet is recommended. This regimen will decrease ghrelin, neuropeptide Y and agouti-related peptides which will decrease appetite and food intake—leading to weight loss. 

Research has shown the idea is to workout smarter, not harder. High intensity over a short period of time provide better results in activating all hormones to build and recover muscles. Maintenance of weight have been found difficult for many individuals, therefore exercise alone is not a prescribed treatment for sustained weight loss and treatment needs to be coupled with other paradigms represented in figure 1 below. 



Endocrine system by Dr. Paul Cottrell

Endocrine Systems


Vivien Cheng

Dr. Paul Cottrell

John Mark Johnson

Amrit Sanal


Human Endocrine Physiology

October 18, 2018

1. Introduction 


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. 


2. Insulin


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 [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 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. 

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 [4]. 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 [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-cellinsulin 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. 

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 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 [8]. 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. 


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

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 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. 

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

7.   Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J Inter Med Suppl1991; 735:41–47. 

8.   De Groot LJ, Chrousos G, Dungan K, et al., editors. South Dartmouth (MA): MDText.com, Inc.; 2000-.


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 [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 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 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 [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.

            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 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 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 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].  Ovarian dysfunction in mice has been discovered with adiponectin deficiency [7]. Evidence shows negative effects of adiponectin on GnRH secretion from the hypothalamus, LH and FSH 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 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.


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

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 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., … 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

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. 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

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


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 [1]. We 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 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 [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 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].

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

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 [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 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 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 [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, 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. [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

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.

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 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 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

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 National Academy of Sciences of the United States of America 95.25 (1998): 15043–15048. Print.


5. Exercise


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 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 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 [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].

            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 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 [10]. 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 [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 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 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 [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 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 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 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 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 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 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

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 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

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. doi:10.1038/scientificamerican0217-26

7.  Serrano, A. L., Baeza-Raja, B., Perdiguero, E., Jardí, M., & Muñoz-Cánoves, P. (2008). 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 Sports Science & Medicine10(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.


6. Conclusion


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.


Advantages and Limitation of GWAS by Dr. Paul Cottrell


With the human genome being sequenced we can perform studies on single nucleotide polymorphisms (SNP) of the whole genome. This sort of study is called genome-wide association studies (GWAS). The goal with GWAS is to make associations of SNPs and diseases. Unfortunately, there are challenges to accurately make these associations between SNPs and diseases. Some have proposed that current biostatistical analysis paradigms need to be more holistic to recognize the true complexity of the genotype-phenotype relationship (Moore, Asselbergs and Williams, 2010). In this essay I go over some of the advantages and limitations of GWAS pertaining to sample size, variant frequency and data interpretation.


There is a utility with GWAS in finding genotype-phenotype relationships that are associated with common and complex diseases (Ghazani, 2017). For diseases that are common it is relatively easy to meet the large sample size requirement of GWAS. The cost of processing GWAS is reasonable, due to the low cost of sequencing and the ability to data mine large data sets. GWAS requires the bi-allelic assumption, which is reasonable because only 1-3% of our genome has random copy number variants. Many studies have been performed and data banked on different diseases, but researchers need to be aware of the methodology used to determine if the genotype-phenotype association conclusions are valid. If the controls and cases are of similar distributions then statistical significance is much stronger, which is very important to consider when validating other researchers conclusions of genotype-phenotype association.


GWAS under certain conditions fails to identify new susceptibility loci for some diseases, even though a study might have a very large sample size (Moore, Asselbergs, and Williams, 2010). GWAS performs poorly in determining genotype-phenotype association with rare diseases because it is difficult to obtain the required large sample size. Validation and discovery sample overlap is a potential pitfall of GWAS. The validation sample is an independent sample with known phenotypes, whereas the discovery sample is where SNPs are selected and estimations of their effects determined. Another pitfall with GWAS pertains to the validation sample, whereby prediction accuracy will be overestimated if the validation sample is closely related to the discovery sample than the target sample (Wray et al., (2013). Lastly, Wray et al. (2013) proposed that population stratification similarity can inflate accuracy when discovery and validation sample stratification matches population stratification, but do not match the targeted sample stratification. Researchers should pay close attention to this stratification issue to assure validity in genotype-phenotype association conclusions. Another important limitation of GWAS is the use of standard logistical regression. Moore et al. (2010) suggested the use of more advanced algorithms: data mining with machine learning, use of decision trees and random forests. These more advanced algorithms for the use in GWAS is to help illuminate the relationship with DNA sequences variation, environmental exposure and variation in disease susceptibility.


GWAS is a powerful method to determine genotype-phenotype association, but researchers must keep in mind the limitation of sample size, variation frequency, and specific data interpretations to come up with valid conclusions of association.


Ghazani, A. A. (2017). Introduction to Genomics [PowerPoint slides]. https://canvas.harvard.edu/courses/35084/files/5290181?module_item_id=354933

Moore, J. H., Asselbergs, F. W., & Williams, S. M. (2010). Bioinformatics challenges for genome-wide association studies. Bioinformatics, 26(4), 445-455. doi:10.1093/bioinformatics/btp713

Wray, N. R., Yang, J., Hayes, B. J., Price, A. L., Goddard, M. E., & Visscher, P. M. (2013). Pitfalls of predicting complex traits from SNPs. Nature Reviews Genetics, 14, 507-515. doi:10.1038/nrg3457