The Hormones involved in natural fasting behavior provide insight into human health and nutrition

Abstract

Many different animals have adapted to undergo long periods of food deprivation in the form of natural fasting. Seals, specifically the northern elephant seal, remain the model organism for animals that experience these fasts while remaining metabolically active, as they are the most widely studied and have a clear fast within their life histories. Penguins also exhibit active natural fasts, which are delineated into three phases. Other animals, such as bears and squirrels, fast naturally through hibernation, where they exist in states of torpor for several months during the year. These animals, however, do not starve, but rather their bodies remain in functional and healthy states while they fast. These different fasts are highly regulated by several hormones such as thyroid hormones, glucocorticoids, and pancreatic hormones, as well as appetite hormones. I review various studies to bring together a more complete picture of the hormones that maintain these natural fasts. The hormones I focus this review on include glucocorticoids, thyroid hormones, pancreatic hormones, leptin, ghrelin, and obestatin. Glucocorticoids were reported to rise in natural fasts, while pancreatic hormones fell during the fasting period. Thyroid hormones rose in elephant seal pups’ post-weaning fast, while concentrations decreased in the hibernation fasts of bears and squirrels. The “satiety hormone” leptin showed conflicting results across studies. Hormones related to leptin include ghrelin and obestatin, both of which need further research to extend our understanding of their roles in natural fasting behavior. These hormones that regulate natural fasting are conserved in most vertebrates, including humans. Thus, these studies have the potential to increase our greater understanding of human metabolism and consequently nutrition, with a specific focus on relevance to nutrition and obesity, as well as bone remodeling and osteoporosis.

Introduction

Many animals have adapted to undergo long duration fasting, long-term natural states of natural food deprivation, as part of their natural life history cycles. Such fasting is highly regulated by many different hormones, yet studies often do not attempt to draw relationships between different hormones and relate such hormones that help regulate and maintain these natural fasts. Furthermore, little data exists on animals that actually display natural fasting in the field and still remain metabolically active (Ortiz, et. al., 2001). Here, I bring together data gathered from a wide variety of animals that display natural fasting behavior and group them based on the known regulating hormones of their fasts. Through a compilation of several hormones and their involvement in the complex metabolic systems of different animals, we can gain a greater understanding of how endocrinology works to maintain natural fasting. Based on such evidence, I attempt to draw greater implications from data collected from natural fasting related to human medicine, and specifically human nutrition.

To maintain homeostasis, healthy animals, including humans, generally must consume food on a day-to-day basis. However, some species have adapted to withstand long periods of food deprivation in which they maintain healthy bodies and do not starve. These are known as natural fasting periods, which many animals include into their normal life history events. Whether these animals have adapted to fast due to lack of food availability, seasons, or perhaps reproductive behaviors, these fasts have become part of the animal’s healthy lifestyle. A critical differentiation lies between fasting and starvation, as animals that undergo natural fasting behavior have adapted homeostatic regulatory mechanisms to maintain their critical organ function. Starvation, however, is not an adaptation, but rather when unnatural food deprivation causes homeostatic functions within the body to shut down, causing loss of critical organ function (Castellini, et. al., 1992).

Examples of Animals That Fast

The northern elephant seal (Mirounga angustirostris) remains a model organism for the study of natural fasting behavior in animals, as many have chosen to study its evident fasting that both pups and adults display throughout their lives. Northern elephant seal pups nurse to increase body fat stores for one month, after which they begin their post-weaning fast for two to three months. The mothers fast as well while nursing their pups. These fat stores that the seal pups acquire from nursing serve as their primary energy source during their post weaning fast. Hormones regulate their transition between nursing and fasting, as well as maintenance of the fast, as they do not starve. The northern elephant seals maintain active lifestyles during their fasts and do not fall into a state of torpor, as do hibernating animals (Ortiz, et. al., 2002). Many have chosen to study the northern elephant seal due to its natural fast as part of its life history, and it has therefore become a model organism for natural fasting study.

Some animals, such as bears and squirrels, undergo natural fasting via hibernation, where they remain in a state of torpor, a sluggish state of sleep, for several months, usually in the winter season. Nutrition during hibernation is highly regulated by hormones. In bears, for instance, cubs are born while the mother hibernates, and they finish developing and begin nursing outside the mother. Due to the constraints of substrate availability during fasting, as mothers utilize hormones to maintain homeostasis in their bodies, the milk that fasting mammals produce is low in carbohydrates, water, and protein, and high in fats. Hormones regulate fasting and aid in the loss of much of these animals’ body weights, while providing appropriate metabolic homeostasis within the body (Oftedal, et. al., 1993).

Non-mammals such as penguins also undergo natural fasting, in which hormonal and metabolic changes occur during these birds’ fast, which is associated with breeding season. King penguins have three defined stages of natural fasting. Phase I is a period of adaptation that lasts only a few days. Rates of body mass loss and nitrogen excretion begin to reduce. Fat mobilization increases during phase I, as the penguin prepares to undergo a fast that will last three to four months. During phase II, rates of body mass loss and energy derived from proteins are low. The energy that the fasting penguins use is mostly from lipids. In phase III, the rates begin to increase. Hormones regulate all three phases, with the most notable changes occurring in phase II. Little is known about the hormonal status of phase III (Cherel, et. al., 1988).

Hormones Associated With Natural Fasting

Many different hormones regulate natural fasting, whether the animal is active or torpid during their fast. Glucocorticoids, and specifically cortisol, play a large role in regulating glucose metabolisms during fasting. The thyroid hormones T3 and T4 play several important roles within the body, especially in relation to energy metabolism. Pancreatic hormones, particularly glucagon and insulin, help regulate blood glucose and lipolysis during fasting. The “appetite hormones,” including leptin, ghrelin, and obestatin help regulate food intake in general and during fasting. Each of these hormones or classes of hormones and their noteworthy effects on natural fasting will be discussed at greater length throughout my review.

Through study of the hormonal regulation and maintenance of natural fasting, we can draw upon larger implications within mammalian nutrition and human health. Research on natural fasting in animals can lead to greater knowledge of human metabolism and nutrition, as well as related health conditions that may negatively affect humans’ lives such as diabetes, obesity, and osteoporosis. Through such study, we may find ways in which knowledge of hormones can be used to alleviate the deleterious effects of such conditions.

Glucocorticoids

Glucocorticoids, also known as glucocorticosteriods, are steroid hormones that help regulate glucose metabolism. These steroid hormones bind to the glucocorticoid receptor that exists in almost every cell of the body. Glucocorticoids extend their effects in many different ways throughout the animal and human body such as metabolism involving glucose, proteins, and lipids. A major part of glucose metabolism in which glucocorticoids are involved in is gluconeogenesis, the production of glucose from non-carbohydrate substances in the body. Glucocorticoids play a role in protein metabolism as well as they tend to inhibit protein synthesis and enhance protein catabolism. Depression of fatty acid synthesis is often a consequence of glucocorticoid actions as well. Glucocorticoid affects can be seen in other areas of metabolism as well, involving vitamins, electrolytes, and various ions, although I will not discuss these in my review (David, et. al., 1970).

The Northern Elephant Seal

Northern elephant seal pups begin to increase their body fat stores as they nurse for approximately one month to prepare for their post-weaning fast. These fat stores gained from nursing serve as the seal pups’ primary source of energy as they undertake their natural post-weaning fast. In this time, plasma cortisol levels, a specific glucocorticoid also found in humans, have been shown to rise from the beginning to the end of nursing, and increase even more by the end of fasting. As cortisol increases from the beginning of nursing period until the end of the fasting period, the hormone appears to play a potential role in the regulation of body fat in these seals. Research has also shown a lack of change during the transition between nursing and fasting in cortisol, as well as thyroid hormones and the hormone leptin. This suggests that while physiological changes occur before the beginning of fasting, weaning may not initiate such changes (Ortiz, et. al., 2003). To my knowledge, it is unknown what exactly initiates these physiological changes, however this may be an area for further research in the field.

Cortisol, a hormone that helps perform gluconeogenesis during fasting states, increases in northern elephant seals during the post-weaning natural fast, a trend that is seen in other animals as well. In several hibernating animals, such as the European ground squirrel (Citellus citellus), the hedgehog (Erinaceus europeus), and the little brown bat (Myotis lucifugus lucifugus), glucocorticoids such as cortisol increase during these prolonged times of food deprivation. Similar to the little brown bat, the increase in cortisol in these seal pups may help with energy demands, the maintenance of gluconeogenesis, and mobilization of fatty acids. Fasting pups receive most of their energy through the oxidation of the fat stores that they acquire during nursing (Ortiz, et. al, 2003).

Elevation in glucocorticoids such as cortisol is also associated with lipolytic and proteolytic activity to provide substrates for hepatic gluconeogenesis in force fasting mammals. Such elevated concentrations may also help cue the body to end fasting and start feeding again. This may be caused by a critical lower limit of fat mass reached at the end of the fast due to increased cortisol-induced lipolysis. Studies have shown a relationship between glucocorticoids and stimulation of the hypothalamus to promote feeding behaviors (Ortiz, et. al., 2001). If glucocorticoids via hypothalamus stimulation do in fact have a large effect on feeding behavior, glucocorticoids could have potential in human medicine to help stimulate or inhibit behaviors based on nutrition. Further research involving glucocorticoids’ effects on feeding may aid in treatment for both underweight and overweight individuals.

Increases in cortisol during natural fasting in northern elephant seals may also play a role in the maintenance of acid-base homeostasis. Such homeostasis synthesizes sodium, potassium, and hydrogen ions and ATPases. The synthesis of these products, aided by the hormone cortisol, help rid the body of a condition associated with fasting called metabolic acidosis. Metabolic acidosis occurs either when the body produces excessive acid or the kidneys cannot remove appropriate acid from the body through excretion. Studies have shown a correlation between glucocorticoids and renal ATPase regulation (Ortiz, et. al., 2001). As metabolic acidosis is a condition that affects humans as well, further studies involving fasting and glucocorticoids may play a role in this area of human medicine.

Cortisol maintains a negative correlation with body mass, and body mass has a positive correlation with fat mass. Due to the relationship of cortisol and body mass becoming significant until only after the early nursing period, this relationship between glucocorticoids and body mass may not ensue until the pups have gained enough body fat to maintain their fasts. Therefore, plasma cortisol concentrations and body fat may share a close relationship despite the positive relationship of body mass and fat mass as well (Ortiz, et. al., 2003), which may prove an important relationship in human health and nutrition as we continue to investigate how and why body mass and fat mass are acquired, and how they effect the body.

The King Penguin

The penguin represents another significant animal in the study of natural fasting behavior. The king penguin (Aptenodytes patagonica) has demonstrated three phases of metabolically active natural fasting related to breeding behavior in which hormonal and metabolic changes occur. Phase II involves significant glucocorticoid changes in relation to protein mobilization as an important factor in glucose homeostasis (Cherel, et. al., 1988).

In a study of the king penguin’s three stages of fasting, corticosterone, a dominant glucocorticoid in birds, decreased in phase II of the penguins’ fast and rose in phase III. Low corticosterone levels in phase II may help explain protein sparing, when the body utilizes other sources than protein for energy, during fasting in these penguins. Fasting adrenalectomized animals have been shown to not maintain glycemia, or adequate glucose levels in the blood via gluconeogenesis. Therefore, low corticosterone levels in phase II of fasting may regulate low rates of gluconeogenesis. As the level of corticosterone rises in phase III of the natural fast, corticosterone helps raise the levels of glucose production in penguins via amino acid delivery to the liver (Cherel, et. al., 1988).

The corticosterone to insulin ratio plays an important role in for the changes in protein synthesis and breakdown that occur during natural fasting, which may increase our understanding of fasting’s effects on other substances in the animal and human body besides for fat. In the same study on king penguins, plasma insulin levels did not change between phases II and III unlike corticosterone levels. As corticosterone levels rise from phase II to phase III, the corticosterone to insulin ratio increases threefold. Cherel and colleagues cite similar corticosterone to insulin ratio changes that have been observed in studies involving molting starvation, a process in which commercial hens are forced to molt simultaneously through starvation. In this process, net protein catabolism increases. Due to the similarities between the corticosterone to insulin ratio in both natural fasting in penguins and molting starvation, evidence points to corticosterone increases as responsible for muscle protein turnover changes (Cherel, et. al., 1988).

Glucocorticoid-induced Osteoporosis and Nutrition

The study of glucocorticoids in relation to natural fasting in animals leads to broader study of human medicine and in specific, glucocorticoid-induced osteoporosis. Glucocorticoid-induced osteoporosis (GIO) remains a common form of secondary osteoporosis, which occurs alongside other human conditions such as Cushing’s syndrome, a condition due to too much exposure to the hormone cortisol via drugs or endogenous hypercortisolism conditions. Teleosts, such as the European silver eel (Anguilla anguilla), use cortisol for mobilization of energy and metabolite reserves in fasting and reproductive periods. These eels therefore serve as a vertebrate model for the investigation of the internal skeleton for storage and mobilization of minerals, and consequently as an aid for GIO research (Sbaihi, et. al., 2009). Migratory fish display periods of starvation as they migrate for reproductive purposes, and consequently organic matter and minerals are mobilized within their bodies for use during food deprivation. Eels accumulate these metabolic and mineral reserves in the juvenile phase (also called the yellow stage) of their growth, culminating in their metamorphosis into silver eels. The silver eels end this accumulation of reserves and begin a fasting period as they begin their reproductive migration and therefore mobilization of reserves (Sbaihi, et. al., 2009). Researchers studied the effects of cortisol on bone remodeling using European silver eels from France that had just ended their juvenile phase and had begun their reproductive migration. Results suggested that cortisol treatment played a role in mineral loss, as eels treated chronically with cortisol had a significant decrease in vertebrae mineral content. Such glucocorticoid induction of bone loss may serve as an ancestral regulatory mechanism, as it is seen in both primitive teleosts such as eels, as well as in GIO in humans (Sbaihi, et. al., 2009).

Chronic treatment with cortisol showed a significant demineralization of the vertebral skeleton in eels, which provides insight into bone resorption methods in other animals as well as humans. Similar to the methods performed on the silver eels in this study, previous studies have used such methods in both rats and fish. Cortisol levels in eels as well as other studies animals increase during sexual maturation. This increase may be involved in bone demineralization in relation to maturation, as cortisol levels increase and cause demineralization. As the study demonstrated that GIO occurs in the adult European eel, these organisms provide a comparative model for GIO in humans and specifically the osteocytic mechanisms of bone resorption. Osteocytes have been found to remain extremely active with the capability of resorbing mineral and organic substances. Cortisol’s demineralization effects may provide a general regulatory mechanism not only in teleosts but in mammals as well (Sbaihi, et. al., 2009). From studies of fasting in animals, the discovery of such a regulatory mechanism for a disease such as GIO that affects many humans may aid in better ways to regulate the disease as well as improve treatment and quality of life for those who suffer from it.

Thyroid Hormones

Thyroid hormones, triiodothyronin (T3) and thyroxine (T4) are produced by the thyroid gland and are tyrosine-based hormones. These hormones play many important roles throughout the body, including in development, differentiation, and metabolism. The receptors that mediate T3 and T4 action are nuclear T receptors (TRs) which high affinity to bind T3 and are encoded by two genes TRα and TRβ. The T3 receptors are part of a larger superfamily of receptors that include receptors for retinoids, vitamin D, and fatty acids (Zhang, et. al., 2000). As thyroid hormones are generally associated with the regulation of energy throughout the body, they appear to play a vital role in natural fasting behavior, which may provide further insight into the energetics of human metabolism.

The Northern Elephant Seal

Thyroid hormones play a key role in the natural post-weaning fast of northern elephant seals, and therefore must have significance in regulation of nutrition in other mammals as well, including humans. While glucocorticoids tend to rise during these extended periods of food deprivation, thyroid hormones tend to decrease. As thyroid hormones are generally associated with increases in metabolic rate, the body decreases their use to conserve energy during fasting. A study on northern elephant seal pups, however, showed elevations in tT3 (total T3), tT4 (total T4), and fT4 (free T4) hormones through the fast, a finding that is not uncommon among marine mammals. These observed increases in thyroid hormones might not have been due to their increased synthesis and therefore release, but rather may have been caused by changes in these seals’ deiodination, a process involved in the activation or deactivation of thyroid hormones (Ortiz, et. al., 2001). While it may prove difficult to test T3 and T4 levels in fasting humans, as humans are not adapted to withstand prolonged fasting periods, research may observe hormone levels in humans who have not eaten in several hours, such as when they just wake up in the morning. Such research may provide additional understanding into thyroid hormone effects on human nutrition as well.

While levels of tT3 and tT4 increased during natural fasting, the ratio between the two hormones decreased over the observed time period. Similar results have been seen in food-restricted manatees, suggesting possible reduced deiodination of T4, which could serve to protect target tissues from cellular actions of T3 that involve oxygen-demanding processes (Ortiz, et. al., 2001). Furthermore, increases in thyroid hormones over the post-weaning fast of northern elephant seals could have effects on fat metabolism due to the lipolytic functions of thyroid hormones. Thyroid hormones have a positive effect on lipolysis, or fat breakdown, and therefore may have a relationship with fat metabolism during natural fasting. Thyroid hormones may only exert such effects if the fast does not cause a significant decrease in the number of nuclear receptors that they bind. Similar studies have shown that hibernating squirrels also display increases in thyroid hormones, however, the hormones do not function properly, as the hibernation fast induces a reduction in the number of receptors. Further study is needed to examine such effects, as lipolysis may be important for human nutritional conditions such as obesity (Ortiz, et. al., 2001).

To further study the effects of thyroid hormones on natural fasting in seals, one study examined the effects of Polybrominated diphenyl ethers (PBDEs), chemical compounds that have slowly found their way, via industry and pollution, into both terrestrial and marine environments through the food chain. Researchers suggested that these PBDEs might function as thyroid hormone endocrine disrupters, which could affect both animals and humans. As key components of the endocrine system, thyroid hormones remain necessary for growth and metabolic regulation. Through a study of grey seal pups (Halichoerus grypus) that acquire PBDEs into their systems from their mothers during lactation, the effects of this contaminant were studied during the seal pups’ post-weaning natural fasts (Hall, et. al., 2003). The study found that plasma thyroid hormone levels were significantly related to total PBDEs in the seals’ blubber during the first year of their lives. Seals with higher blubber PBDEs showed higher plasma T3 and T4 concentrations. The seals showed a significant positive correlation between the serum concentrations of T3 and T4, as seen in humans with hyperthyroidism. Further analysis showed that metabolism of thyroid hormones as well as PBDEs have the same pathway. When the pathway for thyroid hormones is disrupted due to the presence of PBDEs, metabolism rate will be inhibited and the T4 secretion rate will exceed its degradation rate, causing raised serum concentrations of thyroid hormones. Therefore, PBDEs most likely exhibit endocrine disruption of thyroid hormones, and could cause damaging effects on mammalian metabolisms, and consequently nutrition (Hall, et. al., 2003).

Hibernating Animals

Unlike seals, many animals exhibit natural fasting in the torpid state of hibernation. The black bear (Ursus americanus) hibernates for four to seven months per year, during which the female implants blastocysts, gives birth, and lactates. Due to metabolic restraints during the mother’s hibernation, the newborn bear cubs are born in a somewhat undeveloped, or altricial state. Studies have shown declines in thyroid hormone concentrations during hibernation, with concentrations increasing post hibernation (Tomasi, et. al., 1997).

Female black bears were kept in a semi-natural environment to study thyroid hormone levels during hibernation. During the month of December, a time of prehibernation food restriction, concentrations of all studied thyroid hormones except T3 decreased, regardless of reproductive state. Bears that did not hibernate retained stable thyroid hormone levels. Thyroid hormones decrease in response to hibernation, as opposed to seasonality, and might facilitate fat deposition and increase in membrane fluidity at lower body temperatures. Furthermore, pregnancy may not contribute to a significant difference in thyroid hormone levels during hibernation (Tomasi, et. al., 1997).

The Richardson’s ground squirrel (Spermophilus richardsoni) also displays natural fasting due to hibernation. Research shows that total thyroxine (T4) concentrations were shown to have lower levels in the torpid hibernating squirrel versus the active nonhibernating squirrel. One explanation for reduced levels in hibernating squirrels is the selective vasoconstriction exhibited in torpid animals, which reduces available space for circulating T4. tT4 levels decreased from nonhibernating to hibernating squirrels, possibly indicating an increase in the serum’s avidity, or eagerness, to bind to T4. Such results indicate a trend in reduction of thyroid hormones during hibernation, potentially leading to further studies into thyroid hormones roles in the body during active and torpid states (Demeneix, et. al., 1978).

The King Penguin

As discussed in previous sections, penguins undergo natural fasting in response to breeding, in which many hormonal and metabolic changes occur such as timed variations of thyroid hormones T3 and T4, as well as other hormones. As thyroid hormones maintain a strong implication in the regulation of metabolic rates in birds and in mammals, fasting has generally induced a decrease in plasma T3 (Cherel, et. al., 1988). However, as with northern elephant seals, animals that fast and still remain active may not exhibit such decreases in thyroid hormone concentrations (Ortiz, et. al., 2001). It may not be surprising, therefore, that penguin plasma T3 levels were shown to peak at the beginning of their fasts, with a sharp decrease in T4 levels. T3 levels then decreased significantly by the end of phase II of the penguins’ fasts, and decreased further in phase III (Cherel, et. al., 1988).

The timed variations of T3 and T4 in fasting penguins may relate to different metabolic needs and/or the fluctuations of other hormones. For example, corticosterone and glucagon increase in phase III, which inhibit conversion of T4 to T3 in birds. As T4 decreases sharply at the beginning of the fast and remains low for the duration of the fast, the basal metabolic rate decreases once the fast begins and stays low for the entire fast. T4 therefore seems the main circulating thyroid hormone that controls basal metabolic rate (Cherel, et. al., 1988). The study of thyroid hormones during the king penguin’s fast provides a unique angle of natural fasting that does not quite align with levels observed in the fasting seal or hibernating bear and squirrel. Due to their non-mammalian status and fluctuating thyroid hormone levels not seen with mammals in my review, we may find more use in studying seals and hibernating mammals to better relate such research to human health.

Further Health Implications

Along with fasting comes further implications on growth, nutrition, and diet. In animals such as fish, hormones clearly play a central role in growth and nutrient regulation. The thyroid gland relates to exocrine activity, or mucous production, which affects the ingestion of nutrients. Carbohydrates or amino acids may assist in regulation of thyroid hormone production (MacKenzie, et. al., 1998). Understanding hormones and their functionality in fish will help further our knowledge of growth and nutrition in animals and potentially humans. In both humans and animals, thyroid hormones have importance in the initial development of the brain and impact many developmental processes within the brain such as cell proliferation, differentiation, myelination, and formation of synapses. Plasticity in the brain has been shown to occur differently according to different seasons, which can be tied to energy balance within animals and humans. It is clear that thyroid hormones play significant roles in fasting, and consequently growth and nutrition (Ebling, et. al., 2008).

Pancreatic Hormones

Pancreatic hormones are hormones produced and secreted by different cells of the pancreas and can be grouped into four families of peptide hormones: insulin, glucagon, somatostatin, and pancreatic polypeptide (Blundell, et. al., 1980). Glucagon is an important pancreatic hormone that helps in regulating glycemia and hepatic glucose synthesis, as well as promotes lipolysis in mammals and remains the primary bird lipolytic hormone. Glucagon plays a key role in fasting, where it causes increased plasma glucose, insulin, fatty acids, ketones, and urea. The exact role and magnitude of the effects of glucagon on long term fasting is not well understood, however, research has attempted to better clarify its effects (Crocker, et. al., 2013).

The Northern Elephant Seal

Fasting northern elephant seals maintain high glucose production and lipolysis rates, while glucose oxidation and protein catabolism rates remain low. To examine the acute effects of glucagon in long-term fasting mammals, researchers performed a glucagon challenge experiment on fasting northern elephant seals. From the glucagon challenge, different gluconeogenic, insulinogenic, lipolytic, ketogenic, and proteolytic effects were found between different study groups, suggesting that lipid and carbohydrate metabolism regulation have different influences depending on nutrient demands. In all fasting seals, low levels of glucagon were maintained, perhaps to help minimize amino acid loss to gluconeogenic pathways. Adiposity has strong impacts on glucose and insulin responses. Glucagon levels are down regulated to help extend fasting due to their negative effect on protein sparing (Crocker, et. al., 2013).

Insulin is produced by pancreatic beta cells and promotes blood glucose absorption through fat storage. Studies have suggested that due to decreases in plasma insulin associated with northern elephant seal fasting, the seals develop an insulin resistance late in their fasts. Factors connected to insulin resistance include impaired hormone secretion, reduction in key signaling protein expression, and reduced protein activity. When insulin levels are diminished in the body, the pancreas continues to secrete more insulin until it is no longer able to secrete enough of the hormone. Conditions similar to insulin resistance have been found in mammals, including humans, who have been chronically food deprived. This type of insulin resistance appears to be detrimental, although fasting northern elephant seals have adapted to such resistance (Viscarra, et. al., 2011).

Glucose clearance is impaired in fasting seals as evidenced by blood glucose levels that are sustained throughout the fast, a response suggestive of insulin resistance. Plasma cortisol increases significantly during fasting and may suppress insulin secretion. Additionally, free fatty acids inhibit insulin-mediated glucose uptake. Due to these factors, insulin sensitivity is decreased. Further research into the fasting seal’s ability to maintain high levels of cortisol and free fatty acids could provide insight and benefit into our understanding of human type two diabetes mellitus, as well as the ability for mammals to adapt to chronic food deprivation and fasting (Viscarra, et. al., 2011).

Hibernating Animals

The hibernating golden-mantled ground squirrel (Citellus lateralis) displays significantly decreased levels of pancreatic hormones during hibernation. During hibernation, the weight of the pancreatic organ of the squirrel decreased to 57% of the weight of the nonhibernating squirrel’s pancreatic organ. All four pancreatic hormones studied, insulin, pancreatic polypeptide, somatostatin, and glucagon decreased as well (Bauman, et. al., 1986). Unlike with thyroid hormones, pancreatic hormones appear to consistently decrease in active and torpid fasting animals.

The King Penguin

Pancreatic hormones also play a role in the three-phase fasting behavior of penguins. In phase II, which can last for three to four months, the rate of body mass as well as the amount of protein-derived energy remains low. A high glucagon-to-insulin ratio is a primary regulatory signal for gluconeogenesis in short term fasting, but does not assist with protein sparing in long term fasting. In fasting penguins, insulin levels do not significantly change, and glucagon levels increase continuously. Pancreatic hormones in birds and mammals control glucose homeostasis. The glucagon-to-insulin ratio increased slightly during phase II, corresponding to low rates of gluconeogenesis. Humans also experience these low rates during prolonged starvation periods (Cherel, et. al., 1988). As mammals and birds show similar hormonal responses to food deprivation, such research on protein sparing and gluconeogenesis may help future studies involving human fasting and starvation. As the world of human medicine becomes increasingly modernized, knowledge of how to combat dietary issues in humans may provide further understanding of nutritional issues such as obesity and starvation.

Leptin

The hormone leptin, identified several years ago as the deficient gene product in obese mice, may play a major role in food intake, as well as affects the neuroendocrine axis and immunological processes. This circulating hormone helps signal for nutritional status, regulates body weight, energy expenditure, growth and reproduction. Leptin is synthesized by adipose tissue and then secreted into the bloodstream, inhibiting hunger when certain levels of fat storage are reached. The leptin receptor is expressed in the arcuate nucleus of the hypothalamus as well as many different tissues in the body and has at least five different splice variants (Barb, 1998).

When leptin was first discovered, most studies involved humans or rats, however studies involving seals have shown leptin’s role in natural fasting behavior, and have led to further studies involving the implications of leptin in human health issues such as obesity and osteoporosis. Leptin is an obvious target for studies involving the endocrinology of natural fasting due to its function in regulation of food intake and energy expenditure. As the product of the Obese (ob) gene and synthesized primarily by white adipose tissue, leptin is secreted at levels proportional to body energy stores (Arnould, et. al., 2001).

Seals, as well of most of their superfamily Pinnipedia, have extremely high body lipid reserves compared to most animals. Due to their hyperphagia and natural fasting behaviors linked to reproduction, these animals are an ideal model for studying mechanisms involved in hunger and energy expenditure, and therefore the hormone leptin, which may have further implications into human nutritional health.

In a 2001 study (Arnould, et. al., 2001), plasma leptin levels of eight lactating females and twenty pup Antarctic fur seals (Arctocephalus gazelle) were studied for better insight into leptin’s role in these seals’ natural fasting behavior. In the adult female seals, plasma levels at the beginning of the fast were found to be lower than at 24 hours into the fast, but then decreased after 72 hours into the fast. Once the seals began to feed, leptin levels continued to decrease. Leptin levels increasing in the first 24 hours of the fast were unexpected results, and could have been due to different causes. For the pup seals, leptin levels were higher at the beginning of the fast than the end, as decrease in leptin was positively correlated with body mass loss (Arnould, et. al., 2001).

While leptin serves as an indicator of body energy reserves, the discussed study found that plasma leptin levels might not be solely determined by body energy reserves in fur seals and other carnivores. In fur seal pups, mass loss due to fasting was positively associated with a decrease in plasma leptin levels, however the adult females’ leptin levels increased during the first 24 hours of their fasts. To explain such a phenomenon, it is possible that the lower leptin levels at the beginning of the fast were due to a post-exercise effect after the females swam back to their colonies. This post-exercise effect may have diminished in the first 24 hours of the fast. Another explanation for this unlikely rise in leptin could be related to the female pattern of milk production. In humans, prolactin has been shown to influence leptin secretion during lactation. The increase in leptin during the first 24 hours of the fast could be due to a surge in prolactin secretion during the sizeable change in suckling stimulus as the pups begin to suckle. (Arnould, et. al., 2001).

As a natural component of many animals’ life histories, natural fasting behavior can be associated with decreasing body fat, as well as a decrease in circulating leptin levels. However, further studies support that leptin concentrations and body mass may be independent of one another. Research done on northern elephant seals suggest that leptin may not have a role in regulating fat mass in these fasting seals (Ortiz, et. al., 2001). Leptin levels did not reduce between the early and late stages of the fast, possibly due to concentrations having been maximally reduced before the fast even began. Studies done on humans and rodents have shown maximally reduced leptin levels within 24 hours post-fasting independent of body fat content. From such results, it is possible the hormone cortisol plays a larger role than leptin in regulation of body mass and fat mass, as suggested by negative correlations between cortisol and body mass and fat mass (Ortiz, et. al., 2001).

Despite its contested effects on body energy reserves, leptin has been shown to have further implications outside of fasting, such as on the oestrous cycle in mammals. Leptin’s effects are further reaching than just nutrition, as the hormone plays a role in reproduction as well. This is not surprising, as reproductive processes cannot operate successfully without proper nutrition. Without adequate energy, different stages of the oesterous cycle can become functionally inhibited. In relation to reproduction, leptin has been shown to stimulate gonadal function and increase uterine weight, as well as accelerate the onset of puberty in mice. Leptin receptors have also been found in the ovaries and testes (Al-Azraqi, 2007).

A study exploring fasting and its effects on the oestrous cycle and leptin concentration used Ardi goats in two groups: fed and fasted. The results showed that fasting was positively correlated with decreased concentration of plasma leptin, and two sex hormones testosterone and progesterone. Oestrous behavior in the fasting goats was inhibited. Leptin may play a role in the fast-induced inhibition of the goat oestrous cycle, as leptin that is produced inside the ovaries may have an effect on follicular development and luteinization. Further research, perhaps done in the field using the goats’ natural habitat, is needed to further investigate leptin’s role in the oestrous cycle (Al-Azraqi, 2007).

Leptin has further implications on human health related to obesity. Leptin concentrations increase with increases in body fat, unlike in the obese ob/ob mouse, which contains a nonsense mutation that impairs leptin production, which leads to increased food intake and consequently diabetes. Greater production of leptin is caused by increased amounts of adipose tissue mass in obese humans, and amplified adipocyte expression of the ob gene mRNA. The satiety centers for obese humans become insensitive to leptin production, and elevated levels of leptin fail to control hunger and control body weight. The possible interaction of insulin with leptin may play a role in hyperinsulinemia, a condition with excess insulin levels in the blood and a symptom of Type II diabetes, an ailment seen often in obese individuals (Widjaja, et. al., 1997).

In relation to obesity, leptin has also been shown to help regulate bone formation in the sympathetic nervous system. Bone remodeling is maintained via osteoclasts that function in bone resorption and via osteoblasts that function in bone formation. An extremely common bone remodeling disease is osteoporosis, which affects many individuals and is therefore an important area of study in human health. Through the observation that osteoporosis has a low incidence rate in obese humans, leptin was discovered to highly inhibit bone formation. It appears that leptin signaling, as opposed to body weight, controls bone mass, and since obese individuals have shown resistance to leptin central action, and therefore have low osteoporosis incidence rates (Takeda, et. al., 2002).

Leptin, along with hormones such as cortisol, estrogen, thyroid hormone, and insulin have been suggested as a group of “master hormones,” pertaining to their involvement various homeostatic functions. Leptin has many functions including body weight regulation, reproduction, and in this case bone formation. Bone formation appears to be one of leptin’s primary roles in the body, as high bone mass exists even with an increase in bone resorption when leptin signaling is not present. As a master hormone, leptin may utilize different activities to perform different functions throughout the body (Takeda, et. al., 2002).

Ghrelin

Ghrelin, a hormone associated with appetite, is synthesized in the gastrointestinal tract via cells called ghrelin cells and is an endogenous ligand for the growth hormone (GH) secretagogue receptor, a G protein-coupled receptor that binds ghrelin. Studies have shown a relationship between ghrelin and the promotion of increased food intake, weight gain, and adiposity in rodents, as it may provide signaling to the brain to stimulate food intake and adiposity. Ghrelin has also been shown to stimulate food in intake in humans, and could be an important regulator for food intake and body weight (Wren, et. al., 2001).

This gastric-derived protein ghrelin, also known as the “hunger hormone” has been shown to stimulate the secretion of GH, stimulate feeding, as well as have a part in carbohydrate metabolism. Food deprivation has effects on several hormone levels, including ghrelin, and has been well studied in animals that do not display natural fasting behavior, such as rodents and humans. The northern elephant seal, an animal that does display natural fasting behaviors, provides a model to study ghrelin effects in such animals that use fasting as a natural part of their life histories (Ortiz, et. al., 2003).

As a ligand for GH, ghrelin stimulates the release of GH from the pituitary gland. In one study, ghrelin and GH increased with fasting in northern elephant seals, consistent with previous studies done using food-deprived rats (Ortiz, et. al., 2003). Ghrelin may play a role in carbohydrate metabolism in mammals in general, as it induces hyperglycemia, or high blood sugar, in humans by reducing insulin secretion. Normal effects of food deprivation are hypoglycemia as well as insulin secretion. Fasting induces a decrease in glucose, which is counteracted by an increase in glucagon release. Elephant seal pups maintain high blood sugar during their post weaning fasts even though glucose decreases towards the end of their fasts. It is suggested that elevated blood glucose in these seals may be used for other physiological processes such as diving (Ortiz, et. al., 2003).

Studies on humans have shown that ghrelin levels are lower in obese individuals, which provides interesting insight into mammals such as seals. Northern elephant seals consist of approximately 46 percent body fat, however, although ghrelin levels increased during fasting, they still remained lower than obese humans. Such evidence supports the idea that ghrelin in down regulated in obese humans. Since ghrelin stimulates food intake, ghrelin increases through the pups’ fasts may provide hormonal signals that tell the pups to end their fast and begin to feed (Ortiz, et. al., 2003).

Hormones related to fasting, such as ghrelin and obestatin, a hormone that will be further discussed in the next section, may have implications in human obesity. Studies concluded that preprandial ghrelin levels, or levels taken before a meal, were lower in obese versus normal weight individuals, but the ratio of ghrelin to obestatin was higher in obese versus normal weight individuals. These ghrelin to obestatin ratios were positively correlated with BMI. Such results suggest that a high preprandial ghrelin to obestatin ratio may perhaps be involved in the causes and disordered physiological processes associated with obesity (Guo, et. al., 2007).

Obestatin

Obestatin, a hormone generated in the stomach and other body tissues and derived from the same gene as ghrelin, appears to have implications in natural fasting as it may help reduce animal food intake. While obestatin studies have not been performed on wild animals that display natural fasting behaviors, its relationship to ghrelin sheds light unto its potential implications in human appetite and fasting. As discussed in the previous section, the hormone ghrelin stimulates animal and human meal initiation. Obestatin comes from the same gene, but has been shown in some studies to slow gastrointestinal motility, inhibit thirst, induce sleep, and improve memory. Many have thought that obestatin and ghrelin pose opposite effects on animal food intake; however, greater research was needed (Beasley, et. al., 2009).

As obestatin is a more recently discovered hormone, the field needs more research to answer even basic questions concerning its function and various relationships. More recent research has shown that although obestatin is related to ghrelin, it is not an endogenous ghrelin antagonist. Obestatin cannot cross the blood-brain barrier by a saturable transport system like ghrelin. The receptors for obestatin are not yet known, and it is therefore difficult to study obestatin’s exact effect on feeding. As a recently discovered hormone, many questions regarding obestatin remain unanswered, such as whether its effects are direct or indirect, and whether they are endocrine, paracrine, or autocrine. The effects of obestatin on feeding therefore remain controversial (Seim, et. al., 2011).

To better understand the relationship between fasting and its associated appetite hormones in humans, one research group investigated the relationship of obestatin with other fasting appetite hormones ghrelin and leptin (Beasley, et. al., 2009). Blood samples were taken after an overnight fast, which resulted in obese individuals with lower obestatin plasma concentrations than normal weight individuals. Contrary to the original hypothesis, obestatin and ghrelin were highly correlated, which did not support the proposal that obestatin and ghrelin have opposing effects, due to their positive correlation (Beasley, et. al., 2009).

Beasley, et. al. suggests that obestatin and ghrelin share similar associations with human energy balance. Obestatin levels appear to be lower as adiposity increases, as seen with lower concentrations in obese versus normal weight individuals. Similar trends have been shown with ghrelin levels. The hormone leptin is released from adipose tissues themselves, and therefore was shown to have a positive correlation with BMI, and concentrations were higher in obese individuals (Beasley, et. al., 2009).

While studies involving obestatin and its relationship to food intake and consequently body weight remain debated, it is clear that some relationship does exist. Further studies are needed in order to investigate the inner workings of obestatin and its related hormone ghrelin in association with human weight (Guo, et. al., 2007). Such further studies could include research on animals such as the northern elephant seal that display natural fasting behavior, and the effects of obestatin on these seals’ fasts. Through such research, one may not only derive more information on the maintenance and regulation of natural fasting, but also further the research of the hormone obestatin’s implications on human weight.

Conclusion

Hormones play a major role in the maintenance and regulation of natural fasting behavior. I reviewed the role of glucocorticoids, thyroid hormones, and pancreatic hormones, leptin, ghrelin, and obestatin, in natural fasting behavior. While many studies focus on specific animals and hormones that guide these fasts, I used a comparative approach to highlight similarities and differences in endocrine regulation between species and situations. The same hormone may act differently under an active natural fast versus a fast associated with hibernation, as seen with thyroid hormones. Research reveals that thyroid hormones increased in the post-weaning fasts of northern elephant seal pups (Ortiz, et. al., 2001), while the same hormone levels decreased in animals during hibernation (Tomasi, et. al., 1997). Such discrepancies within the hormonal effects of natural fasting implore further research on how the bodies of animals, including humans react to different states of energy metabolism. Hormones such as glucocorticoids and pancreatic hormones showed similar trends from active to torpid states of fasting. Further studies should examine why such vast differences in energy metabolism still produce similar tendencies for some hormones but not others.

Research on the effects of appetite hormones leptin, ghrelin, and obestatin show the need for further analysis of these hormones’ effects on mammals, including human nutrition and consequently weight gain and loss. Leptin is closely associated with the Obese (ob) gene, and may help inhibit hunger when sufficient fat stores are reached in the body (Beasley, et. al., 2009). I found surprising and somewhat conflicting results pertaining to leptin’s role in natural fasting behavior. Additional research of the hormone leptin appears to be of utmost importance in our present times. As the United States and other countries around the world struggle with the rising problem of obesity, a greater understanding of leptin, as well as recently discovered related hormones, ghrelin and obestatin, may help attenuate this difficulty in human health.

Furthermore, studies on mineral storage in relation to hormones such as glucocorticoids may advance research into potential treatments for conditions such as glucocorticoid-induced osteoporosis. It is clear that nutrition plays a vital role in bone resorption and remodeling. Research that relates appetite hormones with hormones generally associated with energy can provide a bigger picture of nutrition’s role in GIO and other related conditions.

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