1Pearland High School, Pearland, Texas, USA.
*Corresponding Author: nathantb225@abbas07moosajee
By Nathan Bui
Published 12:16 EST, Tues October 5th, 2021
The focus of this paper is to examine the mechanisms within humans that allow for both appetite and body weight regulation. The efficiency of humans’ body weight regulation is largely dependent on fluctuations in appetite. Thus, understanding the mechanics of appetite regulation itself may help to optimize body weight regulation. Appetite regulation is a complex biological process that involves the endocrine, digestive, and nervous systems. The sensations of hunger and satiety exist only because of a cohesive system between neurological and physical function. Through analysis of previous medical research, experiments, and data, this paper will outline the function of both a specific hormone as well as a portion of the brain associated with the control of appetite and body weight regulation. This paper will also discuss their applications and future in the field of medicine. Only careful consideration of past and present research, as well as their limitations, will facilitate the development of solutions that optimize both appetite and body weight regulation.
The past few decades have been characterized by drastic increases in the onset of obesity, especially in children. The leptin resistance World Health Organization declared obesity a worldwide epidemic. The negative implications of obesity are many, including diabetes, heart disease, and increased mortality rate. In fact, at least 2.8 million people die each year as a result of being overweight or exhibiting obesity (World Health Organization, 2020). Treating obesity is often difficult and expensive: The United States alone spends approximately $70 billion per year for obesity and obesity-associated complications treatment (Huang and Li, 2000). It becomes clear, then, that effective methods of weight reduction are critical in preventing the onset of obesity.
The hormone leptin is a singular component of an intricate system known as the leptin cycle (Figure 1). Understanding this system is crucial for future developments in obesity treatments. Generally, the leptin cycle can be broken down into two primary steps: adipocyte release and hypothalamic regulation of leptin (Friedman, 2009). While adipocyte release is considered relatively straightforward, the hypothalamic regulation of leptin further comprises many sub-steps including the JAK-STAT pathway, STAT dimerization and translocation, transcription of target genes by STAT, and regulation/distribution of the several hormones.
Figure 1: The image above represents leptin and the regulation of body fat. Leptin is released from adipose (fat) tissue and travels through the bloodstream. Next, leptin binds to receptors located on hypothalamic cells in the brain. The result is a sensation of satiety – the feeling of fullness – and a subsequent decrease in appetite and food intake. As a result, relative body weight can be sustained (Turner, 2020).
This section will explore the background information necessary to first understand the leptin cycle, then explain each component of the leptin cycle, as well as their relationships to each other.
2.1 The Discovery of Leptin and Early Research
In 1949, at the Jackson Laboratories in Maine, scientists inbreeding mice encountered one particularly obese mouse. After performing several genetic crosses, geneticist George Snell and his team discovered that this particular mouse was obese due to an alteration in its DNA sequence, a defection, that caused the mutation of a single gene. Interestingly enough, the mice of interest weighed nearly three times the number of normal mice and also demonstrated an affinity for overeating. Although Snell was unable to identify this gene, his work was foundational to the study of obesity, as it suggested the idea that a defect in just a single gene may have caused a remarkable change in eating behavior. His mice model is now known as ob/ob mice, indicating that it has a recessive trait due to a defective gene responsible for satiety and appetite suppression (Friedman, 2012).
Almost 50 years later, another molecular geneticist by the name of Jeffrey Friedman was experimenting with the same kind of mice that Snell had researched. Friedman successfully identified leptin in 1994. Friedman found several correlations between leptin and obesity that led him to believe that leptin was somehow related to body weight and feeding behavior. The most important aspect of Friedman’s experiments, however, was his ability to clone the leptin gene that reversed metabolic abnormalities and obesity in mice (Koch, et al., 2010). Obese mice that experienced partial leptin resistance were injected with the cloned leptin, resulting in a decreased food intake and significant weight loss (Figure 2).
Friedman’s experiments on leptin in mice reveal the potential of cloning leptin genes implicated with human weight loss. The cloning of leptin served as a particularly significant benchmark for neuroscience developments and obesity research because it provided insight into the relationship between neuronal circuits and obesity in humans. The predominant theory during this time stigmatized that obesity was caused because of a lack of self-discipline and self-control; the reality is that obesity may also be caused by dysregulated neurochemical circuits (Münzberg and Morrison, 2015). Friedman’s findings were confirmed by a series of experiments conducted by a group of researchers from the Pennington Biomedical Research Center and the Department of Veterinary Physiology and Louisiana State University in 1998. In their experiments, the group infused both lean and genetically obese ob/ob mice with increasing doses of recombinant – genetically modified – human leptin. Over the course of 7 days, the researchers sought to determine genotypic differences among the mice in response to the recombinant leptin and to determine which responses to leptin were observed at low concentrations of protein hormone and which required large amounts of protein. Interestingly enough, the scientists found that all doses of leptin greater than 1 μg/day caused significant reductions in the food intake and body weight of the ob/ob mice. Low doses of leptin (between 2 and 5 μg/day) caused an initial drop in food intake that was partially reversed by the end of the experiment and resulted in stabilization at reduced body weight. On the other hand, the two highest doses of leptin caused a stable reduction in food intake and continuous weight loss in obese mice (Figure 3). The group’s findings confirmed that, up to a certain amount, increased leptin is inversely correlated with food intake and body weight (Hao, et al., 2005).
Because leptin functions to regulate body weight and reduce blood glucose and insulin levels, its applications, coupled with the capabilities of the nervous system, could serve to not only address the onset of obesity in the United States but also worldwide.
Figure 2: The image above demonstrates the mice used in the ob/ob mice experiment. On the left is a mouse that exhibits low leptin levels, resulting in obesity and an overall decreased metabolism. On the right is a mouse that has been given leptin supplements and injections, resulting in weight loss and increased activity and metabolism. Both mice were initially identical in mass. Changes in mass can be attributed to differing leptin levels in the mice (Koch, et al., 2010).
Figure 3: The graphs above represent the daily food intakes of lean and obese mice studied by the research teams at Pennington Biomedical Research Center and the Department of Veterinary Physiology and Louisiana State University in 1998. Data are the mean ± SEM (Standard Error of Mean) for groups of six mice. The Standard Error of Mean equation gives the statistical accuracy with which a sample distribution represents a population by using standard deviation. Overlap between data bars represents no statistically significant difference in data values. A pump delivering 0, 1, 2, 5, 10, or 42 μg/day of human recombinant leptin was placed in the peritoneal cavities of the mice on the day indicated by the arrow (Hao, et al., 2005).
2.2 What is Leptin?
Leptin is one of many hormones secreted by fat cells in organisms. It is responsible for regulating sugar and fat levels, inhibiting fat synthesis, and stimulating metabolism. Located on chromosome 7 in humans and composed of 167 amino acids (Figure 4), leptin is produced primarily by adipose tissue, but can also be secreted by skeletal muscle and soft bone tissue (Münzberg and Morrison, 2015). While the number of adipocytes in the human body tends to remain stagnant, the size of these adipocytes varies depending on the amount of food consumed by any given human. Thus, as adipocytes grow in size, they release more leptin. The systematic release of leptin that travels through the bloodstream and binds to leptin receptors (Ob-R) in the hypothalamus plays a crucial role in the complete stimulation of metabolism and decrease of appetite.
Figure 4: Crystallographic structure and amino acid sequence of the human obesity hormone, leptin (Senhal, et al., 2021).
2.3 The Leptin Receptor
To activate the JAK-STAT pathway in hypothalamic cells, leptin must first bind to leptin receptors located on the membranes of hypothalamic neurons. Leptin has been shown to enter these hypothalamic neurons in a saturable manner with the help of specific proteins, namely the leptin receptor (Yu, et al., 1997). The leptin receptor, ObR, is a single membrane-spanning receptor that belongs to the Class I cytokine receptor family (Wauman, et al., 2017). The ObR receptor contains three conserved tyrosine residues (Y985, Y1077, Y1138) required for leptin signaling. The leptin receptor is highly expressed in specific nuclei of the hypothalamus, which will be discussed later. In 2000, an experiment published in the Endocrinology Journal examined the significant role that the ObR receptor plays in the leptin cycle. To study the transport capabilities of the receptor isoform, researchers utilized Madin-Darby Canine Kidney (MDCK) cells, a common mammalian cell line used in biomedical research for their unique cell properties, which helped form functionally distinct plasma membrane domains and tight junctions. Because of their inherent properties, MDCK cells have been widely used in the medical field as a model system for receptor-mediated transcellular transport of ligands, such as leptin. The researchers also utilized thiol-reactive fluorescent probe molecules (CPM) to observe transcellular transport. To determine whether ObR was capable of mediating transcellular leptin transport, the team utilized MDCK cells that specifically expressed ObR. They found that transport of CPM following the addition of 125I-leptin to the MDCK cells occurred primarily in the apical to basolateral (outer membrane-facing to cytosol-facing) direction and that this transport was reduced by the addition of excess leptin. When leptin was present, the most CPM transported across the cell membrane was ~3.5%. When leptin was not present, the most CPM transported across the cell membrane was ~1.2%. In contrast, almost no radioactivity was detected in the apical segment following the addition of 125I-leptin to the basolateral area, and these levels were not affected by the addition of excess leptin, suggesting that these low rates likely were due to passive diffusion (Figure 5). The study suggested that the leptin receptor is capable of mediating the transcellular transport of intact leptin and that this transport is unidirectional, as leptin movement occurred almost exclusively from the apical chamber to the basolateral chamber (Harris, et al., 1998). More specifically, the results provide a framework for understanding exactly how obesity may ensue in humans. When there is an abundance of leptin produced by adipocytic cells, the hypothalamus develops a resistance to leptin and can no longer read excess concentrations of leptin. When there is excess leptin, both percent of transport and effectiveness of leptin decrease. Thus, even as the body continues to produce leptin – in an attempt to stimulate metabolism and decrease body weight – the hypothalamus no longer effectively suppresses food intake. The expression of the ObR receptor at functional levels can further be detected in several other cell types, in correspondence with the pleiotropic effects of leptin. Their expression pattern suggests that the leptin receptor – ObR – is responsible for transporting leptin over the blood-brain barrier during the process of appetite regulation. Not only this, but leptin transport provides a basis of understanding for a variety of other cellular processes. Cells have certain functional ranges – pH, temperature, substrate concentration – that affect the function or effectiveness of the cell. In the case of hypothalamic cells, an increase of cytokine may subsequently decrease the function of the cell.
Figure 5: This graph demonstrates the ObRa capacity to mediate transcellular transport of leptin in MDCK cells. Transcellular transport of cpm following the addition of 125I-leptin in the absence or presence of excess, unlabeled leptin (100 nM) either from the apical to basolateral (A to B) direction or from the B to A direction was assessed for MDCK cells stably expressing ObRa. The upward trend lines from the A to B direction signify that leptin is more efficiently transported from the apical to basolateral direction with the help of the leptin receptor, while leptin from the B to A direction is lower due to passive diffusion. Values represent the mean ± SD (Harris, et al., 1998).
2.4 The Hypothalamus and Its Relationship to Leptin
Making up less than 1% of the brain’s mass, the hypothalamus is a cluster of nuclei responsible for several critical functions including motivated behavior, temperature regulation, hormone release, and appetite regulation. The hypothalamus is composed of three main regions, each containing neurons that perform specific functions. The first region of the hypothalamus is the anterior region, responsible for maintaining circadian rhythms, stress-induced behavior, and regulation of several important reproductive hormones. The mammillary region of the hypothalamus is responsible for temperature regulation and memory function. Perhaps the most important region of the brain, however, is the tuberal region. The tuberal region comprises the ventromedial and arcuate nuclei. While the ventromedial nucleus is responsible for somatic growth and development, the arcuate nucleus is responsible for appetite regulation (Seladi-Schulman, 2018). Leptin interacts with and subsequently regulates arcuate hypothalamic neurons by binding to the leptin receptor, located on the membranes of hypothalamic cells. The effects of this binding and how this binding induces the JAK-STAT pathway will be discussed later in the article. For now, it is important to note that the hypothalamus is responsible for interacting with leptin to maintain body homeostasis and regulate body weight.
2.5 The JAK-STAT Pathway
Leptin is distributed and expressed through a process known as signaling pathways. While there are many complex pathway systems, leptin is distributed and expressed through the JAK-STAT pathway. Mechanistically, the JAK/STAT neurochemical signaling pathway is simple when compared to other signaling pathways. It consists of only a few significant components, namely proteins. Interestingly, this pathway is functionally dependent on the leptin hormone. After leptin is secreted by adipocytes, it is released into the bloodstream. Leptin in the blood eventually reaches the plasma membrane of nerve cells in the arcuate nucleus of the hypothalamus. There, leptin binds to substrate-specific leptin obesity cytokine receptors (Ob-R), the first step in the JAK-STAT pathway.
Because these receptors lack autophosphorylation capabilities and demonstrate no intrinsic kinase activity, each Ob-R cytokine receptor typically requires two receptor subunits, each associated with a Janus Kinase (JAK) monomer, that allow the receptor to initiate the signaling cascade (Mullen and Gonzalez-Perez, 2016). Upon receptor ligation by a specific ligand, which, in this case is leptin, these JAK proteins are trans phosphorylated and activated. Subsequently, activated JAK proteins phosphorylate tyrosines on the tail of the OB receptor. Phosphorylation of tyrosines results in the generation of downstream docking sites and recruitment of downstream effector proteins, one of which is the Signal Transducer and Activation of Transcription (STAT) protein, specifically STAT3 and STAT5 proteins. STAT proteins contain an SH2 domain that allows them to bind to substrate-specific sites of receptor tyrosine phosphorylation. When STAT proteins reach the downstream docking sites generated by tyrosine phosphorylation, they are brought into the proximity of the JAK proteins that initially phosphorylated the tyrosines. This proximity allows JAK proteins to phosphorylate the STAT proteins (Figure 6), beginning the process of STAT translocation to the cell nucleus (Babon, et al., 2014).
Figure 6: Summary of JAK-STAT signaling pathway. Ligation of the OB receptor activates associated JAK proteins. Active JAK proteins phosphorylate tyrosines within the receptor enabling phosphorylation and recruitment of downstream STATs (Babon, et al., 2014).
2.6 STAT3, STAT5, and Regulation of Food Intake
Leptin leads to the phosphorylation of STAT3 in areas involved in appetite regulation – namely the hypothalamus. The role of STAT3 in regulating food intake has been demonstrated in a variety of transgenic mouse lines. To investigate the contribution of STAT3 in energy balance, researchers have utilized tissue-specific conditional gene targeting approaches. A study published in the Proceedings of the National Academy of Sciences in 2003 used gene targeting to examine the role of STAT3 in the leptin cycle and appetite regulation in mice. More specifically, the study utilized two transgenic mouse lines to investigate the role of STAT3 in leptin signaling. The first significant mouse line used in the study was the s/s mouse, in which the phosphorylation site required for typical leptin signaling was absent. As a result of the absence of the phosphorylation site and subsequently disrupted leptin-signaling, the s/s mouse exhibited hyperphagic qualities and obesity. Another mouse line generated to investigate the role of STAT3 was one in which STAT3 were deleted from leptin receptors containing neurons. The deletion of STAT3 in this mouse line yielded similar results to those in the s/s mouse line: obese and hyperphagic mice. In both mouse lines, other functions of leptin such as reproduction and growth were not statistically affected, indicating that the key role of STAT3 in the function of leptin signaling in the JAK-STAT pathway is the regulation of food intake (Ladyman and Grattan, 2013). To investigate the contribution of STAT5 in energy balance, the researchers also utilized a transgenic mouse line with the deletion of STAT5 in the CNS. Similar to the s/s mice and mice with the deletion of STAT3, these mice also developed severe obesity and were hyperphagic. The cumulative results of the study suggest that STAT5 signaling in the hypothalamus is required for the normal regulation of energy balance in the body.
2.7 STAT Dimerization and Translocation
The primary function of STAT molecules – specifically STAT3 and STAT5 – upon phosphorylation is to dimerize and translocate to the hypothalamus cell nucleus where they bind to specific regulatory sequences to either activate or repress transcription of specific target genes. The transcriptional targets involved in appetite regulation of STAT include suppressor of cytokine signaling 3 (SOCS3), POMC, and thyrotropin-releasing hormone (TRH) (Ladyman and Grattan, 2013). What is important to note, however, is that following phosphorylation, STAT proteins are able to form dimers through the molecular association of their SH2 domains with carboxyl sites of tyrosine phosphorylation. To understand the process of STAT dimerization, it is important to understand the mechanics of dimerization as a whole. By definition, a dimerization is an addition reaction in which two molecules of the same compound react with each other to give the adduct (Gunawardena, 2020). The process of protein dimerization is indispensable in regards to governing cell function and acting as a regulatory mechanism. Dimerization allows for unique functions that monomers alone do not have, and serves as a crucial checkpoint in signal transduction. In this case, a single STAT protein is unable to translocate to the nucleus for transcription unless it forms a dimer with another STAT protein. As mentioned earlier, STAT proteins are conserved and phosphorylated at tyrosine residues by Janus Kinase proteins (JAKs) upon receptor binding of cytokines such as leptin, or other growth factors such as epidermal growth factor (EGF). Each STAT protein has a unique SRC homology 2 (SH2) domain that specifically recognizes phosphorylated tyrosine residues, leading to homodimerization or heterodimerization followed by STAT translocation into the nucleus. Translocated STAT dimers induce the transcription of target genes (Okada, et al., 2018). The process of STAT phosphorylation and dimerization reconfigures the subunits within the STAT dimer and subsequently causes the dimer to translocate into the nucleus for transcription (Figure 7). A STAT dimer exposes a nuclear localization signal once it nears the nucleus, associating itself with importin α proteins. Through a series of importin-mediated responses with the nuclear pore, the STAT dimer can migrate into the nucleus (Figure 8).
Figure 7: Summary of STAT dimerization and translocation. A STAT protein requires another STAT protein to form a dimer. Through the process of dimerization, a STAT pair can disassociate itself from the receptor and translocate to the nucleus (Okada, et al., 2018).
Figure 8: Summary of STAT dimer migration into the nucleus. Phosphorylated STAT dimers expose a dimer-specific localization signal and associate themselves with an importin α protein. Through importin β-mediated exchanges with the interior of the nuclear pore (NPC), the STAT dimer successfully migrates into the nucleus (Ihle, 1996).
2.8 Transcription of Target Genes by STAT3 and STAT5
Once the STAT dimer enters the nucleus, it begins the process of transcription. The STAT dimer binds to the promoter of the gene containing the recognition motif and subsequently activates transcription of those genes. The attachment of RNA polymerase to the STAT protein produces mRNA that contains the genes for changes in satiety, or the feeling of fullness. Further, the product mRNA travels out of the nucleus and into the cytoplasm of the cell, a process known as translation. In the nucleus, the mRNA binds to ribosomes, which reads the genetic code of the mRNA to produce a chain of amino acids (Meyer and Vinkemeier, 2004). This chain of amino acids forms a protein, specifically anorectic and orexigenic peptide hormones that are responsible for the feeling of fullness in an organism More specifically, binding of leptin receptor to leptin first activates JAK-STAT signaling in the intracellular domain of the hypothalamic cells and corresponding regulating neuropeptide expression. The decrease in leptin levels during periods of fasting induces hyperphagia and subsequently decreases energy expenditure by increasing the expression of neuropeptide Y (NPY) and agouti-related peptides (AGRP), both of which are potent orexigenic peptides found medially. The decrease in leptin levels also corresponds with decreased levels of the α-melanocyte-stimulating hormone (α-MSH) and cocaine and amphetamine-regulated transcript hormones (CART), located laterally. Reduced leptin levels during periods of low-caloric intake also stimulate MCH and several orexins in the lateral hypothalamic area. On the other hand, rising levels of leptin in the satiated state inhibit food intake by suppressing NPY/AGRP and increasing anorexigenic peptides (Figure 8). Leptin deficiency bears a conceptual similarity to fasting. Similar to fasting, deficiency of leptin signaling in obese and non-obese mice causes hyperphagia and impaired thermogenesis, associated with increased expression of NPY, AGRP, and MCH, and reduced expression of POMC (Yadav, et al., 2009). Ultimately, the increased expression of NPY, AGRP, MCH, and reduced expression of POMC and serotonin culminates in sensations of satiety, stimulation of metabolism, and ultimately weight loss.
Figure 9: The diagram above demonstrates hypothalamic leptin signal transduction. Leptin initially inhibits NPY/AGRP and stimulates POMC/CART. These changes in neuropeptide expression culminate in sensations of satiety, stimulation of metabolism, and ultimately weight loss (Ladyman and Grattan, 2013).
3. Future Study
Ultimately, changes in body weight, feeding behavior, appetite, and metabolism can be attributed to two factors: leptin and the hypothalamus. This information is particularly useful in addressing the issues that cause obesity in humans. We now know that the development of leptin resistance in humans contributes largely to the increasing rate of obesity worldwide.
One solution to this trend lies in leptin replacement therapy. This process would require patients exhibiting lipodystrophy, a disorder in which the body is unable to produce and maintain healthy fat tissue, to be injected with excess leptin. However, the implications of this solution are limited, as it only addresses patients exhibiting lipodystrophy, not obesity in general.
Perhaps researchers could utilize the results of Friedman’s experiments on the ob/ob mice and leptin replacement therapy by injecting patients exhibiting obesity with recombinant leptin. This would require the molecular reconstruction of the leptin hormone, given the fact that a human brain that has been diagnosed with leptin resistance can no longer decode excess amounts of the normal leptin hormone. The recombinant leptin hormone would be injected into humans to subsequently decrease re-catalyze the leptin cycle. Since recombinant proteins are proteins generated or cloned in a system that can decode the DNA of another organism, scientists can use protein recombination to make proteins en masse via bacteria. um. For example, scientists could take the gene that encodes for human hemoglobin and inject it into a bacterium, such as E. coli, and the bacteria will subsequently “read” the human gene and produce human hemoglobin. Typically, scientists and drug developers produce certain medicines and drugs through a system that requires a fume hood. However, this method can be costly and time-consuming. With protein recombination, though, drug developers and pharmaceutical companies could rely on the bacterium to perform the necessary chemical transformations, a method that is not only cheaper but also more efficient. Protein recombination and its potential in the field of medicine are, in some ways, made possible through leptin research and development over the past 50 years. Regardless, understanding the role of leptin and how it functions with the hypothalamus lies at the center of addressing the onset of obesity worldwide.
This paper attempted to provide a framework for understanding the neuroscience behind human appetite, metabolism, and body weight regulation. First, an impetus for further understanding human appetite and metabolism was given: the concerning onset of obesity, as it is the underlying cause for nearly 3 million deaths around the world every year. Next, the leptin cycle was introduced, an elaborate system that comprises adipocytic release and hypothalamic regulation of the hormone leptin. This is crucial for future developments in obesity treatments because the leptin cycle is largely responsible for regulating energy homeostasis and suppressing food intake. Then, background information on the leptin cycle and its discovery were given. Additionally, the majority of this paper explored both the primary components of the leptin cycle – leptin, the brain, Ob-R/leptin receptors, the JAK-STAT pathway, and transcription of target genes – as well as their significance and role in the leptin cycle. In short, each explored component serves a crucial, synergetic role in the leptin cycle that allows the human body to maintain energy homeostasis, regulate body weight, and suppress appetite.
I would like to thank my mentor Staci Hill, a Ph.D. candidate at Yale University for chemistry, for offering guidance throughout this research. Working with Mrs. Hill has taught me a lot of what is required to truly study both biology and neurology in the future.
Nathan Bui, Youth Medical Journal 2021
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