Huong Le, Emily Johns, Julien Grimaud

BY HUONG LE (HARVARD UNIVERSITY), EMILY JOHNS (STANFORD UNIVERSITY SCHOOL OF MEDICINE), & JULIEN GRIMAUD (SUP'BIOTECH RESEARCH DEPARTMENT)

Cover Image: Burger, Soda, and Fries.

Image Source: Pexel

Binge Eating Disorder (BED) is a very common mental illness that significantly reduces the quality of life and health. BED is characterized by consuming an abnormally large amount of food in a short period of time and feeling a lack of control over what and how much you are eating, often resulting in guilt or emotional distress. Despite its prevalence and severity, the neuroscience of BED is not well understood in medical and research communities alike. Recent research on the hormone leptin sheds light on a possible neural map of BED. Understanding the role of leptin signaling in BED may illuminate avenues of future research and treatment.

At first, Amanda L. didn't recognize she had an eating disorder. Until age 15, she never cared much about her eating habits. Like most other teenagers, she enjoyed her food in large quantities and did not give too much thought afterward, even when she felt full.

Her mindset and eating habits changed when Amanda entered college and was immersed in a highly pressured environment and community of self-conscious peers. She became hyper-aware of her meal portions, eating “good” food and avoiding “bad" food. After failing to live up to her impossible standards, Amanda was overcome with an intense sense of guilt and would spend 2+ hours in the gym every day attempting to burn off the excess calories.

However, in the spring of 2020, she was evicted from her college campus and found herself back in her parent's home primarily confined to her childhood bedroom. As the COVID-19 pandemic sent huge waves of panic across the nation most schools and businesses also closed. The combined increase in stress and inactivity from lockdowns prompted Amanda to continually reduce her portions and exercise excessively. Soon, one, three, and six months passed. Prompted by a combination of the stress and anxiety caused by the pandemic and her disordered eating and exercise habits she developed a cycle of restricting caloric intake, binging food, feeling guilty about it, over-exercising, restricting, and so on.

Amanda was not alone. Across the country, the COVID-19 pandemic has wreaked havoc on peoples’ mental and physical health (Von

Keyserlingk et al., 2021). People who struggled with body image and healthy eating behaviors before the onset of the pandemic were some of the most vulnerable to its added stressors (Christensen et al., 2021). A recent study published in the International Journal of Eating Disorders associated the pandemic and its social consequences with increased food consumption, eating as a coping mechanism, as well as caloric restriction (Termorshuizen et al., 2020). For many people, eating is used as a coping mechanism during stressful times. Eating as a stress reliever, combined with food scarcity, prolonged quarantined periods, and increased access to misleading social media (on which uncensored, misleading content about daily caloric intake and diet tips run rampant) have led many individuals like Amanda to develop binge eating behaviors. Over the past few years, various studies have highlighted how the COVID-19 pandemic has exacerbated food insecurity throughout the world, further contributing to disordered eating behaviors (Parekh et al., 2021).

The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) characterizes eating and feeding disorders as the presence of continuous alterations of eating or eatingrelated behavior causing alterations in food consumption leading to impairments in physical and/or psychosocial functioning (American Psychological Association [APA], 2013). Among many devastating eating disorders is binge eating disorder (BED). The five-part diagnostic criteria for the disorder emphasize the frequent and often ritualistic eating of atypically large quantities of food in short periods of time (maximum twohour binges occurring at least once a week for three months) and the distressing nature of such activity in patients (Westerberg et al. 2013) (Table 1).

About 3.5 percent of adult women and 2 percent of adult men suffer from BED, making it the most common eating disorder in the United States. Most people with BED also suffer from obesity, childhood trauma or psychological problems that lead them to overeat as a form of coping (Westerberg et al. 2013). In addition, BED is often associated with mood, anxiety, substance use disorders, and an increased risk of suicide attempts (Udo et al. 2019; Udo and Grilo, 2019).

To this day, despite the high prevalence and negative impacts of BED, its underlying neurological mechanisms remain poorly understood (Steward et al. 2018). However, over the past few decades, various experiments have shed some light on the possible neurobiological basis of disordered eating behaviors.

In 1960’s, Douglas L. Coleman was working at the Jackson Laboratory, a research institute in Maine specializing in mammalian genetics, when he got interested in two of their mouse strains: the ob/ob (obese) and db/db (diabetic) mutants. Both strains showed hyperphagia (lack of satiety) and were obese. The ob and db mutations were located on distinct chromosomes. When Coleman began his investigations, it was known that the db mutation caused issues in insulin

Table 1: DSM-V Diagnostic Criteria for BED. A patient must meet all five criteria to be diagnosed with BED. A binge refers to the rapid consumption of an unusually large amount of food in the absence of hunger, causing an individual to feel guilty, embarrassed, depressed, or out of control. Information adapted from the DSM-V (American Psychological Association [APA], 2013).

Image 1: Douglas L. Coleman’s parabiosis experiments. Two wildtype (WT) joined together remain healthy. When a WT mouse is joined to an ob/ob mouse, the WT animal remains healthy while the ob/ob mutant loses weight. When a WT mouse is joined with a db/ db mutant, the mutant remains obese while the WT mouse lets itself starve to death. Finally, when mutants ob/ob and db/db are joined together, the ob/ob mouse loses weight while the db/ db mutant remains obese. From this set of experiments, Coleman hypothesized the existence of a satiety hormone, now known as leptin. signaling. However, the mechanisms that led to hyperphagia in ob/ob and db/db mice was still unclear. Coleman hypothesized that a hormone may be responsible for the control of satiety. To test his hypothesis, he conducted a set of seminal parabiosis experiments, in which he joined two mice at the hip with surgical suture shortly after birth so that they shared each other’s circulating blood (Coleman, 1973; Coleman, 2014) (Figure 1).

When two wild-type mice were surgically joined together at the hip, they were healthy for the duration of the experiment. When an ob/ob was joined with a wild-type mouse, however, the ob/ob mouse lost weight. This experiment suggested that the wild-type mouse produced a satiety hormone that was either absent or nonfunctional in the ob/ob mouse before their two blood systems were connected. More surprisingly, when joining a wild-type mouse with a db/db animal, the db/db mouse kept gaining weight as normal, while wild-type mouse let itself starve to death. Coleman therefore concluded that the db/ db mouse produced much greater quantities of this satiety hormone – enough to stop any food intake in the wild-type mouse – and was not responsive to it. Finally, when Coleman joined an ob/ob and a db/db mouse together, he observed that the ob/ob mouse lost weight, while the db/ db mouse kept exhibiting the expected behavior (hyperphagia and obesity). This confirmed that the satiety hormone identified in both mutants were the same molecule (Coleman, 1973) (Figure 1). Subsequent genetic studies identified the hormone leptin as Coleman’s satiety factor (Halaas et al., 1995; Barone et al., 1995) Since Coleman’s seminal work, several lines of inquiry on leptin’s role in appetite, obesity, and eating disorders have been pursued. Remarkably, BED is characterized by high levels of circulating leptin, suggesting that it plays an important role in the development and maintenance of the disorder (Monteleone et al., 2000b). Recent studies indicate that the neural pathway that regulates eating behavior might potentially be the site of leptin's actions on mediating feeding behaviors, suggesting that there might be a neurochemical circuit that explains the neurobiological underpinnings of behaviors associated with BED (Branson et al., 2003; Monteleone et al., 2000b; Shah et al., 2014).

The hormone leptin is secreted by adipocytes in proportion to fat mass, providing feedback on the status of lipid amount in the bloodstream. The target tissue of leptin is a subdivision of the hypothalamus called the arcuate nucleus (ARC), where the blood-brain barrier allows for the passage of nutrients and hormones. When it binds to its receptor, leptin acts as a reporter of the amount of fat in the body, promoting both satiety and lipid metabolism. In the ARC, leptin activates two distincts neuronal populations: the pro-opiomelanocortin (POMC) and agouti generelated protein (AgRP) neurons (Andermann & Bradford, 2017; Pan & Myers, 2018; Varela & Horvath, 2012) (Figure 2).

Once activated by leptin, POMC neurons secrete a neuropeptide called α-MSH into the paraventricular nucleus of the hypothalamus (PVH). This, in turn, activates various receptors at the surface of PVH neurons, including

melanocortin-4 receptors (MC4R). Among the PVH neurons, MC4R are known to play a central role in appetite and energy regulation in the brain. Once activated, the PVH ultimately triggers a reduction of food intake, which is why PVH neurons are often called “satiety neurons” (Andermann & Bradford, 2017; Pan & Myers, 2018; Varela & Horvath, 2012) (Figure 2).

In contrast to POMC neurons, AgRP neurons inhibit the PVH through the release of three neuropeptides: AgRP, GABA, and neuropeptide Y (NPY). Peptides AgRP and GABA directly inhibit PVH neurons, while NPY antagonizes MC4R. As a consequence, AgRP neurons trigger an increase in food intake. Overall, the activation of POMC and AgRP neurons have opposite effects on satiety. They are part of a strongly regulated satiety balance (Andermann & Bradford, 2017; Pan & Myers, 2018; Varela & Horvath, 2012) (Figure 2).

BED is a condition characterized by frequent and often ritualistic episodes of binge eating, often resulting in guilt or emotional distress (Westerberg et al. 2013). Despite its prevalence, the physiological mechanisms leading to BED are not well understood (Steward et al. 2018; Westerberg et al. 2013).

Since Coleman’s discovery of leptin as the satiety hormone (Coleman, 1973), various studies have investigated the link between the leptin signaling pathway and eating disorders (Branson et al., 2003; Monteleone et al., 2000b; Shah et al., 2014). For example, it has been found that mutations in the MC4R gene are often associated with binge eating behavior in patients suffering from obesity (Branson et al., 2003). This discovery suggests that MC4R mutation may alter POMC and AgRP communication to the PVH neurons, inhibiting the feeling of satiety and leading to binge eating.

It is important to recognize that the neurochemical environment and genetic basis of binge eating disorder are complex and MC4R mutation is only one piece of our biological understanding of this disorder, albeit an important piece (Branson et al., 2003; Monteleone et al., 2000b; Shah et al., 2014).

The precise role of MC4R and the leptin pathway in BED is still open to testing (Steward et al. 2018; Westerberg et al. 2013). For example, it would be interesting to quantify MC4R mutations in BED patients. Future research could aim to find other mutations associated with MC4R mutations in BED, as only analyzing one gene is far too simplistic and unreliable an approach for such a complex system. After identifying other genes of interest, one potential avenue of study would be to knock out the genes of interest in mice and see how eating behaviors change accordingly. Such experiments will help advance our understanding of the genetics of BED in a systematic manner.

The authors have no competing interests to declare.

HL and EJ designed and drafted the manuscript with support from JG. All authors contributed to the final manuscript. The first draft of this manuscript was written as part of HL and EJ's final submission for the year-long course NEURO101J "Maps of the Brain", taught at Harvard University in 2020-2021 by JG.

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