Health

The Inflammation Station

Posted on by / 0 Comment

All aboard! All aboard! You’ve just purchased your ticket on the Obesity Train, and you have no idea what to expect. Still, you keep a positive outlook, hoping that this train ride will tell you all you need to know about the neurochemistry of obesity. Next stop, the inflammation station!

The Hypothalamus

You’ve just arrived at the train, and it’s time to get your ticket taken. The nametag of the person taking your ticket is “hypothalamus.” You think it’s odd, but you decide to listen to what it has to say. The hypothalamus mentions that it has a vital role in many metabolic and homeostatic functions, including the ever-so important melanocortin system, which binds hormones and controls food intake and energy expenditure. There needs to be a proper balance between food intake and energy expenditure, but this balance is tipped in individuals who are obese. The hypothalamus also tells you that one of its components is UDP, which is able to activate AgRP neurons. In obesity, these UDP levels are elevated, meaning a higher activation of AgRP neurons. This is not ideal, as those neurons will positively regulate feeding behavior. The hypothalamus has one more thing to tell you, which is that it hates inflammation. Hypothalamic inflammatory responses occur in two phases, both of which have harmful effects on the brain and body.

High Fat Diet

You finally reach your seat, thinking of the odd conversation you just had with Hypothalamus. Kind of an interesting character, but it gave you good information nonetheless. Your seat neighbor, though, also seems like a talker. It says its name is “high fat diet” and it wants to tell you about its effects on the body. You decide to hear it out, because what could it hurt at this point! High fat diet (HFD) tells you that the people who succumb to its pressure definitely feel the consequences. An HFD means that the brain has a tougher time telling you when to stop eating, almost constantly craving high-fat foods. This is somewhat of a habit, as once your brain gets used to an HFD, it will not like if you try to go off of it. HFD explains this to you saying it’s a likeable character, but you have a hard time believing it. This does not sound like something you’d want to get yourself into. The HFD wraps up its spiel to you by telling you why it’s on this train—heading to the inflammation station of course! A high fat diet causes activation of proinflammatory cytokines and inflammatory pathways in the hypothalamus. Not exactly good news!

Leptin & Insulin

You head down to the snack bar (in the “basement” of the train – how cool!), trying to escape these odd passengers you’ve talked to so far. There are two little kids in the snack bar, and they tell you their names are Leptin and Insulin. They’re cute kids, but they look very sick. When you ask if they’re feeling okay, they say no. They tell you that typically, they are able to effectively share with one another (suggesting a good balance between the two), but lately they’ve been unable to do so. Considering you’re on the train to the inflammation station, this makes you very nervous. They tell you that they too are not a fan of inflammation, as it causes a disruption in the signaling of Leptin and Insulin. Both of these hormones have crucial signaling pathways, so inflammation is quite detrimental to normal food intake and regulation, which is why it is such an important factor leading to obesity. The figure shown here helps give a visual of the balance between insulin and leptin and what is going wrong.

Last Stop: The Inflammation Station

When you reach the final destination, you come to the realization that inflammation is such a key player in obesity. Each character you talked to had a poor relationship with inflammation, demonstrating that it has widespread negative effects. Still, you feel as though this train ride has given you much to think about and has given you good information on obesity in the brain and body.

Uncategorized

Second-Order-What? Is This Causing My Weight Gain?

Posted on by / 0 Comment

Each year this seems to continue to be a “hot topic” as well as on the forefront of many American’s mind. Something that, statistically, seems to be increasing as in years past and remains a challenging matter to talk to anyone about, family or patient. This is obesity. What causes it? It seems as of late, there has been an increased focus on the hypothalamus and inflammation. Could there be such a pathway that outlines the “need” we feel to eat just one more candy bar or plate of food at the buffet?

Bain and Body communication 101

So, how does our body communicate with our brain and vice versa? Mainly through the use of neurons, cells that transfer information between our brain and the environment around us. Generally, we can think of these neurons communicating body wide, with first-order neurons receiving the signals from our limbs and ultimately transferring them up to the brain with the help of second motor neurons that act as an “intermediate”, running the signal up the spinal cord and to the brain before sending the message to another neuron.

 

Remember these “second-order neurons” as it will come back into the picture soon!

 

From Adipose to Brain

What gets the ball rolling exactly? Hormones such as leptin will be released from adipose tissues in the body and travel through the bloodstream until reaching the brain, specifically the hypothalamus. Here, it will trigger the activation of a neuron in the area of the hypothalamus known as the arcuate nucleus (ARC) that will, for our purpose, travel specifically to the paraventricular nucleus (PVN). These neurons will then pass their messages on to second-order neurons (as represented by the dotted line in the image below), which in turn will make their way to the brainstem where it will inform the body to continue eating.

More information can be found regarding the specifics of signaling and activation/inhibitions of proteins and pathways here. Of course, there are more pathways and functions that get carried out by each of the structures listed above, but what if an area of this pathway, let’s say the pathway of the second-order neurons, is damaged or gets out of whack? What then could happen? Damages to the PVN or just the pathway these neurons take to inform the brainstem of continual eating will be unable to function properly and may lead to issues such as overeating or even undereating. The damage or loss of these second-order neurons may even impact some of the inflammation regulator proteins such as CCKs that plays a role in feeding behavior.

Looking Ahead

This raises questions beyond the role that second-order neurons play within the brain and body, as in if this is what initially causes obesity to start occurring or if it is a side product of something larger. Is it and/or should it start being considered more of a mental illness under categories such as addiction? Are there true relationships between obesity and other areas of health such as Alzheimer’s disease or Type 2 Diabetes? With many additional aspects and environmental factors, it remains a challenge to determine what the “main contributor” could be for such a topic. This is why continual research is needed as well as the spread of information to the general public as a whole.

Uncategorized

DNA Methylation in ASD

Posted on by / 0 Comment

Autism Spectrum Disorder (ASD) is incredibly common, with about one in every 59 children being diagnosed, yet varies widely in its manifestation. Diagnosis of ASD is typically made by age two developmental medical check-ups and is based on behavioral observations. Some characteristic behaviors include eye contact avoidance, limited or lack of language development, delay in language acquisition, repetitive body movements,

Nothing in ASD makes sense except in the light of various genetic and epigenetic mutations resulting in problems with synaptic transmission. Dysregulation in gene networks forming the synaptic transmission supporting system is implicated in the development of ASD, but no specific single gene modulation is sufficient to cause ASD symptom formation, therefore more study is needed to elucidate the specific gene-environment & gene-gene interactions giving rise to ASD symptoms.

Inside the Brain

However, before we dive into understanding what is going wrong with the synaptic transmission in ASD, we should first understand synaptic transmission more generally. Broadly speaking, synaptic transmission is how your brain sends and receives information from stimuli both internal and external. How the brain makes sense of all of these signals is still an active and exceedingly exciting area of research. Diving down to the cellular level, synaptic transmission occurs when a neuron sends an electrical signal called an action potential down its axon to the synapse, where the sending neuron physically interfaces with the dendrites of the receiving neuron.

Once at the synapse, the action potential triggers the release of neurotransmitters (figure 1). The exact neurotransmitter and how much neurotransmitter is released is a highly controlled process involving many different proteins and signaling cascades. It’s incredibly interesting, but sadly we won’t be spending any time on it today. Instead, we’ll be focusing on the receiving neuron.

Figure 1: Access for free at https://openstax.org/books/biology-2e/pages/1-introduction

Once the neurotransmitter molecules are released, they diffuse across the synapse and bind to receptors on the dendrites of the receiving cell (figure 1). These receptors then interact with a network of support proteins known as the postsynaptic density (PSD). The PSD is incredibly important in maintaining synaptic transmission. Interestingly, in ASD, deficits in several of the PSD proteins have been identified. Specifically, we’ll be looking at the Shank family of proteins. Shank1, Shank2, and Shank3 all appear in the PSD and help form a sort of molecular scaffolding system to literally support and anchor receptors in the membrane and maintain proper dendritic shape. Specifically, deficits in Shank proteins are known to cause ASD-like behaviors in mice, and analysis of ASD patient samples commonly reveals Shank protein deficits in humans.

In ASD, methylation of the promoter regions of these genes causes a decrease in protein expression (figure 2). Ok, that sentence had a lot of jargon. Let’s break it down. Methylation is a key method of epigenetic gene regulation where specific parts of a gene’s promoter region are given a methyl group by an enzyme called DNA Methyltransferase. Promoter regions are regions of DNA that do not code for protein but offer a site for transcription factors, proteins that help induce gene transcription, to bind to help start transcription of protein-coding regions. Methylation of promoter regions at specific sites known as CpG islands makes the promoter sequence more bulky than usual, thus hindering transcription factors from binding and lowering protein expression (figure 2). This decreased expression of Shank proteins hinders the receiving cell’s ability to translate the signal into action.

Figure 2: Diagram of DNA sequence with methylated CpG islands in the promoter, transcriptional start site, and protein-coding region labeled.

Conclusion

It’s becoming increasingly clear that the interaction between genes and the environment is incredibly important in understanding complex human disorders like ASD. It’s also clear that while much research has been done and every day our knowledge of these conditions is expanding, much more work needs to be done in order to translate our basic understanding of the formation and development of ASD symptoms into treatments or therapies that improve quality of life for those living with ASD. However, in the meantime, support research by reading and sharing information from scientifically valid sources, financially support charities working to improve the lives of people with ASD and their families.

Uncategorized

Hypothalamic Inflammation & Obesity

Posted on by / 0 Comment

Having read a number of articles within my neurochemistry course, mostly related to neurological conditions and cognitive diseases, it appears inflammation is a significant and central component. This made me wonder if inflammation is a significant factor in other conditions as well. This week’s article answered my question suggesting a link between hypothalamic inflammation and obesity. The general gist of the article explains that inflammation of the hypothalamus impairs energy balance and contributes to insulin resistance which through a number of pathways leads to the development of obesity through altered neurocircuitry.

 

Image indicating relationship between signaling pathways of Ghrelin, Leptin, & Insulin.

The hypothalamus is a region of the brain critical in the regulation of eating and drinking, body temperature and energy maintenance, memory and stress control, and regulator of the endocrine system. Because of its significant roles, inflammation of the hypothalamus could result in dysregulation within these functions yielding several unfavorable events such as the development of obesity.

 

Molecular signaling & interactions related to development of obesity

Typically within a healthy individual, there is a balance between the signaling of leptin, ghrelin, and insulin. The leptin receptor when activated stimulates a protein abbreviated as Stat through a cascade of signaling. When Stat is activated, it moves into the nucleus of the cell and activates the transcription of proteins. Stat activates a protein abbreviated as POMC ( an appetite suppressor) and inhibits another abbreviated as AgRP ( an appetite stimulator) which signals satiety and suppresses the desire to feed. When activated, the insulin receptor, also through a cascade of signaling, activates a series of proteins (abbreviated respectively as IRS1, Grb, SoS, PI3K, and Akt) that stimulate the molecule that follows leading to the final activation of Akt. Akt similar to Stat, enters the nucleus of the cell but activates a protein abbreviated as Foxo which typically blocks the activity of Stat preventing the sensation of satiety and allowing for feeding when necessary. When Foxo is activated by Akt, it leaves the nucleus of the cell and is unable to inhibit Stat which allows for the sensation of satiety when necessary and stops the feeding behavior. These pathways help to regulate the intake of nutrients and maintenance of a healthy weight. Ghrelin works similarly but ultimately stimulates AgRP to elevate hunger and encourage feeding when the body requires more energy and nutrients.

 

Balance vs imbalance in hypothalamic signaling in obesity

Issues arise when an individual consistently consumes a high-fat and unhealthy diet, specifically those consisting of high concentrations of saturated fatty acids. Generally speaking, unsaturated fatty acids are healthier than saturated fatty acids as saturated fatty acids can stack upon one another and lead to clots or cholesterol buildup within arteries. A general rule of distinction between these two types of fat is that saturated fats are typically solids at room temperature while unsaturated fats are typically liquid. When consistently consumed in high concentrations, saturated fatty acids activate receptors abbreviated as TNF-alpha and TLR4. These receptors also use a cascade of signaling and activate JNK which phosphorylates (in this case inhibits) IRS1 blocking insulin signaling and NF-kappa-B which activates another protein (SOCS) which inhibits both insulin and leptin signaling. With disruptions in both insulin and leptin signaling, ghrelin becomes the primary stimulator leading to increased feeding, dysregulation of the sensation of satiety, and imbalances with energy maintenance leading to increased and continued storage as fat.

The challenges of obesity are not only limited to the molecular implications but society as a whole. With increased access to unhealthy foods, increasing prices of fresh produce, and the time commitment to create a healthy and well-balanced meal, temptations sway in the direction of fast, cheap, and easy. Advancements in technology decrease the amount of energy we expend throughout the day as food can be delivered to our door, we sit for hours on end, and we pursue the use of technology and entertainment over physical labor and exercise. Obesity and so many of the conditions we face go beyond just the molecular implications and often include an environmental or societal component as well. To truly address these matters; we must confront the influencing factors, both the micro and the macro. Thanks for reading.

Community/Health/Hot topics

Obesity and Body Positivity on the Brain

Posted on by / 0 Comment

Take a moment to look at the image above. Does something seem to be missing between the person standing on the scale, sad, then looking in a mirror, happy? If you jumped to the same conclusion as me, the answer is “weight loss”! In order to be so happy with their reflection, shouldn’t the person in the drawing have lost dozens of pounds and be smiling at their new, thinner figure?

Not only is it possible to reach the right side of the image without strictly focusing on losing weight, but finding happiness with your body may be even better for you than losing weight. Let’s take a look at obesity and body positivity on the brain!

Controlling Food Intake

First, it’s important to know how the brain normally maintains the appetite balance of being hungry and full. Two key players in this pathway are the hormones leptin and insulin.

Leptin:

  1. The hormone leptin is released from brain cells (neurons) after food is consumed
  2. Leptin binds to and activates leptin receptors on the outside of other neurons
  3. The activated leptin receptor in turn activates proteins called Janus kinases (JAK) which then activate signal transducer and activator of transcription (STAT) proteins
  4. STAT enters the neuron’s nucleus and causes certain portions of DNA to be transcribed into proteins
  5. These proteins transfer signals to neurons in the hypothalamus, a central brain region. These signals suppress the orexigenic pathway, which signals that you are hungry, and activate the anorexigenic pathway, which signals that you are full

Insulin:

  1. The hormone insulin is released from neurons after food is consumed
  2. Insulin binds to and activates insulin receptors on the outside of other neurons
  3. The insulin receptors activate a protein called IRS1, which in turn activates a cascade of proteins ending in protein kinase B, also known as Akt
  4. Akt enters the neuron’s nucleus and causes the FOXO1 protein to leave the nucleus
  5. When it is in the nucleus, FOXO1 causes DNA to transcribe proteins that suppress STAT activity. Looking back at the leptin pathway, STAT is necessary in the signaling pathway telling your brain that you are no longer hungry. By banishing FOXO1 from the nucleus, the insulin pathway also helps make you feel full

High-Fat Diet = Bad News for Appetite Control

The way the brain controls appetite and food cravings changes substantially after consuming foods high in fat. Like many “bad” habits, eating high-calorie, high-fat foods can be difficult to stop once you’ve become accustomed to the diet—some even argue that such foods are as addictive as drugs of abuse. The following changes take place in as little as 24 hours after initiation of a high-fat diet (HFD):

  1. Saturated fatty acids (SFAs) enter the brain through the bloodstream and bind to TLR receptors
  2. Now activated, TLR receptors activate a protein called IKK
  3. IKK goes on to free NF-κB to enter the nucleus, a transcription factor that is normally “blocked”
  4. NF-κB causes DNA transcription of the SOCS3 gene
  5. The SOCS3 protein inhibits the insulin and leptin signaling pathways described above, preventing your brain from telling you that you are “full” despite having consumed food

Since the SFAs prevent signaling that makes you feel full, you’re more likely to continue consuming unnecessary food. Not only does a high-fat diet prevent satiation, but it also leads to inflammation in the brain. Proinflammatory cytokines (small molecules inducing inflammation) such as TNF-α are produced following consumption of fatty food and bind to TNF receptors. These receptors activate JNK, a protein that inhibits IRS1, further preventing insulin signaling and compounding the effect of SFAs. Chronic inflammation in the brain, as well as the elevated appetite resulting from SFA consumption, results in bodily inflammation and weight gain.

In summary, eating a high-fat diet leads to brain inflammation and insulin and leptin resistance, resulting in bodily inflammation, increased food intake, and weight gain. But what do weight gain and obesity mean for the individual?

Obesity on the Brain

We’ve looked at how a high-fat diet impacts signaling in the brain leading to obesity. But how does obesity impact the brain and a person’s physical, mental, and emotional well-being?

First, let’s take a brief look at physical health. Obesity is a well-known risk factor for diseases including diabetes and cardiovascular disease. However, there is endless variety among bodies, and it is a simple fact that there is no “healthy weight”. People can be healthy across a wide range of weights, and the number on the scale provides little information about how healthy a person really is. As ingrained as it is in our brains, we must accept the idea that being thin is not equal to being healthy.

Obesity’s effect on mental and emotional health is another story. The modern Western attitude towards beauty informs us that our worth is reliant on our appearance, especially our weight, and that thinness is the ultimate ideal (this is nuanced in the muscular ideal for men, but we’ll loosely use thinness as the opposite of obesity for the purposes of this post). The evidence for the “thin ideal” is nearly endless: people perceived as attractive are more financially successful, the vast majority of models and actresses portrayed as beautiful are thin, and overweight people are stereotyped as lazy.

The societal obsession with thinness often has significant detrimental effects on the mental health of obese and overweight individuals. The constant outright or subliminal messaging that fat bodies are not wanted, not ideal, and worth less than thin bodies can cause serious stress in people who feel they don’t fit the “correct” beauty image. Not only is constant stress and negative body image clearly bad for mental health and quality of life, but elevated rates of cortisol, the stress hormone, can also further interrupt the appetite regulation pathway discussed above, leading to further weight gain and often compounding stress and body dissatisfaction.

Body Positivity

The body positivity movement seeks to combat the stigma around bodies that don’t fit the thin ideal or other aspects of the Western beauty standard. By promoting acceptance of all body types, body positivity advocates for love and shifting the idea that a person’s intrinsic worth is wrapped at all in their physical appearance. And body positivity is not just for overweight and obese individuals: a jaw-dropping 2% of women report being “totally happy” with their bodies. With such rampant dissatisfaction with our bodies, we can all benefit from a shift towards body positivity.

Critics of the movement claim that body positivity simply excuses obesity and ignores the health risks that go along with it. However, studies have shown that body positivity movements have nothing but positive effects on health: individuals who think positively about their physical appearance tend to have better mental health and are more likely to take care of themselves. By first destigmatizing obesity and fat bodies, we can send the message that all bodies are beautiful and worthy of love, and thus have a strong foundation from which to build healthy eating and exercise habits for the purpose of health rather than adherence to thin beauty standards.

Uncategorized

Obesity: A Mental Disorder?

Posted on by / 0 Comment

If you live in the US, you’re probably aware of the problem we have with obesity. Even if you don’t live in the US you most likely have the perception that all Americans are fat, which isn’t completely false. America has nearly 40% of the world’s McDonalds, and over 11,000 more restaurants than the country with the

2nd most McDonalds. Eating badly is ingrained in our culture, and in some cases, is our culture. 

With the existence of concepts such as fat shaming, some people believe that obese individuals can simply stop eating more than they have to. Now I don’t want to say that overeating isn’t a part of being overweight or being unhealthy, because it is, but are overweight individuals as in control as we think they are? Everyone has the choice of what they eat (assuming you have the income, although this isn’t a fair assumption either), but in a lot of ways, overweight people should not be fully blamed for the pounds they put on. Recent research shows that certain types of food, such as food that is high in fat, can be neurologically addictive. Because of this addictive quality, some are arguing for a place to be made in the Diagnostic and Statistical Manual (DSM V) for obesity as a mental disorder. 

It has been found that there are a number of ways in which food, specifically food that is high in fat, can have addictive qualities. In some ways this assertion is already intuitive, as you never just want to have one donut. However, we can see the effects of this addictive quality on a deeper, more scientific level than simply being aware of its effects. For instance, deficits in dopamine transmission are induced within a high fat diet. Simplified, this means you don’t feel as good over time while eating the same amount of unhealthy food; the enjoyment diminishes on a neurological level. This in many ways parallels when a tolerance has been built up through repeated drug use. 

It is commonly understood in research that obesity most likely causes increased inflammation, and inflammation may result in higher levels of obesity, though all the exact mechanisms for this loop aren’t known yet. What we do know is that obesity-related systemic inflammation reduces the integrity of brain structures involved in reward and feeding behaviors. To simplify this, this means that obesity triggers system-wide inflammation, which reduces the amount of control that we have over rewarding behaviors, including our food intake. Over time, our mental system of self-protection against resisting treats may be eroded by the fact that we’re eating these treats. A reduced integrity of reward systems has been found in drug addicts, where cortical brain regions involved in executive control and decision making have been heavily implicated. Through eating a high fat diet, we might be allowing our brains to think that eating more high fat items is what should occur. 

One study looked at fibrinogen (a protein that’s found in blood) as a marker for inflammation, in which more fibrinogen means more inflammation. Unsurprisingly, fibrinogen was higher among obese individuals. An interesting finding however was that volumes of the orbitofrontal cortex in obese participants were negatively associated with fibrinogen levels. One of the functions of the orbitofrontal cortex is impulse control, and so damage to this area can lead to both impulsivity and compulsivity. Just because there is a difference in volume here however doesn’t mean it’s due to fibrinogen, so researchers controlled for variables within lean subjects, and found that 9% of the variance in OFC volume could be explained by fibrinogen. This, unfortunately, doesn’t bode well for obese individuals. In the case of obesity, we might be our own worst enemies, as we may be unintentionally sabotaging our own willpower by consuming a high-fat diet. 

 

Uncategorized

The Complexity of Autistic Spectrum Disorder

Posted on by / 0 Comment

 

Recently in class discussions we had the chance to look at Autism Spectrum Disorders (ASD). ASD currently affects roughly 1 in 68 children. ASD shows abnormalities in social behavior. While I was growing up, I was fortunate enough to get to know two kids with ASD. The two kids were both in my grade and each of the showed a skill that they exceeded in. One of the kids would take sports statistics and memorize them. His brain loved numbers, but only numbers specific to sports. If I had asked him a certain score of a game played in 1990 between the Minnesota Vikings and Green Bay Packer, he would have told me right on the spot. The other kid was a walking calculator. He knew any math problem laid in front of him.

As these skills continued to progress, the two kids’ social behaviors drastically continued to decrease. Social interactions and communication started to become exceedingly difficult and that is when I found out they had ASD. Both kids also shared a rare diagnosis of savant’s syndrome as well. Savants syndrome basically sums up to be where one area of your brain shows extreme supremacy over others. This would explain the rare skills that both these kids showed. In most cases, savant patients also have ASD. After reading our class discussion, it started to make sense to me on how this might come to be. One of the theories discussed in the development of ASD is neural connectivity. In autism, patients undergo an overabundant number of neurons. This overabundance disables connections between the brain interactions. So, we ultimately get cut off connections which impair the brain in certain areas down the way, but in some cases these neurons may drastically increase the capability of the portion of the brain they are stuck in. This would perhaps explain savant syndrome.

There are many other theories that tie into the development of ASD with one of them being the impairment of synaptogenesis. This theory explains how in early life, our brain has a lot of synapse formation and with synaptogenesis, the removal of certain synapses takes place. This process is important in the fact that synapses are being taken out and they are the correct ones. In ASD this process is impaired, and the consequences would be brain underdevelopment leading to dysfunctional behaviors.

Although both theories make sense, I like to focus on neural connectivity. Again, bringing it back to my experience and relating savant syndrome to autism, I feel neural connectivity is the main issue. In savants I now can picture their brain. In my artstract below you can see an outline of what I feel is going on. In a human brain connection are supposed to connect the dots. These connections are supposed to be smooth and transfer from one to another without issues. In a ASD or savant syndrome brain we see that only a few of the dots are connected before there is a barrier where you cannot get to the next dot. In my experience, the portion of the brain that was controlling numbers was the dot that was connected, but then there became a barrier when trying to connect to the social interaction dot.

Of course, ASD is a lot more complicated then connecting dots but it is a graphic that helps me. In my experience with ASD  I never had the chance to see others. In the cases where I knew the individual I thought their behavior was normal for ASD. However, they also had the rare diagnosis of Savants as well. Learning about ASD more in depth and the complexity of the disease has opened my eyes to the severity that ASD holds.

Disease/Health

Polycystic Ovarian Syndrome (PCOS) and Obesity: A “Chicken or the Egg” Paradox

Posted on by / 0 Comment

What is PCOS?

Polycystic Ovarian Syndrome (PCOS) is a condition in which the ovaries produces excessive amounts of androgens, the male sex hormone. Excess of the male sex hormone in women disrupts the fragile balance that is maintained between estrogen, progesterone, and the androgens. This hormonal imbalance often results in the development of cysts within the ovaries, contributing to irregular menstrual cycles, infertility, and anxiety/depression. Additionally, overproduction of these androgens leads to excess hair all over the body, acne, and insulin resistance and obesity.

Studies have concluded that women affected by obesity have a greater risk for PCOS and women diagnosed with PCOS have an increased risk for obesity.

Obesity as Risk Factor for PCOS

The majority of women with PCOS are obese or overweight and/or have insulin resistance (50-90%). Resistance to insulin is a primary driving factor for obesity and type 2 diabetes, as insulin is a key regulator in maintaining normal blood sugar levels. An emerging theory of the cause of insulin resistance can be seen in studies of the hypothalamus, a structure of the brain responsible for regulating appetite, hormone release, and many other key metabolic roles. When there is inflammation occurring in the hypothalamus, however, there is disruption to many of these metabolic pathways that are vital for normal insulin signaling. This inflammation within the hypothalamus is prompted by a high-fat diet, further emphasizing the importance of a healthy diet in the maintenance of effective peripheral and neurological functioning.

Insulin resistance in peripheral tissues was actually found to enhance steroidogenesis in the ovaries, leading to higher production and consequent levels of androgens. This feature results in the hormone imbalance that contributes to many of the symptoms of PCOS. 

PCOS as Risk Factor for Obesity

On the other side of the paradox, elevated androgen levelsin women with PCOS have been shown to impair insulin signaling, contributing to insulin resistance. As demonstrated above, insulin resistance promotes androgen production. As androgen elevations promote insulin resistance, the positive feedback mechanism present between PCOS and obesity can clearly be seen. 

As indicated in the figure, there are a number of additional overlapping factors that perpetuate this sort of positive feedback mechanism that can be found between PCOS and obesity within patients.

Clinical Implications

Since PCOS and obesity undoubtedly compound the effects of the other, it is necessary to develop novel, effective treatments that will target both conditions. A strategy that has been used for a while to combat PCOS symptoms and infertility is hormonal oral contraception. This form of contraception provides supplemental estrogen and progesterone, thereby attempting to restore hormonal balance and allow for normal ovarian function. Additionally, antiandrogens have been reported to be effective in both lowering androgen levels improving insulin sensitivity. These drug strategies hold great potential for effective treatment of those who struggle with both PCOS and obesity. 

Promotion of exercise and a healthy diet in those with PCOS is important in the clinical setting, as these strategies help to both undermine the severity of PCOS symptoms and combat the effects of obesity. However, this feat is easier said than done, as many women with PCOS also struggle with anxiety or depression that may hinder efforts to stay active and eat well. 

It is ultimately necessary to increase research about PCOS and obesity so that more effective treatments emerge in the hopes of minimizing the difficulties that each condition brings about. 

 

Disease/Health/Uncategorized

To go or not to go: how excitatory/inhibitory imbalances can shape ASD

Posted on by / 0 Comment

Hello everyone! Today I’d like to talk a little bit about some factors that influence the development of Autism Spectrum Disorders (ASD), specifically how maternal infection/stress can increase the risk of ASD.

ASD is a spectrum of neurodevelopmental disorders that affects 1/58 children in the United States.  The key symptoms of ASD, which can range widely in severity, are impaired social interactions, problems with language/communication, and repetitive behaviors.

A lifelong condition, the cause of ASD is not yet known, although strides are being made to identify risk factors and molecular mechanisms that cause ASD.  Changes in the typical balance between neurons that stimulate other neurons (excitatory: Glutamate) and those that inhibitory other neurons (GABA) represent a key process that may explain ASD.

GLUTAMATE & GABA:

Picture two different neurons—If you’d like you can even color-code them in your head, one green one red. The green neuron produces and uses a neurotransmitter called glutamate to communicate with the other neurons it talks to, while the red neuron uses GABA.

When the green neuron is activated, glutamate is released into the synapse. Glutamate then binds to its receptor on the post-synaptic membrane and ultimately opens up a sodium channel. Positively charged sodium (highly concentrated outside the cell) rushes inside the post-synaptic neuron and makes that neuron more likely to fire, hence glutamate is excitatory. Cool!

Conversely, the red neuron does all the same steps, just swap out glutamate for GABA and chloride for sodium. Just like sodium, chloride is highly concentrated outside the cell and rushes inside once the chloride channel is opened. However, because chloride is negatively charged, increasing intracellular chloride decreases the likelihood of post-synaptic neuronal activation—making GABA inhibitory. The interactions between glutamate and GABA maintain balance in the brain.

At this point, you might be wondering how exactly this relates to ASD etiology. This is the part of the post where I admit that some of what I just told you was wrong. You see, every first-year neuroscience student learns about glutamate and GABA as I just described it, it’s a foundational “ying-and-yang” pillar of neurotransmission. And while it’s true that GABA works like that “most” of the time,  GABA works the exact opposite way during brain development.

During development, GABA is excitatory—as crazy as that might sound! The brain achieves this by implementing two different chloride ion pumps at different stages of development; an importer and an exporter. During fetal development, the chloride importer (NCKK1) is active and establishes a high intracellular chloride concentration. Once GABA binds and opens its receptor negatively-charged chloride rushes out, causing a net positive effect which makes the neuron more likely to fire—essentially excitatory. This mechanism is critically important during early development, but as fetal development draws to a close an excitatory-inhibitory GABA shift happens. NCKK1 is deactivated and the chloride exporter pump (KCC2) is activated, establishing the typical inhibitory functions of GABA.

This GABA shift is hypothesized to malfunction/be delayed in the context of ASD. This can cause the brains of individuals with ASD to have too many connections, sensory overload, enlarged cerebrums, and other symptoms of ASD. This begs the question, what dysregulates the chloride ion pumps and causes the malfunctional GABA shift in the first place?

Interestingly, these changes are impacted by changes in the maternal environment during pregnancy. Specific factors (especially prenatal infection and stress) can elevate pro-inflammatory cytokines, one of which (IL-1b) may directly impair the excitatory-inhibitory GABA switch! A rat model of ASD demonstrated that the administration of an NKCC1-blocking drug one day before birth restores many brain functions, especially in the hippocampus, compared to controls. This shows that birth is a critical period for the GABA shift and by proxy ASD development. This same drug decreases ASD symptom severity in humans with few side effects and is a promising avenue of treatment.

https://www.nature.com/articles/s41398-020-01027-6/figures/1

The take-home message is that maternal inflammation can cause prenatal neuroinflammation and impair the inhibitory-excitatory GABA shift, which can cause excitatory-inhibitory imbalances throughout postnatal development, increasing the risk of ASD. Understanding how these ion pumps initially go “out of whack” can help researchers design better drugs that more effectively repair the GABA switch with the fewest side effects!

Uncategorized

The Tangled Web of Autism Spectrum Disorder

Posted on by / 0 Comment

 

Do you remember the first time you saw a spider’s web? If you are like me, you were a young kid looking at it in a state of wonder. How can a spider create such a thing? Each thread looks perfectly placed and is clearly there for a reason. The threads come together to paint a picture of one of the most awe-inspiring parts of nature. I like to think of our brains in a similar way. Millions upon millions of connections come together, painting an intricate web between our ears, that ultimately makes up who we are.

The Web of ASD

Now I want you to think about taking that web and adding more and more threads. Now the perfect spider web is becoming muddled, with threads on top of each other where there shouldn’t be. Where there should be threads, there are too many, and now this perfect picture is becoming more and more confusing the more you look at it. This web does not look as functional, and it leads one to wonder what went wrong.

We can think of the brain, in almost an identical way to the muddled web as it relates to ASD. The causes of ASD are complex, to say the least, and involve a myriad of genetic and environmental risk factors. The effects, particularly on neural circuitry, are much better understood. Revisiting the spider web analogy, there are simply too many neuronal connections in ASD, as there would be in a crowded web. In a normal brain, around early childhood, neurons are pruned and refined to make connections more efficient. So in a more complex web, if a spider wants to travel from one side of the web to another, they are met with many more crossroads than would normally be anticipated. The spider ultimately takes longer to cross the web. Similarly in the brain, if a message needs to be sent across a greater distance the extra neuronal connections will mean that message is delivered slower and less efficient.

artract created by B. Swanson

Further complicating the brain in ASD, neurons can also simply be in the wrong place. Indeed, neural migration is also affected during ASD and during development. Now you can imagine a web with threads where they should not be, it does not look right, and maybe not even function right. With neurons in the wrong place, the issues of neural communication are further complicated.

Bringing it all Together

            With the brain seeming so out of whack, it’s hard to imagine a scenario where this brain even work. In ASD, the brain is largely functional, however it would not be considered neurotypical. The inefficient wiring leads to some of the big picture symptoms such as:

  • Difficulty with verbal and non-verbal language
  • Gestures
  • Facial expressions
  • Expressions of emotion
  • Lack of understanding of person space

The big picture symptoms are a result of a tangled web of neurons. However, the neurons mostly get the job done, and the messages sent, despite the difficulties. Much like a tangled spider’s web, it may not look and act how it should, but in the imperfection, there is a level of beauty.

Spam prevention powered by Akismet