I have for you two scenarios (These stories are not based on any person in particular, but are just general possible scenarios.)
First is a story about Edward. Edward has been a respectable CPA for the same business for the last 12 years. His family consists of his wife of ten years. A few evenings a week after a stressful day, Edward and some of his colleagues go out for a few drinks. By the time the night is over, Edward has consumed six or seven drinks and heads home. When he gets there, his wife has gone to bed. It’s late and he didn’t answer his phone. Edward storms into the bedroom and he screams and cusses at her supposed incompetence. His fury builds in the wake of his drunkenness. He takes a swing at her face. Edward is an aggressive and abusive alcoholic.
Second is a story about Lenny. Lenny is and has been a hardworking man doing construction for 25 years. He has a beautiful family of two sons, a daughter, and wife of 24 years. His family appears normal from the outside. No neighbors see any issues with the family across the street. They are just a normal working class family with a moderate income. But what cannot be seen from the outside is that each night before Lenny comes home. He stops at the bar with his buddies and has a few…then drives home. When he gets there supper’s on the table. His wife offers to make his plate, but he politely refuses. He goes back outside and underneath his workbench in the garage takes out a can beer…and another…and another…and another. Until it’s almost time for bed. This takes place day after day, week after week. Lenny is a passive alcoholic.
These two stories are different on so many levels. But the one common link between the two is the alcohol. How is it possible that alcohol can have such polar-opposite effects on two individuals as similar as these? This is a difficult question to answer and to be honest experts still don’t know.
Image from: http://usdrugstore.blog.com/alcoholism-learn-about-alcoholism-symptoms-stages-and-how-are-alcoholism-treated/
This week our neurochemistry class explored the reasons behind the behaviors that alcohol causes. Biochemically alcohol (ethanol) has an effect on all parts of the body including the nervous system. Alcohol’s complex impact on the body makes it difficult to pin point the reasons for certain behaviors. However, one effect that alcohol always seems to be true to is that of becoming uninhibited. Individuals who have had only a couple of drinks tend to show signs of uninhibitedness and “loosen up.” The truth starts coming out. Individuals become unafraid and senseless. They lose their reasoning for making good decision making. This may be the point where individuals differ in their actions. This may be why there are passive drunks, funny drunks, aggressive drunks, etc. Perhaps their own personality and history is what leads them to their choices—good or bad—after a few drinks. Generally speaking, alcoholism tends to be a common (so-called) disease across the United States. However alcoholism has many shapes and molds. Alcohol can result in many different and often opposing behaviors depending on the person it is acting within.
Alcohol is commonly consumed beverage throughout the world. According to the CDC about 52% of the US population over the age of 18 are considered regular drinkers (12 or more drinks per year). Alcohol is the drink of choice for celebrations, break-ups, deaths, divorce, marriage, any event under the sun (minus a child’s birthday party). So why is it that with a beverage so common that there are addictive qualities that come along with it? Why is it that certain individuals are more prone to alcohol addiction than others? I mean, drinking is not illegal, so there must be a reason. The prohibition in the thirties didn’t work so well so the lawmakers learned better. People like alcohol and there’s nothing wrong with that. But, there’s nothing good about alcohol addiction either. So where so we draw the line?
If you or someone you know need help in an abusive situation please call the National Domestic Violence Hotline at 1-800-799-7233 (SAFE)
Or get help online at:
http://www.helpguide.org/mental/domestic_violence_abuse_help_treatment_prevention.htm
For more information about statistics of alcohol addiction please see:
http://www.cdc.gov/nchs/fastats/alcohol.htm
Alcohol as a social issue
This week’s discussions centred around ethanol and it’s many different pathways that it effects. This is relatively new research, and not much is known about how this knowledge can be used to fight issues surrounding alcohol use. For me, the biggest issues with alcohol use and abuse are societal issues. I have known many foreign exchange students from Germany and other European countries. Many of them say that the difference between the United States and other countries’ drinking practices is that because alcohol is so much a part of their society, in Europe they drink for social reasons, and in America a lot of young people drink to get drunk. This is where a lot of problems come in, when alcohol is drunken for its effects. I think that alcohol will always be a substance that is both legal and widely used because it is so engrained into our society. Knowing how alcohol takes its effects is useful from the point of view of simply “knowledge is power,” but until we can find a helpful use for this knowledge, it doesn’t help those that are using alcohol all that much. Perhaps the scientific community can develop a sort of pill that can be taken while drinking to stop the aversive effects before they start. Most people continue to drink because they like the initial feel of relaxation and disinhibition, but if we can stop the pathway of ethanol before it inhibits reasoning and decision making this would be a very beneficial use of the knowledge we have.
Brain to Fat Communication
A steamy slab of steak lies on a plate soaked in steak sauce accompanied by garlic-mashed potatoes and cheese-covered broccoli. You reach for your fork and take a bite. Little by little the massive helping of food is soon demolished. Already feeling full and a bit lethargic, you stare at a luscious piece of strawberry cheesecake. You think to yourself, “I don’t need this… I definitely shouldn’t eat it… But wait, it looks so good. I’ll just have a bite.” Before you know it, you’ve eaten the whole thing and moved onto another piece. Feeling bloated and almost sick, you sit back and relax as the lump of food sitting in your stomach begins to travel through your digestive system.
To many, this may seem like an exquisite meal. However, those that eat this excessively on a regular basis, usually combined with other unhealthy choices, commonly experience obesity. Fact is, eating like this has a huge impact on not only the digestive system but adiposity signaling as well. Adiposity signaling is communication between the brain and body fat stores in the body via the bloodstream. The way in which adiposity signaling functions has become an area of scientific interest.
For a molecule to be considered for adiposity signaling it must meet certain conditions. It must be able to secrete into the plasma relative to the fat stores, move from the brain into the bloodstream, show expression in the brain of signaling molecules that are involved with energy homeostasis, and decrease food intake. As of now, only two molecules are known to be directly associated with adiposity signaling, leptin and insulin. The effects of the molecules’ actions on neurons occur in the hypothalamus of the brain. More specifically, the region most concerned with these effects is called the hypothalamic arcuate nucleus. This area contains two neurons, proopiomelanocortin (POMC) and neuropeptide Y (NPY) with agouti related protein (AgRP), that express insulin and leptin receptors. However, POMC and NPY/AgRP have different effects depending on the levels of leptin and insulin. POMC is activated by insulin and leptin and reduces food intake and increases energy usage. NPY/AgRP also reduces food intake but is inhibited by leptin and insulin. In other words, if NPY/AgRP is secreted, food intake is stimulated.
Although the mechanism in which fat stores and the brain are connected is much more complicated than what has been explained, POMC and NPY/AgRP play an integral role. It is their existence that tells the body to eat more food or not. Even though regular exercise combined with a healthy diet should deter obesity, not everyone is able to maintain such a lifestyle. If scientists are able to engineer a drug capable of inhibiting NPY/AgRP and promoting POMC, weight loss could become more efficient.
Cheers!
What is something 52% of American adults do on a regular basis? Brush their teeth? (Just kidding…78% of adults do that). The real answer is drink alcohol. Yeah. Since drinking is such a common thing, you’d think scientists would know how alcohol affects our brains. Oddly, however, alcohol’s story in the brain is still a very complicated and confusing tale.
According to Newton and Messing in their article, “Intracellular signaling pathways that regulate behavioral responses to ethanol” Some aspects of the alcohol story are being uncovered. These effects seem to somehow involve the proteins adenylyl cyclase (AC), protein kinase A (PKA), DARPP-32, fyn kinase, protein kinase C (PKC), phospholipase D (PLD), and a fun little transcription factor called CREB.
AC, PKA, and CREB
How does ethanol signal through these molecules? It seems that ethanol decreases function of a transporter protein called ENT1. Usually ENT1 would take up adenosine, but when it’s inhibited it doesn’t – a ton of adenosine builds up outside the cell. Once this happens, there is more adenosine to activate its receptor. Since adenosine’s receptor has interactions with a Gs protein, its increased activity leads to increase AC production. Increased AC in the cell leads to cAMP production and eventually signaling via PKA. PKA signaling activates CREB which is a transcription factor and can change gene regulation! Phew. What affects does this signaling have? According to mice studies, this pathway could be important in ethanol preference and self-administration. But, it seems that effects depend on brain region.
DARPP-32 and Fyn kinase
These two proteins have some interesting and rather confusing effects on our brains. PKA pathways stimulated by dopamine signaling (which is stimulated by ethanol) activate DARPP-32 by phosphorylation. DARPP-32 then goes on to inhibit a phosphatase, PP1. PP1’s usual role is to dephosphorylate NMDA receptors to decrease brain excitability. However, when it’s inhibited, NMDA receptors remain active.
Fyn acts in a similar way. Ethanol seems to allow Fyn kinase to disassociate from its regulatory scaffolding protein, RACK. Once it gets rid of RACK it can go on to do whatever it’s feelin’……which happens to be phosphorylating NMDA receptors. And, like before, NMDA receptors are activated. It is hypothesized that this NMDA activation is important in the reward and reinforcement in ethanol consumption.
PKC
Since there are many forms of PKC acting in many brain areas, its actions can get quite complicated. Mice lacking PKCγ have decreased response to the “sleepiness/decreased brain activity” typical of alcohol and they also have decreased preference for ethanol. Mice lacking PKCε also show decreased hypnotic effects and consume less ethanol. It is thought that possibly PKC could signal through GABA receptors, glycine receptors, and voltage-gated Ca2+ channels although the facts behind this are still murky.
PLD
PLD is one molecule that can directly use ethanol as a substrate. This protein’s normal function is to hydrolyze membrane phospholipids to make phosphatidic acid (PA). PA acts as a second messenger for many things including PKC, PLC, mTOR, Raf1, phosphatidylinositol 5-kinase, and others. However, in the presence of ethanol, instead of producing PA, PLD uses ethanol to produce another molecule, phosphatidylethanol (PEth). This switch-up can produce two effects: first, you don’t make PA, and second, PEth is incorporated into cell membranes to make them more fluid. Because of these, cell signaling will be altered and neurotransmitter release may be inhibited.
It seems that alcohol has some interesting effects on our brains; however, the knowledge is certainly incomplete. Alcohol seems to have very different effects on different brain areas. In fact, some signaling molecules even have opposing effects depending on brain area. So…until we figure out more….ignorance is bliss? Drink up!
Newton, P.M., Messing, R.O. (2006) Intracellular signaling pathways that regulate behavioral responses to ethanol. Pharmacology & Therapeutics 109, 227-237.
http://crystalwineglasses78.webs.com/
Hello School, Goodbye life.
http://www.iuma.be/reverse%20punch.html
Who are we? Concussions and the like
Concussions are becoming an increasingly popular topic. The concern mainly being focused around professional athletes and the increasing literature in the dangers of suffering from multiple concussions or back-to-back concussions. This is a topic that strikes me in particular. I have suffered from multiple concussions throughout my life, a couple of which were rather severe.
After suffering from a traumatic blow to the head there is a rush of neurotransmitters into the synapses of neurons. This rush creates a large number of unchecked ionic fluctuations. This series of initial events after an impact result in some small changes in cellular physiology. The brain responds to these fluctuations by trying to restore balance. In the process of balancing, the brain experiences the hypermetabolism of glucose. This hypermetabolism of glucose is one reason why some researchers think a second concussion so early is so dangerous. The brain cannot respond adequately to a second impact, because it is already doing too much. The third stage is a depressed metabolism.
The more we know about concussions the better we can respond to one when it occurs. Unfortunately, the literature is lacking when it comes to the long term effects of suffering multiple concussions, spaced generously apart. However, many athletes have reported experiencing CTE, or chronic traumatic encephalitis, after their playing careers are over. The cognitive impairments involved in CTE are obvious and measurable. It is the subtle cognitive changes after one or a few concussions that plague the average concussion sufferer.
I hate to indulge in self-absorbed story telling in a blog, but I find this particular personal dilemma too common to not be compelling. Don’t we all wonder if something from our past or our gene pool affects us now in a profound way? I often wonder these things, and the concussions I’ve suffered from often make me wonder how different I would be if I hadn’t had them. I will reserve myself to two telling.
My first major concussion occurred when I was around three years old. I fell out of the basket of a grocery cart at my local COSCO store. I landed on my head of course. I don’t remember much of it and the story’s facts rely on my mom, who was there to witness it. To this day she gets the chills going into COSCO. I had lost consciousness that time, and often wonder how this major concussion at the age of three affected my cognitive and personal development. The second major concussion occurred when I was about 6 or 7. Me and a friend at set up a nifty “dive down the stairs onto cushions” game and were having fun. It only takes one bad jump and one misplaced cushion to make the fun go away. This is what happened. I leaped from the top of the stair case, began toppling down the cushioned stairs, and eventually slammed the back of my head at the bottom of the stairs on a cushionless area of the carpeted floor. I didn’t lose consciousness this time, but I distinctly remember seeing stars. Apparently the expression isn’t metaphorical but literal. This is it I guess. It’s interesting to wonder how these have affected us. But inevitably we can’t really know. There are just too many variables, and we really shouldn’t spend too much time worrying about it. We are who we are, regardless of what causes us.
Does this make me look fat? Treating obesity and leptin resistance
Thanksgiving: one of those holidays of the year where gluttony is encouraged. Americans make enough food to put themselves into a calorie-induced coma for days. This happens only a few times a year, though, so why not indulge once in a while?
Lately, we have been talking about weight regulation and obesity—a relevant topic indeed close to Thanksgiving! The articles we have been reading discuss leptin, a very important hormone in the brain for feeding behavior.
What is leptin?
Leptin is a hormone that is secreted from fat cells in the body. When released, leptin suppresses appetite and tells the body to stop eating. How does this regulate body weight long-term? When more fat is being stored, leptin levels will increase; leptin is telling the brain that the person should stop eating so much. This yields in a decrease of food intake and, ideally, a decrease in weight as well. Leptin is a natural regulator of weight and food intake, in this way.
Leptin produces this effect by influencing the signaling of neurons in the hypothalamus. The hypothalamus is an area in the brain that regulates hunger and feeling full. There are many signaling pathways involved in feeding behavior that are affected by leptin. Researchers are trying to target these pathways in order to find a treatment for obesity.
What about obesity?
If leptin regulates body weight, then obesity shouldn’t be the problem we see today. However, research indicates that if a person has high levels of circulating leptin (due to long-term over-eating, poor nutrition, a high-fat diet, etc.), eventually he or she can become resistant to the appetite-suppressing effect of leptin. Leptin has tried very hard to tell the brain to decrease food intake, but over time the body becomes used to it and doesn’t even listen anymore. High levels of leptin, then, cannot decrease food intake and weight because the body is resistant to it. This is why giving leptin to treat obesity doesn’t work—obese people are probably resistant to the effects of leptin already.
Treating obesity
Leptin resistance is certainly a problem. Discovery of leptin held great potential for finding a good treatment for obesity. But leptin resistance brought much of this research to a grinding halt. So how can leptin resistance (and obesity) be treated?
Well, researchers are still working on that. But there are a few ideas out there. In 2009, Harvard University researchers found two compounds that reduced leptin resistance in mice. These substances reduce inflammation in the nerves and may simply restore natural leptin functioning. It will probably be years before this treatment is available for use.
Another option that physicians are increasingly turning to in cases of extreme and difficult-to-treat obesity is gastric bypass surgery. This should be a last option after all others have been exhausted. This involves a surgery stapling a section of the stomach to form a small pouch, the “new” stomach (see diagram below). When we eat food and our stomachs fill up, the stomach walls start to stretch. Nerves in the wall sense this stretching and send messages to the brain to stop eating. This involves the signaling of a number of chemicals and hormones, including leptin. After gastric bypass surgery, the stomach fills much faster, causing a sense of fullness rapidly as well. Additionally, leptin levels are decreased (according to recent studies in 2010 and 2011). While obese people often have chronically, stubbornly high leptin levels, gastric bypass surgery may reduce leptin resistance, allowing levels to drop and normal functioning to resume.
Medication and surgery are drastic measures to treat obesity. Exercise and careful monitoring of food intake may also affect leptin and obesity. In chronic over-eating and snacking, levels of leptin rise as the brain tries to tell the body to stop eating. If a person is always eating, however, these levels will remain high all the time. Not good. Constant advertising of food, easy access to fast food, and supersized food portions may all have contributed to the high rates of obesity in America. In the 1950s, a 12-oz can of soda was considered “king size,” big enough for two servings. Now, a 12 oz. soda at McDonald’s is considered child-size, and people regularly order their 22 and 32 oz. sizes. Do we really need all those calories? The burgeoning obesity rates in our country suggest not.
Another option is good old fashioned exercise. Leptin levels increase in the brain shortly after exercise, telling the body not to eat. In people with obesity problems, long-term exercise may eventually reduce high levels of leptin. Additionally, some research has indicated that exercise can make the body more sensitive to leptin and insulin, both essential hormones for metabolism. Increased sensitivity to these hormones makes the body more efficient in using them, and resistance is reduced. Exercise is a great natural way to help restore natural leptin functioning and beat obesity.
Extra Sugar
High Fructose Corn Syrup!!!
First of all, what exactly is it? We all know that it makes an appearance in all of our food. According to the USDA, high fructose corn syrup is 3% water, 42% glucose, and 55% fructose. This particular mix is used in the soft drinks that most of us consume on a daily basis. High fructose corn syrup has replaced our table sugars as the sweetener in most of our meals. The main reason for this is because it is easier and cheaper to make. So, needless to say, since high fructose corn syrup is everywhere, do we have to worry about what it does inside our body?
Take a min to watch this SNL skit.
http://www.hulu.com/watch/223360/saturday-night-live-corn-syrup-commercial
Although humorous, the video does bring up valid points about the public being uninformed on the side effects of high fructose corn syrup, as well as the idea of moderation.
Related to the paper we just read, I found another paper that suggests that high fructose corn syrup reduces the amount of leptin and insulin in our blood stream. This is bad news for us, because leptin is what regulates our hunger, and our body’s ability to increase energy production. Without leptin, we will always be hungry. That will lead to caloric intake, and from there, to obesity!
Here is a neat graphic depicting the effects of leptin signaling from adipose tissue.
http://www.nature.com/nature/journal/v395/n6704/fig_tab/395763a0_F3.html
As you can see, increase in leptin, comes from weight gain, and this signals our body to stop eating. However, if our leptin is decreased, it will lead to hunger and caloric intake. The reason for this decrease in signaling, is that fructose doesn’t trigger the leptin signaling pathway. So, we just eat and eat and eat and nobody tells us to stop.
However, I’m still unsure on what exactly this means for our intake of high fructose corn syrup. Should I be eating it? Should I be eating only some of it? How much can really affect my body weight? These are a few questions I would like to explore further.
Which came first? Diabetes or obesity?
This week’s article talked about obesity and how some of the pathways that trigger in our bodies that we are full may not be working properly. These chemicals that signal we are full and can reduce or stop our food intake are called insulin and leptin. These chemicals work together so that when there are high levels of insulin and leptin we decrease our food intake and increase our energy spent, but when these levels are low we increase our food intake and decrease the amount of energy we spend. The article stated that there is a balance between the chemical levels, food intake and energy expenditure. When and if something gets off balance, something in the body goes awry one of these possibilities is obesity.
One theory out there is that obese individuals have a hard time lowering their food intake because of something called resistance. These leptin and insulin levels that used to be enough to tell us to stop eating are no longer at high enough concentrations so our brains and our bodies don’t know to stop eating. The increased glucose from the foods we eat can’t all be used in energy so it is stored in the body for later use as fat cells, thus causing a build up in fat stores and leading to obesity.
Some articles that I found focus more on insulin resistance as the key factor rather than leptin. According to one article, obesity is actually said to promote insulin resistance because the body no longer recognizes the smaller amounts of insulin to signal a cessation of eating. To find more about this article you can check out this link: http://diabetes.webmd.com/guide/insulin-resistance-syndrome
This diagram depicts other things that can also happen when the body is resistant to insulin.
http://table.ta.funpic.org/04/insulin-resistant-symptoms.html
There is also a link between type 2 diabetes, obesity and insulin resistance. Type 2 diabetes is characterized by the body producing insulin, but not enough for the body to use it correctly, thus resulting in insulin resistance. To learn more about Type 2 Diabetes, follow this link: http://diabetes.webmd.com/diabetes-men
So people that are overweight are more likely to develop insulin resistance and thus diabetes, but people that have diabetes are also more likely to become overweight. Therefore it is still unclear which comes first; it is kind of like the chicken or the egg debate. Scientists do propose that there is a genetic link however, so a word of caution to those that have either obesity or diabetes in their family; take care of your body, eat right and exercise so that you don’t have to find out which comes first for you, obesity or insulin resistance.
Step Away From the Ice Cream!
Obesity has unarguably become one of the biggest issues facing our society. This week we discussed two molecules, insulin and leptin, specifically relating to obesity. Insulin and leptin are considered ‘adiposity signals’ meaning that the levels of these molecules is directly related to the amount of adipose tissue (fat) that we have circulating in our bodies. Research has shown an increase in insulin results in a decrease in food intake and therefore a decrease in body weight; conversely, those deficient in insulin experience hyperphagia (excessive eating) resulting in an increase in body weight. Leptin has been shown to be necessary for normal control of food intake and body weight. Individuals deficient in leptin or leptin receptors experience extreme hyperphagia and therefore obesity.
Neurologically, there are two sets of neurons located in the hypothalamus that can relay the signals of insulin and leptin. The two types of neurons have opposite effects on food intake and energy expenditure. First are neurons which express proopiomelanocortin (POMC); they are activated by an increase in insulin and leptin and result in a reduction in food intake and an increase in energy expenditure. Second are neurons which express neuropeptide Y (NPY) and agouti related protein (AgRP); they are activated by a decrease in insulin and leptin and result in an increase in food intake and a decrease in energy expenditure.
The issue with this system seems to be that we can become insulin or leptin resistant, meaning our brain can no longer control our eating habits. The exact mechanism of this is not entirely known however, high fat diets have been shown to lead to resistance. So, if we decrease the amount of high fat foods we consume, we could help ourselves prevent this control system from falling apart.
In order to do this we must look at reasons we have diets that are high in fat: one such reason is emotional eating. Emotional eating can be defined as eating for reasons other than physical ones. It occurs when we eat to satisfy or reach a certain feeling; we eat when we are sad, stressed, bored, happy – basically eating can be associated with any emotion. A representative from the University of Maryland indicated that, in fact, over 75% of over-eating is emotional eating – that is a shocking number considering the only reason we need to eat is for physical reasons (need for more energy).
Research has shown that ice cream is the number one go-to emotional food; for women, chocolate and cookies are next on the list and for men pizza and steak are most commonly eaten. Researchers have found that many ‘comfort foods’ consumed during emotional eating are very high in fat. This becomes an issue when emotional eating is the only coping mechanism one has to deal with emotions. We take in significantly more calories than our bodies need and the foods we eat tend not to be very healthy. So what can we do about it? Well many sources indicate that becoming aware of emotional eating is the start. Every time before you start eating, determine your emotion, how strong that emotion is, and what food you are reaching for. By keeping a food diary you may notice how often you are eating for reasons other than physical ones and how much of an unhealthy food you are taking in. So, put down the ice cream and rate your emotion!
*For more information on how to control your emotional eating check out: WebMD: Controlling your emotional eating
Obesity as a Disease
This week’s article was about insulin and leptin signalling in the human body. Signals from our fat tissues, or adipose, release insulin which tells our bodies to decrease food intake. Therefore, if we have less fat tissue, we will have less insulin signalling and increased food intake, and if we have more fat tissue, insulin will be released and food intake will decrease. Leptin is a similar adiposity signal. Mutations in the expression of leptin have been linked to morbid obesity.
For me, this was one of the first times that I have taken an in-depth look at the mechanisms surrounding food intake and weight gain. I have previously learned that obesity can have strong genetic links, and often it isn’t a person’s conscious decision to become obese. But learning of these intricate systems and how one little alteration can lead to increased food intake and obesity, has given me a better understanding. There are opinions out there that obesity isn’t a disease, that it is solely a person’s choice to not take care of their body that leads them to becoming obese. There is also the opinion that obesity is a disease. I have come to agree with the later of these opinions. If there is something that changes inside a person chemically that causes a chain reaction of events to occur, that is through little fault of the individual. Many of the foods that are being made today contain ingredients that can throw these insulin and leptin signals off. It is kind of like the issue of alcoholism as a disease. Yes, the first initial few drinks are conscious choices of the individual. But after that, it has been shown that physiological and chemical changes in the brain occur, making the taking of a drink beyond simple choice. I think the issue of obesity in some cases can be similar to this if changes in the leptin and insulin signalling are changed by the diets of those who are obese.