Endocannabinoid System; Helpful, and Not the Same as Cannabis

Obviously, cannabis, weed, marijuana, etc. and its legalization have been a controversial, polemic, political hot button for the past 40+ years. However, this stigma and demonization of the cannabis plant, and its psychoactive product: marijuana, has resulted in many misconceptions and confusion about how they actually work. Misunderstanding and fear have caused claims like, “weed melts your brain cells” which can be a dangerous misconception. Why would it be dangerous? Because a brain melting drug is terrifying and the psychoactive ingredient in marijuana, THC, does not melt brain cells, at all.

So how does marijuana actually work in the brain? Let’s focus on THC, the most active part of marijuana. THC is the drug that is active in the brain which can be said to be psychoactive. THC works by binding to proteins in the endocannabinoid system. Endocannabinoids? We have marijuana products in our brains?!? No, not quite. The endocannabinoid system was coined that because scientists discovered it by seeing which proteins cannabis binds to. The endo- part is in reference to the small endogenous (naturally occuring in the body) molecules that bind to these receptors. 

What are these mysterious receptors? There are two receptors and they are known as CB1 and CB2. CB = Cannabinoid. The figure below from this pharmacy explains quite well the differences in the two receptor types, their function, and their locations in the body. 

THC or Tetrahydrocannabinol, like was mentioned before, is the most potent psychoactive ingredient in weed/cannabis. THC binds mostly to the CB1 receptors. Knowing this, we can start to see how some of the common symptoms of smoking weed or ingesting THC could arise. Looking at the figure above, we can see CB1 targets pain perception which we can connect to how some people use cannabis for pain. Additionally, CB1 impacts appetite, if we think about how people commonly get the “munchies” or temporarily increased appetite while using cannabis, now we can see how to connect THC to the CB1 receptor to then appetite.

Tetrahydrocannabinol (THC)

Next let us learn about what are these endogenous molecules, or ligands, that would bind to these receptors in a normally functioning brain. 

Anandamide (AEA)

2-Arachidonoylglycerol (2 – AG)

Above the paragraph, these two molecules are the main ligands, AEA and 2-AG. Now a chemical structure can be intimidating, but the function of these molecules is relatively simple. They are messengers that will attach to the CB receptors that result in signals sent in the brain. When these endogenous ligands are used instead of THC or CBD, the endocannabinoid system works on regulating the body, whether that be hunger, temperature, energy, and so many more. 

Nevertheless, the key to how THC and CBD are active in the brain and body is the endocannabinoid system. However, the endocannabinoid system is no boogeyman that should be demonized and feared like cannabis has in the past; it is a natural part of the body’s functions in and outside of the brain. 

 

 

References:

Artstract made in Canva

 Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294

Endocannabinoid System: A Simple Guide to How It Works. (2019, May 17). Healthline. https://www.healthline.com/health/endocannabinoid-system

Mosher, C. J., & Atkins, S. (2020). In the Weeds: Demonization, Legalization, and the Evolution of US Marijuana Policy. Social Forces, 98(4), 1–3. https://doi.org/10.1093/sf/soaa003

MD, P. G. (2021, August 11). The endocannabinoid system: Essential and mysterious. Harvard Health. https://www.health.harvard.edu/blog/the-endocannabinoid-system-essential-and-mysterious-202108112569

What is the Endocannabinoid System? | Sona Pharmacy + Clinic. (2020, April 1). https://sonapharmacy.com/what-is-the-endocannabinoid-system/

2-Arachidonoylglycerol. (2023). In Wikipedia. https://en.wikipedia.org/w/index.php?title=2-Arachidonoylglycerol&oldid=1165555760

Anandamide. (2024). In Wikipedia. https://en.wikipedia.org/w/index.php?title=Anandamide&oldid=1211788315

Glioblastoma; A Case Study of Converging and Complex Cell Signaling Pathways

Glioblastoma is a type of brain tumor; glio means ‘from glial cells’ which are cells that support neuronal cells in the brain, and blastoma means ‘a form of tumor.’ Glioblastoma is a very deadly form of cancerous tumor because of how fast it grows, how resistant it is to treatment, how invasive it is,  and the fact that it is located in the brain, one of the most essential organs in the body. Patients with glioblastoma experience common symptoms with neurological disease and brain injury, for example, headache, seizures, nausea, personality changes, drowsiness, etc. 

Now we know what a glioblastoma is, let us learn about how the cancer works and what makes the tumor grow so fast. In normal cells, there are multiple cellular signaling pathways that will signal to the cell that it needs to grow and divide. The major ones to focus on, for glioblastomas, are cAMP, MAPK, and PI3K pathways. Looking at the set of figures below that outline each of these pathways, we can see that the structure of these pathways is not so different from one another. They all involve signals coming from outside of the cell, in the extracellular space; the signals join with a receptor on the membrane whether that be a GPCR like in the cAMP or RTKs in the PI3K and MAPK pathways. Yes, all of these pathways are their own individual pathways, but there are key points and proteins where they converge. Convergence is when a protein or system is used in two or more pathways, so it is conserved. This makes it an attractive target for drugs because a drug could more efficiently impact multiple pathways.

A                                                         B

C

Figure 1: Collection of signaling pathways that lead to cell growth, A the cAMP pathway which is named after the key second messenger cAMP. B the MAPK pathway which refers to the protein MAPK which is a key step in the pathway whether it goes from a cellular signal to a change in gene expression. C the PI3K pathway which is named after the PI3K complex of two proteins p85 and p110.

 One convergent protein between MAPK and PI3K is Ras. The Ras protein is a g-protein which binds to GTP, a molecule that can give proteins and other molecules the energy to function. The Ras + GTP will then go and activate more proteins in both the MAPK and PI3K pathways. Ras has been identified as a convergent target by many scientists, and the National Cancer Institute (NCI) has started a Ras initiative which will focus research and funding on learning more about Ras and how to target it with drugs and cancer treatments. When Ras does not work correctly, cells can divide and grow too fast and become cancerous. 30% of cancers can be traced back to a malfunction with the Ras protein.

Ras is just one of these proteins that is conserved across signaling pathways. Like was aforementioned, these proteins are very attractive treatment options for cancer. However, like most cancer treatments, these proteins and pathways are necessary in all cells, so if they were to be shut off that would negatively impact all cells in the body, just like in chemotherapy.

 

 

 

References:

Gliosis. (2023). In Wikipedia. https://en.wikipedia.org/w/index.php?title=Gliosis&oldid=1188134830
Med Terms B- Med Term Prefixes-suffixes—Medical Terminology B – GlobalRPH. (n.d.). Retrieved April 24, 2024, from https://globalrph.com/medterm/b/
Med terms G- med term root list. (n.d.). GlobalRPH. Retrieved April 24, 2024, from https://globalrph.com/medterm/g/
Morrison, D. K. (2012). MAP Kinase Pathways. Cold Spring Harbor Perspectives in Biology, 4(11), a011254. https://doi.org/10.1101/cshperspect.a011254
Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer—ScienceDirect. (n.d.). Retrieved April 25, 2024, from https://www-sciencedirect-com.cordproxy.mnpals.net/science/article/pii/S0898656819300208?via%3Dihub
About the RAS Initiative—NCI (nciglobal,ncienterprise). (2016, September 14). [cgvArticle]. https://www.cancer.gov/research/key-initiatives/ras/about
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017). RAS Proteins and Their Regulators in Human Disease. Cell, 170(1), 17–33. https://doi.org/10.1016/j.cell.2017.06.009
Wen, P. Y., Weller, M., Lee, E. Q., Alexander, B. M., Barnholtz-Sloan, J. S., Barthel, F. P., Batchelor, T. T., Bindra, R. S., Chang, S. M., Chiocca, E. A., Cloughesy, T. F., DeGroot, J. F., Galanis, E., Gilbert, M. R., Hegi, M. E., Horbinski, C., Huang, R. Y., Lassman, A. B., Le Rhun, E., … Van Den Bent, M. J. (2020). Glioblastoma in adults: A Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-Oncology, 22(8), 1073–1113. https://doi.org/10.1093/neuonc/noaa106

High Fat Diets Can Change Our Brains

It is painfully aware to us that as technology advances and society modernizes, obesity is becoming a severe epidemic. Why did obesity appear as we became more advanced? It is due to the increased access to a high fat diet. People have more access to low cost, high-fat foods and lower access to healthy, low-fat foods because healthier foods are more expensive. This has resulted in more and more people eating a high fat diet which will cause you to gain weight and fat which can lead to obesity. However, an interesting facet of this high fat diet and the path to obesity is how your brain changes and becomes imbalanced.

First, let us define a high fat diet. You may have heard of “good vs bad” or “healthy vs unhealthy” fats, the medical term is “unsaturated vs saturated” fats. Saturated and unsaturated fats have distinct structures and can perform different functions in the body. For example, saturated fats can stack up like a box of toothpicks and clog up arteries which harms blood flow. To learn more visit this link

In your brain, there is one part of it that controls your hunger and thirst signals. This is the hypothalamus (Figure 1). The hypothalamus is what will get messages from the rest of your organs saying “I don’t have enough energy!” and send signals to your brain telling you to eat; Or the opposite can happen and your body says “I have all the energy I need.” and you will feel satisfied based off of the signals from the hypothalamus. What are these mysterious signals? The brain does not communicate through letters or text messages, the brain communicates chemically and the signals the hypothalamus uses are hormones. The two major hormones to discuss are insulin and leptin. They both end up telling the hypothalamus that no more energy is needed and the body can stop eating. However, in a high fat diet and obesity, these two hormones are not functioning as they should; let’s find out why.

 

Figure 1: Diagram of the brain with the hypothalamus highlighted in blue. The hypothalamus is deep in the central part of the brain.

The saturated fatty acids from a high fat diet can actually cross the blood brain barrier which allows them to enter the brain and accumulate. Unsurprisingly, they accumulate mostly in the hypothalamus where they can block these hormones from reaching their receptors. Why is it bad if insulin and leptin can’t send their messages to the hypothalamus? If insulin and leptin are telling your body to stop eating, but they can’t get the message across, your brain will tell you to keep eating. You are feeling the pangs of hunger, even though your body has enough energy. This can result in overfeeding which leads to obesity. This can be called insensitivity to insulin which is a major part of diabetes; by giving the body more insulin, usually via injection, a bigger insulin signal is formed which means there is a higher chance the insulin signal can be received.

So know that a high fat diet is not only dangerous because of the weight gain and the accumulation of fat in the body, but it can also impact your brain function. Unfortunately, this impact will cause someone to keep overeating which can create a vicious cycle.

 

 

References:

Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. Journal of Clinical Investigation, 127(1), 24–32. https://doi.org/10.1172/JCI88878

Hypothalamus Damage: Causes, Symptoms, and Treatment. (2022, September 8). Flint Rehab. https://www.flintrehab.com/hypothalamus-brain-injury/

Hypothalamus: What It Is, Function, Conditions & Disorders. (n.d.). Cleveland Clinic. Retrieved April 22, 2024, from https://my.clevelandclinic.org/health/body/22566-hypothalamus

Learn the Key Differences Between Saturated and Unsaturated Fats. (n.d.). Verywell Health. Retrieved April 22, 2024, from https://www.verywellhealth.com/difference-between-saturated-fats-and-unsaturated-fats-697517

Temple, N. J. (2022). The Origins of the Obesity Epidemic in the USA–Lessons for Today. Nutrients, 14(20), 4253. https://doi.org/10.3390/nu14204253

The Endocannabinoid System

The endocannabinoid system (ECS) has a lot to do with homeostatic processes within the brain. It controls mood regulation, pain perception, learning, and memory [1]. Much of the research that has been done to understand the role of the ECS in patients with drug dependencies has been with the use of cannabis.

ECS Receptors and Ligands

There are two main types of receptors of the endocannabinoid system, CB1 and CB2. The CB1 receptors are much more abundant, especially in presynaptic and axonal areas. These receptors are known for binding the active ingredient of Cannabis, delta 9-THC, and is responsible for the effects cannabis has on the central nervous system. CB1 receptors can also bind 2-arachidonylglycerol (2-AG) and arachidonylethanolamine (AEA) which are the two main endocannabinoids. Once these receptors are activated the levels of cAMP drop due to the inhibition of adenylyl cyclase. This inhibition stems from not having an agonist present.

The CB2 receptor is far less abundant, being found mostly in cells and tissues of the immune system. This receptor’s expression is usually involved in inflammation but can also play a role in synaptic plasticity and drug abuse. In a mouse model a CB2 receptor agonist led to inhibition of dopaminergic firing and less cocaine self-administration. The functions of the CB2 receptors have a role in Alzheimer’s disease. They have very selective localization and modulate microglia, which are highly associated with Alzheimer’s disease.

The ligands that bind the CB1 and CB2 receptors are known as endocannabinoids (eCBs). These molecules are produced when there is too high of a Ca2+ concentration within the cell. Endocannabinoids mediate feedback inhibition and modulate synaptic plasticity. The production of eCBs lead to a decrease of neurotransmitter release at either excitatory or inhibitory synapses. AEA and 2-AG act as receptor orthosteric agonists. Other allosteric eCBs are being identified and may have some therapeutic benefits by regulating the ECS.

One hypothesis explaining the process of selecting which signaling cascade is activated or inhibited has to do with phosphorylation by GPCR kinases that create targets for beta-arrestins. These targets are called bar-codes. Beta-arrestin signaling from the CB1 receptors can control the activation of different signaling cascades including the ERK pathways, JNK pathways, and the CREB cycle pathways.

Diacylglycerol lipase and phospholipase D produce AEA and 2-AG that can go on to activate the CB1 receptors [1].

Effects of Cannabis

As mentioned earlier, the active ingredient in cannabis, delta 9-THC, is what binds to the CB1 receptors. When humans are exposed to delta 9-THC they experience feelings of relaxation, auditory or visual illusions, pseudo hallucinations, and dissociation. In mice, exposure to delta 9-THC results in antinociception, hypothermia, hypoactivity, and catalepsy [1]. These psychoactive symptoms are due to the fact that delta 9-THC acts as a partial agonist of the CB1 receptor.

There is still an immense amount of research needed to be done on the affects of cannabis and THC on the human brain. Currently, there is only one university that is allowed to partake in cannabis use for research purposes. Knowing more about the harmful and therapeutic effects of cannabis use will be very beneficial for its possible use for medicinal purposes and even recreational purposes.

CNS Diseases

Disorders localized in the central nervous system, specifically Alzheimer’s disease, Huntington’s disease, and multiple sclerosis, can benefit from some therapeutic qualities of cannabis or delta-9 THC. An oromucosal spray known as Sativex can relieve motor dysfunction and pain symptoms in people with multiple sclerosis and help with neuroprotection for people with Huntington’s disease. Synthetic cannabinoids can reduce inflammation and pain.

References

  1. Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294

 

Metabolic Disorder, and Hypothalamic Inflammation

Artstract: healthy foods = healthy brain. 

Obesity is a rising problem for the global population, and can give rise to a variety of other health issues, such as metabolic syndrome and its aftereffects. This rise comes from new eating patterns occurring from a high-fat and calorie dense foods, in combination with physical activity levels, etc. Through different pathways obesity causes changes in metabolism and has been linked to hypothalamic inflammation. And it was found that diet induced brain inflammation leads to uncoupling of food intake and energy expenditure[1].

What is metabolic syndrome?

Metabolic syndrome is an accumulation of several disorders, that togher raise a risk of developing a number of diseases and health conditions such as cardiovascular disease, insulin resistance, and diabetes type 2, additionally developing vascular and neurological complications[2]. It is believed to affect about 25% of adults worldwide[3].

There is various contributors to the development of metabolic syndrome, from genetics, to life style and environmental factors such as overeating and lack of physical activity. The contributors further contribute to mechanisms proposed to play a further role in the development of metabolic syndrome, as well as the progression to subsequent disorders (cardiovascular disease and diabetes type 2), these are insulin resistance, chronic inflammation, and neurohormonal activation[4].

Figure 1: The route of development of metabolic syndrome, to futher progression to diseases[5].

Hypothalamic inflammation

Hypothalamic inflammation has been linked to the development and progression of obesity, and it impacts various mechanisms, such as energy balance, insulin resistance, and alterations in the blood-brain barrier (BBB).

Figure 2: Hypothalamic control of energy homeostasis[6].

The hypothalamus controls a number of functions that incorporate metabolic feedback and that regulates energy homeostasis. Balancing energy intake and energy expenditure is energy homeostasis. This energy homeostasis happens when the body is exposed to an increased energy intake and decreased energy expenditure that causes inhibition of POMC activation and activates AgRP neurons by inhibiting insulin and leptin, which is shown in Figure 1. Insulin and Leptin are important to control your bodies regulation to tell you when you are full, and when they are inhibited that messes with this regulation. The inhibition affects POMC which is a anorexigenic peptide that tells the body to not eat, while the activation of AgRP that is an orexigenic peptide oppositely tells the body to eat. The inflammatory process is a two step process divided into an early inflammatory phase, and a secondary prolonged inflammatory phase that is sustained by the exposure to a high-fat diet (HFD) which leads to the activation of cellular stress mechanisms[7].

Figure 3: The molecular pathway of hypothalamic inflammation[8].

As pictured in Figure 2, the different inhibitors of insulin and leptin pathways, that alterates transcription. JNK from TNFR and PKC from saturated fatty acids (SFA) inhibits the the Insulin (PI3K pathway), and inhibits Akt. That leads FOXO1 to inhibit JAK/STAT signaling, and it activates AgRP and inhibits POMC, which leads us to eat more or keep eating. However, when Akt is active it keeps FOXO1 out of the nucleus.

In the matter of the blood-brain barrier (BBB), there has been found alterations that are involved in the development of hypothalamic inflammation. These alterations concern permeability and disruption of the BBBs integrity, which has been found to be caused by long-term HFD (through VEGF expression in astrocytes and tanycytes in the hypothalamus)[9].

Acute and Chronic Effects

The exposure to HFD has acute effects on the brain, it was found in rodents that already after three days it was found to significantly red ce hypothalamic insulin sensitivity[10]. And was found to upregulate SOCS3 in AgRP neurons, which lead to the effects on previous mentioned mechanisms such as energy imbalance and leptin and insulin resistance. Chronically, inflammatory mediators can give rise to long-lasting impaired metabolic control of the hypothalamus, that leads to apoptosis of neurons and a reduction of synaptic inputs[11].

 


Bibliography 

[1] Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. The Journal of clinical investigation127(1), 24–32. https://doi.org/10.1172/JCI88878

[2] Swarup S, Goyal A, Grigorova Y, et al. Metabolic Syndrome. [Updated 2022 Oct 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459248/

[3] Rojas, M., Chávez-Castillo, M., Pirela, D., Parra, H., Nava, M., Chacín, M., Angarita, L., Añez, R., Salazar, J., Ortiz, R., Durán Agüero, S., Gravini-Donado, M., Bermúdez, V., & Díaz-Camargo, E. (2021). Metabolic Syndrome: Is It Time to Add the Central Nervous System?. Nutrients13(7), 2254. https://doi.org/10.3390/nu13072254

[4] Fahed, G., Aoun, L., Bou Zerdan, M., Allam, S., Bou Zerdan, M., Bouferraa, Y., & Assi, H. I. (2022). Metabolic Syndrome: Updates on Pathophysiology and Management in 2021. International journal of molecular sciences23(2), 786. https://doi.org/10.3390/ijms23020786

[5] Ibid.

[6] Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. The Journal of clinical investigation127(1), 24–32. https://doi.org/10.1172/JCI88878

[7] Ibid.

[8] Ibid.

[9] Ibid.

[10] Ibid.

[11] Ibid.

 

How much is too much THC?

Possible therapeutic effects of cannabis

Psychoactive drugs such as THC and CBD contain synthetic ligands for receptors called CB1 and CB2, which makes them a possible therapeutic approach for central nervous system (CNS) disorders. An article by Kendall et al. explains CB1 receptors as the most abundant GPCRs in the CNS and bind to the main active ingredient of marijuana (2017). Because of this, they play a major role in the endocannabinoid system which is vital for various processes in the brain such as pain, perception, learning, mood, etc. This system can also provide neuroprotection and modulate neuroplasticity and neuroinflammation. THC contains a psychoactive molecule that activates CB1 receptors, which may be neuroprotective and inhibit neuroinflammatory factors, specifically through β-arrestin, a scaffolding protein that carries out various CB receptor signaling pathways (Figure 1). This type of treatment has potential in neurodegenerative diseases such as Huntington’s and Alzheimer’s disease where CB1 expression is reduced, and the endocannabinoid system is altered [1]. However, there are few treatment options available through cannabis, partly because of the risks of overuse and addiction.

Figure 1. β-arrestin signaling pathways [2].

Short term effects of THC

When an individual smokes THC, it passes through the lungs and into the bloodstream where it travels to the brain and other organs in the body. When someone eats or drinks cannabis, however, it is absorbed much more slowly. This spreading of specific molecules throughout the body creates the “high” that people feel due to the activation in the brain where the most CB receptors are (Figure 2). The symptoms include altered senses, sense of time, mood, movement, and more. The individual may also have a raised heart rate for up to three hours after using the drug [3]. Each of these symptoms are organized into a tetrad response with four categories of effects from the CB1 agonists in THC which include (1) Hypolocomotion, a decrease of horizontal activity (2) Hypothermia, decreased body temperature (3) Catalepsy, an impaired ability to initiate movement (4) Analgesia, decreased pain sensitivity [4].

Figure 2. Areas of the brain with an abundance of CB1 receptors [3].

Long term effects of THC

THC contains addictive properties which may lead to cannabis use disorder if used too often. To be diagnosed with this disorder, the patient must meet 2/11 DSM-5 criteria which include the inability to reduce consumption, constant cravings, and relationship and social problems due to using the drug [5]. For those who continuously smoke THC, lung and breathing problems similar to those from tobacco may occur. Moreover, memory and attention deficits, hallucinations, paranoia, and worsened symptoms in individuals with schizophrenia may occur, linking long term use to mental illness. Attention, memory, and problem solving can be altered in children whose mother used THC while pregnant as well. Furthermore, regular vomiting, nausea, and dehydration caused by cannabis use has been termed Cannabinoid Hyperemesis Syndrome [3].

Treatment or dangerous?

Overall, due to the synthetic ligands in THC that bind to CB receptors, this psychoactive drug may be a therapeutic approach for CNS disorders due to these receptors’ roles in neuroprotection, inflammation, and plasticity. However, more research must be done on how to add and dose these specific molecules in useable and safe medications. Moreover, other drugs from cannabis, such as CBD, may be better suited for therapeutic purposes because of its differing effects [1].

References

[1] Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience, 10, 294. https://doi.org/10.3389/fncel.2016.00294

[2] Nogueras-Ortiz, C., & Yudowski, G. A. (2016). The Multiple Waves of Cannabinoid 1 Receptor Signaling. Molecular Pharmacology, 90(5), 620–626. https://doi.org/10.1124/mol.116.104539

[3] Abuse, N. I. on D. (2019, December 24). Cannabis (Marijuana) DrugFacts | National Institute on Drug Abuse (NIDA). https://nida.nih.gov/publications/drugfacts/cannabis-marijuana

[4] Metna-Laurent, M., Mondésir, M., Grel, A., Vallee, M., & Piazza, P.-V. (2017). Cannabinoid-Induced Tetrad in Mice: Cannabinoid-Induced Tetrad. In Current protocols in neuroscience / editorial board, Jacqueline N. Crawley … [Et al.] (Vol. 2017, p. 9.59.1-9.59.10). https://doi.org/10.1002/cpns.31

[5] Cannabis/Marijuana Use Disorder. (n.d.). Yale Medicine. Retrieved April 12, 2024, from https://www.yalemedicine.org/conditions/marijuana-use-disorder

Hypothalamus Inflammation Caused by Diet

Design created by Olivia Tuhy using Magic Media Canva.

 

A high fat diet or high caloric intake can activate inflammatory mediators leading to hypothalamic inflammation. Inflammation of the hypothalamus resulting from obesity can affect brain regions that control energy homeostasis and metabolism. This inflammation impairs the energy expenditure and consumption balance resulting in a negative feedback look of overeating and obesity related insulin resistance and inflammation in the brain. There are specific neuronal populations in the brain that express a large number of receptors that bind hormones to be able to respond to cues indicating if you should take in food or expend energy. Because of a high fat diet and the resulting hypothalamic inflammation, the energy expending/ consuming balance is disrupted.

Normal Energy Homeostasis

After eating, AgRP neurons are inhibited when inulin or leptin levels fluctuate due to consuming energy. This causes the activation of POMC neurons to tell the body to stop eating and expend energy. A protein known as FOXO1 is phosphorylated upon insulin signaling and its repression on POMC gene expression is inhibited [1]. Leptin signaling causes STAT3 phosphorylation which induces POMC expression. Melanocyte signaling hormones are released from POMC and act on neurons in the paraventricular nucleus (PVN) of the hypothalamus to diminish food intake [1].

Energy Homeostasis after Eating High Fat Foods

Studies have shown that a high fat diet sustained for at least 3 days in mice can alter insulin and leptin sensitivity in the hypothalamus in rodents. This causes dysfunction with the exergy consuming/ expending feedback loop. Saturated fatty acids specifically are able to cross the blood brain barrier and accumulate in the hypothalamus, leading to inflammation. A high fat diet can also lead to the activation and accumulation of cytokines, which are proinflammatory proteins.

A high fat diet can also activate microglia, astrocytes, and other cell types within the brain. Activated microglia accumulate in the hypothalamus, contributing to inflammation and the production of inflammatory cytokines. Astrocytes maintain synaptic plasticity and aid in cell survival. Following high fat consumption, astrocytes in the hypothalamus release inflammatory signals, also contributing to hypothalamic inflammation. The blood brain barrier can be affected by hypothalamic inflammation due to the decrease in production of tight junction proteins following prolonged exposure to high fat foods. Tanycytes are another cell type that lead to hypothalamic inflammation [1]. They are glial cells that respond to leptin.

TLR4 can be inhibited by pharmacological intervention causing an inhibition of fatty acid induced leptin and insulin resistance. The TLR4 pathway also activates other pathways like the MAPK pathway, triggering the inhibition of insulin action. Another result of high fat diets is the inhibition of the PI3K pathway. Certain downstream affects lead to ER stress and unfolded protein response causing insulin and leptin resistance.

Normal metabolic homeostasis vs obesity and metabolic syndrome homeostasis [1].

Conclusion

There are a lot of issues that arise from consuming high fat foods including a disruption in the energy expending/ consuming signaling balance and cognitive impairments. Exercises that increase heart rate like running or swimming have reverse effects on hypothalamic inflammation. Being conscious of the food you are eating and being careful of consuming too much fat is a good way to manage hypothalamic inflammation, although it can be hard to truly understand what is in the foods we eat.

References

  1. Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. Journal of Clinical Investigation, 127(1), 24–32. https://doi.org/10.1172/JCI88878

High-fat Diets Do More Than Cause Weight Gain

Metabolic Syndrome and Obesity

Metabolic Syndrome encompasses several risk factors for heart disease and type 2 diabetes, including high blood pressure, impaired fasting glucose, and obesity. Obesity causes a state of inflammation in the body but can also affect brain regions that regulate energy homeostasis and metabolism. Genetic mutations underlying the development of obesity are almost exclusively found in brain regions that regulate food intake.

Figure 1. Metabolic syndrome and obesity (3).

Melanocortin System

The melanocortin system in the brain is important for the regulation of food intake and energy expenditure (balance), responding to metabolic cues. It operates through the balance between 2 types of neurons: AgRP (orexigenic) and POMC (anorexigenic). When functioning normally, insulin and leptin work in the hypothalamus’s arcuate nucleus (ARC) to activate AgRP neurons when we need to eat and POMC neurons (a-MSH) when we’re full and need to stop eating. AgRP and a-MSH bind to melanocortin receptors (MC4R) in the paraventricular nucleus (PVN) hypothalamic brain region. When inflammation disrupts the melanocortin system, often seen in conditions like obesity and metabolic syndrome, it can disrupt the signals that tell us when to eat and when to stop, leading to overeating and an energy imbalance.

Figure 2. Hypothalamic control of energy homeostasis through the melanocortin system (1).

High-Fat Diets (HFD)

High-fat diets come from the consumption of calorie-dense, high-fat, and high-carbohydrate foods that promote overconsumption and metabolic dysregulation. A high-fat diet elevates the activation of key inflammatory mediators in the hypothalamic pathway like JNK and IKK. The acute effects of HFD feeding are the rapid changes that occur in response to dietary changes. Starting within 3 days, insulin sensitivity in the hypothalamus can decrease, leading to insulin resistance.

Long-chain saturated fatty acids (SFAs) cause resistance to insulin and leptin hormones in how they cross the blood-brain barrier and activate inflammatory pathways (TLR4) that further inhibit insulin and leptin signaling. Apart from TLR4 signaling, the IKK complex keeps NF-kB bound and inactive. When TLR4 becomes active, the IKK and NF-kB separate, and NK-kB becomes active. This activates MAPK signaling and JNK enzymes that inhibit the insulin receptor substrate (IRS) and leads to insulin signaling being inhibited.

Figure 3. High-fat diets can change your body’s energy balance in a matter of 3 days (4).

Hypothalamic Inflammation

Hypothalamic inflammation from HFD is critical in the development of insulin and leptin resistance, disrupting the body’s ability to regulate glucose metabolism and appetite. As a result, individuals may experience increased food intake, weight gain, and reduced glucose metabolism, contributing to the development of obesity and metabolic dysfunction.

HFD-induced inflammation in the hypothalamus leads to insulin and leptin resistance, eventually causing an imbalance in energy homeostasis (uncoupling of food intake and energy expenditure).

Figure 4. Insulin and leptin resistance in the hypothalamus from HFDs (2).

Microglia and astrocytes are specialized cells in the brain but also contribute to hypothalamic inflammation. Prolonged HFD consumption leads to the accumulation of activated microglia and astrocytes, which produce pro-inflammatory cytokines (TNF-a, IL-6, etc.).

Leaky BBB

Inflammation in the hypothalamus can affect the blood-brain barrier, increasing its permeability. Hypothalamic inflammation triggers the release of pro-inflammatory cytokines and activates glial cells which disrupt the tight junctions between endothelial cells that form and maintain the BBB, leading to increased permeability. This “leak” allows inflammatory mediators to enter the brain, increasing the risk for metabolic dysfunction.

Understanding the neurochemistry of metabolic syndrome, particularly the role of hypothalamic inflammation, offers insights into potential therapeutic targets for addressing obesity, insulin resistance, and related metabolic disorders. By unraveling the complexities of these pathways, researchers aim to develop strategies that restore energy balance and improve metabolic health.

ARTstract created by Kate Loidolt on Canva depicts the pressures of HFDs in today’s society when junk food is everywhere, cheaper, and faster.

 

References

[1]  A. Jais and J. C. Brüning, “Hypothalamic inflammation in obesity and metabolic disease,” Journal of Clinical Investigation, vol. 127, no. 1, pp. 24–32, Jan. 2017, doi: 10.1172/JCI88878.
[2] B. Russo, M. Menduni, P. Borboni, F. Picconi, and S. Frontoni, “Autonomic Nervous System in Obesity and Insulin-Resistance—The Complex Interplay between Leptin and Central Nervous System,” International Journal of Molecular Sciences, vol. 22, no. 10, Art. no. 10, Jan. 2021, doi: 10.3390/ijms22105187.
[3]  “Obesity and Metabolic Syndrome – Best Hospital in Salem | Multi Speciality Hospital in Salem | Shanmuga Hospital.” Accessed: Apr. 13, 2024. [Online]. Available: https://shanmugahospital.com/obesity-and-metabolic-syndrome/
[4]  R. Ullah, N. Rauf, G. Nabi, S. Yi, Z. Yu-Dong, and J. Fu, “Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus,” Biomedicine & Pharmacotherapy, vol. 142, p. 112012, Oct. 2021, doi: 10.1016/j.biopha.2021.112012.

How Does a High Fat Diet Correlate with Hypothalamic Inflammation?

How the body controls and regulates healthy eating 

There are two primary neurons that send signals to our brain to either start eating or stop eating, which maintains metabolic homeostasis in the body. An article by Jais and Brüning states that AgRP neurons are considered orexigenic neurons which stimulate appetite, whereas POMC neurons are anorexigenic neurons that inhibit appetite through hormones like insulin and leptin (2017). These neurons receive signals in the arcuate nucleus (ARC) of the hypothalamus followed by binding to other neurons in the paraventricular nucleus of the hypothalamus. These processes and signaling pathways generally regulate energy homeostasis and cues for food intake. However, different diets and foods may alter this process, specifically through insulin and leptin resistance [1].

Insulin and leptin resistance occurs when an individual obtains too many nutrients or too many of a specific nutrient and their receptors no longer function correctly due to the blockage of their receptors from proteins like SOCS. This, along with inflammatory responses due to the foods that often taste good and are high in fat negatively regulate insulin, leptin, and inflammation, causing less synapses and even apoptosis of AgRP and POMC neurons. This cascade of events in the brain diminishes the cue of being full and to stop eating, leading to obesity and metabolic syndrome. One diet that may contribute is a high fat diet (HFD). [1]

What is a high fat diet?

HFD is defined by the ratio of macro-nutrients consumed which are fats, carbohydrates, and protein. To be high fat, fat must take up 40-45% of the daily caloric intake as 20-40% is considered moderate [2]. There are, however, healthy fats and high fatty foods and unhealthy fats as portrayed in figure 1. Moreover, some fats help maintain the brains function because of its high energy intake. As such, healthy fats may help absorb vitamins like vitamin A, D, and E, which are fat soluble instead of water soluble [3].

Figure 1. Healthy fatty foods compared to bad fatty foods [4].

Healthy vs unhealthy fats

Unsaturated fats are typically considered the “healthy” fats which can either be monounsaturated or polyunsaturated (Figure 2). Foods of this sort consist of avocado, olives, some nuts and seeds, fish, and dark chocolate. On the other hand, saturated fats and trans fats are unhealthy if consumed too much. These mostly come from animal sources and some plant sources and include fatty meat, butter, cheese, cream, and more. Due to the composition of saturated fats, the body cannot break them down as easily causing blockages and harm to enzymes [5].

Figure 2. What healthy fats are compared to unhealthy fats [5].

Conclusion of the effects of HFD on hypothalamic inflammation and eating habits

Many stress response pathways such as pro-inflammatory pathways in the hypothalamus are activated by HFD which leads to insulin and leptin resistance due to inflammatory mediators like cytokines. These changes can take place as early as 24 hours after eating or over longer periods of time leading to more chronic effects like altered synaptic plasticity. Altogether, the inflammation in the brain from a HFD contributes to the uncoupling of food intake and energy expenditure, furthering obesity and metabolic syndrome (Figure 3) [1].

Figure 3. The uncoupling of food intake and energy expenditure.

Fig. 3. Artstract created by M. Olson

References

[1] Jais, A., & Brüning, J. C. (n.d.). Hypothalamic inflammation in obesity and metabolic disease. The Journal of Clinical Investigation, 127(1), 24–32. https://doi.org/10.1172/JCI88878

[2] David, M. (2014, February 27). What is a High-Fat Diet: Is it Healthy and Safe? Institute for the Psychology of Eating. https://psychologyofeating.com/high-fat-diet-healthy-safe/

[3] What Are Healthy Fats? 8 High-Fat Foods for Your Diet. (n.d.). Verywell Health. Retrieved April 7, 2024, from https://www.verywellhealth.com/healthy-fats-7498653

[4] Admin. (2022, June 1). Four Myths About Eating Fats. YMCA. https://lafayettefamilyymca.org/myths-about-eating-fats-2/

[5] Facts about fat. (2022, February 23). Nhs.Uk. https://www.nhs.uk/live-well/eat-well/food-types/different-fats-nutrition/

Metabolic syndrome and Obesity 101

Metabolic syndrome and obesity have become pressing health concerns worldwide, affecting millions of individuals across all age groups. Even Though these conditions are interpreted to be more like personal health matters, their impact extends far beyond individual lives. Metabolic syndrome and obesity pose significant challenges to public health systems, communities and individual lives. Therefore, understanding and addressing these issues is crucial for everyone.

Figure 1. What is Metabolic syndrome?

 

 

 

What should the public know about metabolic syndrome and obesity?

Firstly, these conditions are closely linked to a multitude of serious health problems. High blood pressure, elevated blood sugar levels, abnormal cholesterol levels, and excess abdominal fat are all risk factors associated with Metabolic syndrome[1]. These factors can significantly increase the risk of developing other chronic diseases such as type 2 diabetes, heart disease and even certain types of cancer[2]. Obesity, often a component of metabolic syndrome, can further worsen these risks, leading to a higher likelihood of premature death and decreased quality of life.

In the article “Hypothalamic inflammation in obesity and metabolic disease”, by Alexander Jais  and Jens C. Brüning, they discuss the role and relationship that hypothalamic inflammation has to do with metabolic disease and obesity. The authors discuss how chronic overnutrition, characterized by excessive intake of high-calorie, high-fat diets, triggers a state of low-grade inflammation in the hypothalamus[3]. This inflammatory response involves the activation of resident immune cells such as microglia and the infiltration of peripheral immune cells into the brain. These immune cells release pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which disrupt normal hypothalamic neuronal function, and instigate inflammation in the hypothalamus[3].

One critical consequence of hypothalamic inflammation is the development of leptin and insulin resistance. Leptin and insulin are key hormones that signal satiety and regulate energy balance. However, in the context of obesity and hypothalamic inflammation, the responsiveness of hypothalamic neurons to these hormones is impaired, leading to a failure to suppress appetite and promote energy expenditure effectively[3].

 

Figure 2. Metabolic homeostasis

 

Why should the public care about metabolic syndrome and obesity?

 

Beyond individual health, the implications that metabolic syndrome and obesity have on society and the economy are extensive. The burden on healthcare systems is immense, with billions of dollars spent annually on medical treatments, medications, and interventions related to these conditions[4]. Additionally, metabolic syndrome and obesity disproportionately affect marginalized communities and contribute to health disparities. Factors such as socioeconomic status and access to healthcare play significant roles in the prevalence and management of these conditions. Addressing these disparities requires collective action and societal awareness[5].

Despite these challenges, there is hope in ongoing research and interventions aimed at combating metabolic syndrome and obesity. Scientists are continually uncovering new insights into the complex biological mechanisms underlying these conditions. From understanding the role of genetics and hormones, to exploring the influence of gut microbiota and environmental factors, research is helping us to develop innovative prevention and treatment strategies[6].

It’s important for the public to recognize that metabolic syndrome and obesity are not simply personal issues but rather societal challenges that require collective action. Whether it’s making healthier food choices, engaging in regular physical activity, or supporting policies that prioritize public health, everyone has a role to play in tackling these issues.

Figure 3. Artstract by E.Phiri

 

References

 

Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. The Journal of Clinical Investigation, 127(1), 24-32.

National Heart, Lung, and Blood Institute. (n.d.). Metabolic syndrome. Retrieved from https://www.nhlbi.nih.gov/health-topics/metabolic-syndrome

World Health Organization. (2021). Obesity and overweight. Retrieved from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

Centers for Disease Control and Prevention. (2021). Adult obesity facts. Retrieved from https://www.cdc.gov/obesity/data/adult.html

World Health Organization. (2016). Obesity and overweight. Retrieved from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

United States Department of Agriculture. (n.d.). Economic costs of obesity. Retrieved from https://www.ers.usda.gov/webdocs/publications/94849/err270_summary.pdf?v=9633.4

Reilly, J. J., & Kelly, J. (2011). Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: Systematic review. International Journal of Obesity, 35(7), 891-898.

Gloy, V. L., Briel, M., Bhatt, D. L., Kashyap, S. R., Schauer, P. R., Mingrone, G., & Bucher, H. C. (2013). Bariatric surgery versus non-surgical treatment for obesity: A systematic review and meta-analysis of randomised controlled trials. BMJ, 347, f5934.

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