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].



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

[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:

[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.

[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.

[5] Ibid.

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

[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].


[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.

[2] Nogueras-Ortiz, C., & Yudowski, G. A. (2016). The Multiple Waves of Cannabinoid 1 Receptor Signaling. Molecular Pharmacology, 90(5), 620–626.

[3] Abuse, N. I. on D. (2019, December 24). Cannabis (Marijuana) DrugFacts | National Institute on Drug Abuse (NIDA).

[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).

[5] Cannabis/Marijuana Use Disorder. (n.d.). Yale Medicine. Retrieved April 12, 2024, from

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].


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.


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

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.



[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:
[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


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

[2] David, M. (2014, February 27). What is a High-Fat Diet: Is it Healthy and Safe? Institute for the Psychology of Eating.

[3] What Are Healthy Fats? 8 High-Fat Foods for Your Diet. (n.d.). Verywell Health. Retrieved April 7, 2024, from

[4] Admin. (2022, June 1). Four Myths About Eating Fats. YMCA.

[5] Facts about fat. (2022, February 23). Nhs.Uk.

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




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

World Health Organization. (2021). Obesity and overweight. Retrieved from

Centers for Disease Control and Prevention. (2021). Adult obesity facts. Retrieved from

World Health Organization. (2016). Obesity and overweight. Retrieved from

United States Department of Agriculture. (n.d.). Economic costs of obesity. Retrieved from

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.

The Impact of Concussions on the Brain

Picture 1: Impact to the brain[1].  

Concussion or mild traumatic brain injury(mTBI) is something that is prevalent, especially within sports, and something quite a lot of people experience in their lifetime. Recently, there has been an increase in the interest in researching the biological bases of concussions, and with more advanced neuroimaging it allows to look at the pathophysiology post-injury.

Definition of concussion/mild TBI:

The hallmarks of concussion or mTBI can be defined by having impaired neurobiological signs and symptoms after having biomechanical force to the brain. Described as a neurometabolic cascade of events, these involve bioenergetic challenges, cytoskeletal and axonal alterations, impairments in neurotransmission, vulnerability to delayed cell death and chronic dysfunction. It was found in adult animals that the impaired metabollism that comes post-injury can last up from 7 to 10 days, and was additionally found to be associated with behavioral impairments in spatial learning[2].

Symptoms and signs of concussion: [3]

Artstract: Typical symptoms and signs of concussions illustrated.

The acute pathophysiology: 

There are a various acute neurometabolic changes that occur in the brain after a concussion and has been described as a neurometabolic cascade of events. This cascade involves bioenergetic challenges, axonal and cytoskeletal alternations, neurotransmission impairments, vulnerability to delayed cell death and chronic dysfunction[4].

As illustrated in Figure 1 an ionic flux and hyper acute indiscriminate glutamate release happens as a result of the biochemical injury. In an effort to restore the ionic and homeostasis, the membrane ionic pumps that are APR causing hyperglycolysis (overdrive). This created relative depilation of intracellular energy reserves, and also increases levels of ADP. The intra-axonal calcium flux can result in loss of structural integrity in axons and cause cytoskeletal damage as neurofilaments side-arms can be phosphorylated and collapse. Further the damages to the neurofilaments and additionally microtubules lead to axonal dysfunction and is potential for disconnection. Lastly, an alteration in glutamate, NMDA, receptor subunit composition and function can be found after a concussion, this alters neurotransmission. This alteration interferes with normal developmental plasticity, electrophysiology, and memory[5].

Figure 1: The acute cellular biological processes that occur after a concussion or a mTBI[6].

The various activations and infiltrations of the microglia was found to cause inflammatory changes in the brain. After a TBI there is an extensive upregulation of cytokine and inflammatory genes. While for cell death, mTBI generally show little cell death, but with the impact of repeated mTBI may cause functional impairments, and there may be longer-term structural changes[7].

As for the repeated concussive injuries since the intracellular redox state is altered in the concussed brain if it`s hit with another impact it puts additional stress on the damaged free radicals and shifted metabolic pathways. That can trigger impairments that are longer lasting and is why the brain is more vulnerable to repeated injury[8].

Age differences with susceptibility and severity:

The young brain concusses more easily than the adult brain and can often have worse prognosis for the outcomes after the injury[9]. mTBI has demonstrated damage to white matter and have been associated with cognitive impairments. The injury disturbs growth and development in the brain. It was found in 2017, that TBI is the leading cause of death and disability in children[10]. As for adults over the age of 65, they were found to be four times more likely to have a negative outcome from a mTBI[11]. Additionally, there might be a gender difference in susceptibility for concussion, where females are more susceptible than males.


[1] What to do if someone is showing concussion symptoms. (2022, July 25). Livi.

[2] Giza, C. C., & Hovda, D. A. (2014). The new neurometabolic cascade of concussion. Neurosurgery75 Suppl 4(0 4), S24–S33.

[3] Concussion; Symptoms and causes. Mayo Clinic. (2024, January 12). Mayo Clinic.

[4] Giza, C. C., & Hovda, D. A. (2014). The new neurometabolic cascade of concussion. Neurosurgery75 Suppl 4(0 4), S24–S33.

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Tator C. H. (2013). Concussions and their consequences: current diagnosis, management and prevention. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne185(11), 975–979.

[10] Araki, T., Yokota, H., & Morita, A. (2017). Pediatric Traumatic Brain Injury: Characteristic Features, Diagnosis, and Management. Neurologia medico-chirurgica57(2), 82–93.

[11] Lele A. V. (2022). Traumatic Brain Injury in Different Age Groups. Journal of clinical medicine11(22), 6739.

Importance of research on mental illness

Mental illness remains a serious challenge in our society, affecting millions of individuals worldwide. From depression and anxiety to schizophrenia and bipolar disorder, the spectrum of mental health conditions is vast and multidimensional. In recent years the public has become increasingly aware of mental health issues, but there is still much to be done to fully understand, support, and treat those affected. Exploring and understanding mental illness research not only sheds light on how complex our human minds can be, but also holds promise for innovative treatments and interventions.[1]




There are several reasons why the public should care about this topic but the main one is the effect that mental illness has on individuals, families, and communities[1] . Mental illness has no boundaries and it can affect people of all ages, backgrounds, and socioeconomic statuses. It can hinder personal relationships, impair work or academic performance, and in severe cases, lead to tragic outcomes such as suicide. By addressing mental health issues, not only do we help individuals suffering from these illnesses, but also cultivate a more compassionate and mindful society [2].

There is a lot of research being done to understand the biological, psychological, and social factors underlying mental illness. One interesting area of study revolves around the role of signaling pathways in mental health disorders. Signaling pathways are intricate networks of cellular communication that regulate various physiological processes in the brain[3]. Dysregulation of these pathways has been implicated in numerous psychiatric conditions. Studies have highlighted the involvement of the dopamine signaling pathway in schizophrenia, a complex disorder characterized by hallucinations, delusions, and cognitive deficits[3]. Abnormalities in dopamine transmission can disrupt neuronal circuits involved in perception, cognition, and emotion regulation, contributing to the manifestation of psychotic symptoms.

An important biochemical involved in mental illness is GSK-3. GSK-3 is a key enzyme involved in various cellular processes, including neurodevelopment, synaptic plasticity, and neurotransmitter signaling[4]. Dysregulation of GSK-3 activity has been implicated in schizophrenia pathology. GSK-3 dysregulation may contribute to aberrant neurotransmitter signaling, disrupted synaptic function, and impaired neuronal survival, all of which are implicated in schizophrenia pathogenesis[5].


Similarly, dysfunctions in the serotonin signaling pathway have been linked to depression and anxiety disorders. Serotonin, which is popularly known as the “feel-good” neurotransmitter, plays a crucial role in mood regulation, sleep-wake cycles, and stress response. Alterations in serotonin levels or receptor function can disrupt emotional equilibrium, leading to persistent feelings of sadness, worry, or fear[3].

Understanding these signaling pathways not only broadens our perspective of mental illness but also leads to exciting areas for future research. Researchers are exploring pharmacological agents that can modulate specific neurotransmitter systems with the aim of restoring balance and alleviating symptoms[1]. Additionally, advancements in neuroimaging techniques allow scientists to visualize brain activity and connectivity patterns associated with different psychiatric disorders, facilitating early diagnosis and personalized treatment approaches[2].

In conclusion, mental illness research is a rapidly evolving field with profound implications for public health and well-being. By supporting scientific research, advocating for mental health awareness, and fostering empathy and understanding, we can all contribute in addressing the challenges caused by mental illness and help create a more compassionate future.


Insel, T. R. (2008). Assessing the economic costs of serious mental illness. American Journal of Psychiatry, 165(6), 663-665.

Nestler, E. J., Hyman, S. E., & Malenka, R. C. (Eds.). (2015). Molecular neuropharmacology: A foundation for clinical neuroscience (3rd ed.). McGraw-Hill Education.

Kalkman, H. O., & Loetscher, E. (2003). GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. Journal of Neural Transmission, 110(7), 803-812.

Singh KK. An emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clin Genet 2013: 83: 511–517. © John Wiley & Sons A/S. Published by Blackwell Publishing Ltd, 2013

De Filippis, R., & Wagner, G. K. (2014). Targeting glycogen synthase kinase-3 in the treatment of schizophrenia. The Current Medicinal Chemistry, 21(3), 329-344.


FRAGILE! Your Brain Needs Time to Repair Itself

Artstract made in Canva

Concussions are well understood by some, usually those who have had a concussion or been in concussion prone settings like sports, but not understood by many [1]. Athletes and their parents probably are aware of the symptoms and signs of concussions, but another aspect is how the concussion impacts the brain (no pun intended). Concussions directly result from an injury to the head which then affects the brain. However, is the brain bruised? Fractured? Sprained? It can be quite unclear how the brain is exactly hurt after a concussion. 

In medical terms, a concussion is called a mild traumatic brain injury (TBI); however, don’t confuse their meaning with mild [2]. Mild in this case means non-life threatening. [2]. In their effort to increase concussion awareness, the CDC (center for disease control) has created this video to explain what a concussion is [2]. The head receives some type of trauma that causes the sudden movement of the brain back and forth inside the skull [2]. I mentioned sports earlier, because contact sports like football, soccer, hockey, etc. are the places that people and kids are most likely to get a concussion [1]. 


The next question is:

What happens to your brain after a concussion?

A neuroscience article by Doctors Giza and Hovda, provides insight into how the brain reacts to a concussion on the cellular level [1].

One of the first things after your brain rattles, is an ionic flux, which means all the ions flow rapidly into the brain cells. An ion is a small atom with a charge, and the most common one in the brain is the calcium ion also shown as Ca²+ [3]. Ions are key to making the brain work regularly, but like an overfilled balloon, the brain cells can stretch and burst if there are too many ions (air) in the cell (balloon). The medical term for this swelling is called cerebral edema [2].


In addition to swelling, the ions that flow into the cell will flow into the mitochondria, “the powerhouse of the cell” [1]. This puts stress on the mitochondria. Since the mitochondria is the power source for the cell, if it’s not functioning properly due to stress, the whole cell cannot function properly; this can result in an energy crisis [1].

Your body tries to handle this energy crisis by going into hyperglycolysis. Hyper = more than normal, and glycolysis is how your body consumes glucose (sugar and carbohydrates) that you get from your diet. So your body is trying to use all of its energy to solve this mitochondria stress situation in the brain. This initial period of hyperglycolysis is followed by hypoglycolysis wish is essentially the opposite. Your body isn’t processing food into energy as much as it should. This lessened glucose consumption happens for 7-10 days in adults [1]. 

What I have pointed out about ionic flux and the energy crisis can be seen in this figure from the article by Giza and Hovda. I would like to emphasize the movement of Ca²+ into the cell and then towards that mitochondria labeled Mito in the figure.


In addition to ions not moving correctly, and the body not consuming energy normally, there can be serious structural damage. The most common place for these injuries in brain cells is the axon. In the diagram below you can see that the axon is this long thin section of the brain cell. This thin structure makes it really sensitive to the jostling and rattling the brain experiences in a concussion. However, when an axon is damaged the brain can’t send signals properly; this is when you get the symptoms of confusion and memory loss in concussions. Luckily, axons can be repaired after damage, but it takes time like all construction and repairs [1].


These are three of the major occurrences at the cellular level in the brain after a concussion. Your brain is doing these changes in ions, glucose consumption, and axon repair in order to try and heal. The brain is trying to get things back in working order, but, like in all injuries, healing takes time. I am hoping that this discussion of things on a small scale can help you to understand how a concussion works and why healing is so important after a concussion.


[1] Giza, C. C., & Hovda, D. A. (2014). The new neurometabolic cascade of concussion.
Neurosurgery, 75 Suppl 4(0 4), S24-33.
[2]  What Is a Concussion? | HEADS UP | CDC Injury Center. (2023, April 28).
[3]  ION | definition in the Cambridge English Dictionary. (n.d.). Retrieved April 4, 2024, from
[4]  Unsplash. (2020, September 9). Photo by Avinash Kumar on Unsplash.
[5]  Hedges, V. (2022). Cells of the Nervous System: The Neuron.

Protect Your Head: Discussion on Concussions

Traumatic Brain Injuries

Concussions are brain injuries that happen when your head is hit and can affect the way the brain works. Symptoms include headaches, hypersensitivity, and problems with learning and sleep. Most concussions in kids happen while playing sports, but they can also happen in a car accident, a fight, or a fall. In the medical world, concussions are known as mild traumatic brain injuries (mTBIs) and while they may be labeled as “mild,” the effects are anything but, making it an important topic for the public to take seriously. Concussions are being looked at with increasing concern for long-term impairment caused by chronic altered neurotransmission, an energy crisis, and axonal dysfunction.

Figure 1. An interesting article titled “A Gray Matter” by the NCAA regarding concussions in athletes (2).

To understand the symptoms, let’s take a closer look at the neurochemical events that occur right after a concussion. Functionally, concussions cause ionic shifts, hypometabolism, and impaired neurotransmission. These changes cause a neurometabolic cascade, leading to acute responses and chronic dysfunction.

Figure 2. The neurometabolic cascade that occurs following a concussion highlights the simultaneous impact of ionic flux, the energy crisis, and axonal injury on neurotransmission (1).

Altered Neurotransmission

When the injury occurs, the membrane gets leaky, and too much calcium ions come into the cell which causes an imbalance. The neurotransmitter glutamate also gets released in excess, this triggers the cell to depolarize and diffuse a “spreading depression-like” state. The way ionic flux contributes to migraine symptoms of concussions is in the hyperacute release of glutamate which can lead to excitotoxicity. Changes in NMDA receptor activity and excitatory/inhibitory imbalances cause altered neurotransmission post-concussion.

In the immature brain, metabolic changes are short-term, but axonal vulnerability may last longer. TBIs to immature brains are more vulnerable to long-lasting deficits in learning and memory because of the loss of experience-dependent plasticity.

Energy Crisis

Simultaneously in an effort to restore the ionic imbalance and return to homeostasis, an energy crisis occurs as the ATP-driven sodium/potassium ion pump becomes overactive. This causes hyperglycolysis, which is when there is an increase in glucose levels to support reduced blood flow and brain function (or healing in the case of concussions), and depleted intracellular energy (ATP) reserves. This shortage of ATP causes hypometabolism.

Because there is an increase in calcium coming into the cell, the mitochondria takes up excess as a short-term solution. The amount of calcium being taken into the cell for extended periods leads to mitochondrial dysfunctions and problems with oxidative metabolism.

Energy Crisis and Vulnerability to a Second Injury

The risk of a second concussion is the greatest in the first 10 days postinjury because of the ongoing energy crisis trying to heal your brain. The timing of repeat injuries has significant consequences on symptomology and long-term impacts as well.

Figure 3. The Energy Crisis is why the brain is so vulnerable to a second TBI injury (3).

Axonal Dysfunction

The force of the concussion also results in damage to microstructural components of neurons, like the axons and dendrites. The biomechanical stretch of axons disrupts microtubules, and the calcium influx causes neurofilaments to collapse, compromising axonal integrity and impairing neurotransmission. Axonal dysfunction in mTBIs often results in damage to white matter tracts, which are bundles of axons that connect different brain regions. While mTBIs are considered “mild,” the cumulative effects of repeated axonal dysfunction can have long-term consequences, especially in immature brains.

The impaired cognitive functioning and slowed reaction times observed in individuals with concussions could be from slower conductance, damage to cerebral networks, or impaired neurotransmission. One aspect that needs to be studied further is whether damaged axons can recover fully and if neurons can survive after axonal disconnection. This issue is particularly problematic in cases of repeat mTBIs where insufficient time for recovery between injuries, immature myelination, or genetic vulnerabilities may increase the risk of long-term effects.

Figure 4. The different types of axonal injuries that are experienced post-concussion (4).

Chronic Dysfunction: A Lingering Impact

The occurrence of repeat mTBIs before your brain is fully recovered can cause long-lasting metabolic changes because chronic energy crises trigger protease activation and cell death, leading to brain atrophy. Altered protein degradation after mTBIs can lead to the accumulation of toxic proteins like tau. 

I Have a Concussion… What Now?

Rest and let your brain heal!

ARTstract created by Kate Loidolt on canvas depicting the pressure of returning to sports after a concussion.



[1]  C. C. Giza and D. A. Hovda, “The New Neurometabolic Cascade of Concussion,” Neurosurgery, vol. 75, no. 0 4, pp. S24–S33, Oct. 2014, doi: 10.1227/NEU.0000000000000505.
[2]  “A Gray Matter,” Accessed: Apr. 03, 2024. [Online]. Available:
[3]  “Brain changes during a concussion. Concussion clinic. Belfast. SMNI.,” Sports Medicine. Accessed: Apr. 03, 2024. [Online]. Available:
[4]  E. G. Psy.D, “Neuropsychological Evaluation of Traumatic Brain Injury: The Definitive Guide,” Verdugo Psychological Associates. Accessed: Apr. 03, 2024. [Online]. Available:

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