Alzheimers Image by Z
The Cycle of Obesity
Obesity
Obesity is an extremely dangerous and costly condition affecting 41.9% of US adults and 19.7% of US children and adolescents. This is not just as issue in the US; obesity also affects 650 million adults worldwide [1]. These statistics are alarming, but even more concerning is the fact that these numbers are expected to increase significantly in the coming years. How is it possible that so many people are being affected by this condition? Aside from obvious genetic, epigenetic, and environmental influences, the key stimulus that kickstarts the metabolic changes associated with obesity is overnutrition which leads to altered chemical signaling within the body [2].
Food intake affects and is affected by two sets of neural pathways (Figure 1) within the melanocortin system of the hypothalamus. These two pathways lead to behavioral expressions of energy expenditure and caloric intake with the goal of maintaining nutritional homeostasis. The agouti-related peptide (AGRP) pathway is orexigenic, meaning it induces feeding, and it works antagonistically to the anorexigenic proopiomelanocortin (POMC) pathway which restricts feeding behaviors. Insulin and leptin are hormones that are released following food intake to inhibit AgRP neurons and activate POMC neurons. This sends neural signals to decrease food intake while increasing energy expenditure to limit overnutrition. When insulin and leptin are no longer present in the receptors, feeding behavior will be triggered and energy expenditure should decrease. [2].
Signaling Dysruption
Insulin and leptin signaling dysregulation are one of the first changes that occur in the development of metabolic syndrome and obesity. Just three days of feeding on a high fat diet can significantly reduce hypothalamic insulin sensitivity. This occurs when the insulin receptors are receiving too much input. When there are too many signaling molecules trying to bind to receptors, the receptors become desensitized to the constant stimulation of insulin. When insulin sensitivity is reduced, anorexigenic signals are not able to be properly sent to the brainstem (Figure 1). This not only induces more feeding behavior leading to body weight gain, but also leads to a state of hyperinsulinemia which produces other negative effects [2,3].
High fat diets also affect other signaling pathways in the hypothalamus. Proinflammatory gene expression in the hypothalamus occurs via the IKK complex and NF-kB activation. High fat diets also can impair insulin action by phosphorylating and inhibiting the insulin receptor substrate proteins at serine 307. This is another mechanism that promotes activation of the AgRP neurons (Figure 1) which induces over-eating behaviors [2].
The Cycle
Although there are many different mechanistic explanations for the changes we see in hypothalamic signaling, they all come from the same stimulus and produce similar behavioral and physiological responses. High fat diets are the impetus for each of these metabolic alterations, and each of these alterations produce negative effects of insulin/leptin resistance, increased food consumptions, inflammation, and eventual weight gain. When a high fat diet is consumed regularly, both the acute and long-term effects perpetuate the same behaviors – over fueling and under activity.
The inflammation associated with obesity specifically affects the brain structures involved in reward and feeding behaviors. Because of this, the reward pathways in the brain seek out more highly-palatable high fat foods, further perpetuating this cycle. Inflammation also affects peripheral tissues and organs within the body leading to negative effects in other body systems.
Conclusion
Through all of the signaling, chemical, metabolic, and behavioral changes that occur with obesity, the most important thing to understand is that they are all connected. Once the cycle of obesity is initiated, it continues to perpetuate itself through all of the mechanisms discussed above. This process is usually initiated by dietary choices and often is not stopped unless deliberate action is taken. The first step in ending the cycle of obesity is bringing awareness to the problem and educating about how and why this is occurring.
References:
(1) Emily Laurence. Obesity Statistics And Facts In 2024. Forbes Health. https://www.forbes.com/health/weight-loss/obesity-statistics/.
(2) Jais, A.; Brüning, J. C. Hypothalamic Inflammation in Obesity and Metabolic Disease. Journal of Clinical Investigation 2017, 127 (1), 24–32. https://doi.org/10.1172/JCI88878.
(3) Hyperinsulinemia. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/24178-hyperinsulinemia.
Obesity, Metabolic Diseases, and Diet Across The Planet
A. Obesity and metabolic diseases
Obesity and metabolic diseases such as type 2 diabetes are major public health challenges worldwide, characterized by chronic low-grade inflammation and dysregulated energy homeostasis. The hypothalamus, a key brain region involved in the regulation of appetite, energy expenditure, and glucose metabolism, has recently emerged as a critical site of inflammation in the context of metabolic dysfunction.
B. The Paper
Hypothalamic Inflammation in Obesity and Metabolic Disease explores the role of hypothalamic inflammation in the pathogenesis of obesity and metabolic disorders. The paper focuses on the complex interplay between metabolic dysregulation, immune responses, and neural circuits within the hypothalamus, shedding light on potential therapeutic targets for combating these conditions.
The paper discusses how various factors, including high-fat diet consumption, systemic inflammation, and cellular stress, can trigger inflammatory responses within the hypothalamus. These inflammatory signals disrupt the normal functioning of hypothalamic neurons and glial cells, leading to impaired energy balance and insulin sensitivity.
Furthermore, the paper explores the molecular mechanisms underlying hypothalamic inflammation, highlighting the role of pro-inflammatory cytokines, chemokines, and immune cell infiltration in driving metabolic dysregulation. They also mention the involvement of intracellular signaling pathways, such as the IκB kinase (IKK)/nuclear factor-κB (NF-κB) pathway and the c-Jun N-terminal kinase (JNK) pathway, in mediating the effects of inflammation on hypothalamic function.
Importantly, the paper explains the bidirectional communication between the hypothalamus and peripheral tissues, whereby hypothalamic inflammation can exacerbate systemic metabolic dysfunction, while metabolic signals from peripheral tissues can influence hypothalamic inflammation. This crosstalk between the central nervous system and peripheral organs contributes to the vicious cycle of obesity and metabolic disease.
Furthermore, the paper discusses potential therapeutic strategies for targeting hypothalamic inflammation in the treatment of obesity and metabolic disorders. Strategies aimed at modulating immune responses, restoring neuronal function, or enhancing metabolic flexibility within the hypothalamus hold promise for ameliorating metabolic dysfunction and improving overall health outcomes.
The AHEI score ranged from 0 to 100 (correction for trans fat shown). Healthy components: fruit, non-starchy vegetables, legumes/nuts, whole grains, PUFAs, and seafood omega-3 fat; unhealthy components: red/processed meat, SSBs, and sodium.
The mean national score was computed as the sum of the stratum-level component scores and aggregated to the national mean using weighted population proportions for 2018 from 0 to 100. The mean national score was computed as the sum of the stratum-level component scores and aggregated to the national mean using weighted population proportions for 2018.
Only ten countries, representing <1% of the world’s population, had AHEI scores ≥50. Among the world’s 25 most populous countries, the mean AHEI score was highest in Vietnam, Iran, Indonesia, and India (54.5 to 48.2) and lowest in Brazil, Mexico, the United States, and Egypt (27.1–33.5).
Schizophrenia
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A. What is Schizophrenia
Schizophrenia is a complex neuropsychiatric disorder characterized by disturbances in cognition, perception, and behavior. While the precise etiology of schizophrenia remains elusive, growing evidence suggests that dysregulation of various signaling pathways may contribute to its development. Schizophrenia can affect anyone, regardless of age, gender, or socioeconomic status.
B. The Paper
An Emerging Role for Wnt and GSK3 Signaling Pathways in Schizophrenia explores the increasingly recognized involvement of the Wnt and GSK3 (glycogen synthase kinase 3) signaling pathways in the pathophysiology of schizophrenia, offering insights into potential mechanisms underlying the disorder.
C. Wnt
The paper begins by providing an overview of the Wnt signaling pathway, which plays critical roles in neurodevelopment, synaptic plasticity, and adult neurogenesis. Singh discusses how aberrant Wnt signaling has been implicated in schizophrenia, with alterations observed in Wnt ligands, receptors, and downstream effectors in postmortem brain studies and animal models of the disorder. Dysfunctional Wnt signaling may disrupt neural circuitry and synaptic connectivity, contributing to the cognitive and behavioral deficits observed in schizophrenia.
D. GSK3 and its relation to Wnt
Furthermore, the paper explores the role of GSK3, a key regulator of the Wnt pathway, in schizophrenia pathogenesis. Dysregulated GSK3 activity has been implicated in various aspects of schizophrenia, including neurodevelopmental abnormalities, neurotransmitter dysregulation, and synaptic dysfunction. GSK3 dysregulation may contribute to the imbalance between excitatory and inhibitory neurotransmission observed in schizophrenia, leading to altered synaptic plasticity and neuronal communication.
Moreover, the paper discusses the potential interactions between the Wnt and GSK3 signaling pathways in schizophrenia. Singh highlights how GSK3 can modulate Wnt signaling by phosphorylating key components of the pathway, thereby influencing downstream transcriptional responses and cellular processes. Dysregulated crosstalk between Wnt and GSK3 signaling may disrupt neurodevelopmental processes and synaptic function, ultimately contributing to the pathophysiology of schizophrenia.
E. Treatment
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The paper concludes by underscoring the therapeutic potential of targeting Wnt and GSK3 signaling pathways in schizophrenia. Singh discusses preclinical and clinical studies investigating pharmacological agents that modulate Wnt signaling or inhibit GSK3 activity as potential treatments for schizophrenia. By restoring the balance of Wnt and GSK3 signaling, these interventions may offer novel therapeutic strategies for ameliorating the cognitive and behavioral symptoms of schizophrenia.
In the traditional setting, schizophrenia is treated with antipsychotics with the help of psychotherapy counseling.
Concussion and Navigating In School
A. The Paper
The New Neurometabolic Cascade of Concussion looks into the evolving understanding of the pathophysiological mechanisms underlying concussions, shedding light on a paradigm shift in how these injuries are conceptualized and managed.
Traditionally, concussions have been viewed as purely functional disturbances, characterized by transient neurological dysfunction without structural damage. However, Giza and Hovda propose a new perspective, suggesting that concussions involve complex neurometabolic cascades that can lead to long-lasting consequences.
B. Steps of concussion
The paper outlines a multi-step cascade of events triggered by concussive impacts, starting with the immediate disruption of ion gradients and neurotransmitter release. This initial phase is followed by a metabolic crisis, characterized by increased energy demands and compromised cerebral blood flow regulation. As a result, neurons experience energy depletion and mitochondrial dysfunction, leading to oxidative stress and cellular damage.
Moreover, the role of neuroinflammation is highlighted in the secondary injury phase of concussions, where activated microglia release inflammatory mediators and exacerbate neuronal damage. This inflammatory response can persist for days to weeks following the initial injury, contributing to ongoing neurological dysfunction and potential long-term consequences.
C. Imaging
There was a large interest in imaging tools that can be used to diagnose concussions. My part was about fMRI. A Functional Magnetic Resonance Image (fMRI) is an imaging technique used to diagnose concussion and recognize changes in the brain while you are asked to engage in cognitive tasks.
D. Recovery and Being in School
The paper emphasizes the importance of considering individual variability in concussion outcomes, noting that factors such as age, sex, genetic predisposition, and prior injury history can influence the severity and duration of symptoms. It also stresses the need for personalized approaches to concussion management, including targeted interventions aimed at mitigating specific aspects of the neurometabolic cascade.
Furthermore, the paper discusses the implications of their proposed model for concussion diagnosis, treatment, and prevention. They advocate for a comprehensive approach that integrates clinical assessment, neuroimaging, biomarker analysis, and neuropsychological testing to better understand and manage concussive injuries.
I found this website from the University of Michigan particularly helpful for the treatment and recovery information, especially if you are still in school: Concussion Treatment and Recovery
Reference:
Favorite Part; Peer Discussion
One aspect of the semester that I would like to highlight is the end of week discussions that the class would have on each paper we read. This discussion really helped me learn how to communicate my ideas effectively, and in an interesting way.
As a chemistry major, I understand how intimidating chemistry and science in general can be. However, I also know and have learned the benefit of understanding how things work. Having knowledge of the natural world around you allows you to make better, more informed decisions. In my mind, chemistry, biology, and neuroscience should not be intimidating topics. Yes, they are notorious for being confusing, but with practice we can be better at explaining them. This is why the discussions are so important because they allow us to explain things to an informal audience. I hope that in my future as a scientist that I will have many science communication opportunities. I have discovered that I adore public speaking when it comes to science communication. I would not have known this if courses like this one and other courses at Concordia had not pushed me to communicate effectively.
In almost every discussion we had for this course, we brought up the idea of how to educate the public on this topic. Although this was just a thought experiment and will not lead to actual implementation, we talked a lot about educating children early on topics such as diet, mental health, physical health, etc. I think it is very important to have scientists who understand science to be the ones to create the educational materials to be presented to these boards of education.
Additionally, I became better at listening to others. That statement makes it sound like I was not listening to others before, which I believe I was, just not in the most effective nor helpful way. Before, I would have the urge to rapidly jump into a conversation whenever I had something to say. Usually, this was me trying to relate to a person and their thoughts/ideas/emotions, however I realize now I was unknowingly interrupting them. These weekly discussions have taught me that even when someone finishes a sentence, it can be best to wait and let the words hang in the air. This allows for them to add on or clarify their thoughts, or just allows for deeper contemplation of the topic.
While I was listening more to my peers, I was learning more about them than ever before. Concordia has many goals and policies to promote multiculturalism which I believe are invaluable. However, the most value from having people from different backgrounds and cultures meet is when they actually listen to each other. While we were discussing neurochemical topics like schizophrenia, cancer, and Alzheimer’s disease; I was simultaneously learning about how the school system works in Norway, or the ordinary diet in Nigeria, or how people access mental health care in rural North Dakota. Learning about the background of my peers gave me their own personal context. It allowed me to see the reasons why they think the way they do.
The Ethics of Marijuana
A. The Paper
The paper Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease provides an in-depth exploration of the signaling mechanisms and functional roles of cannabinoid receptors in the central nervous system (CNS), as well as their implications in various diseases.
Cannabinoid receptors, particularly CB1 and CB2, are integral components of the endocannabinoid system, which plays crucial roles in regulating numerous physiological processes within the CNS. The intricate signaling pathways activated by cannabinoid receptors, including G protein-coupled signaling cascades, regulation of ion channels, and modulation of neurotransmitter release.
In the CNS, cannabinoid receptors have a lot of functions, ranging from the modulation of synaptic transmission and neuronal excitability to the regulation of neuroinflammation and neuroprotection. The paper discusses how the endocannabinoid system influences processes such as pain perception, mood regulation, memory formation, and motor control, highlighting the broad impact of cannabinoid receptor signaling on brain function.
B. Marijuana as a treatment
Importantly, the paper explores the involvement of cannabinoid receptors in various neurological and neuropsychiatric disorders, including epilepsy, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, schizophrenia, and anxiety disorders. They examine the potential therapeutic implications of targeting cannabinoid receptors in the treatment of these conditions, emphasizing the need for further research to elucidate the precise mechanisms underlying their therapeutic effects.
Moreover, the paper discusses the pharmacological modulation of cannabinoid receptors through exogenous ligands, including phytocannabinoids from cannabis plants and synthetic cannabinoids. The authors evaluate the therapeutic potential and limitations of cannabinoid-based medications in treating CNS disorders, highlighting the importance of considering factors such as efficacy, side effects, and individual variability in response.
C. The ethics
Cannabis research that can inform public health and keep pace with changes in cannabis policy and patterns of use requires funding. In the U.S., the National Institute for Health (NIH) is responsible for funding research across many health domains. However, because cannabis was historically perceived to have only negative effects, most cannabis research has been conducted under the auspices of the National Institute of Drug Abuse (NIDA).
Paradoxically, most harms related to cannabis arise from its illegality and the associated risks of seeking out an illicit substance. For example, criminalizing cannabis has led to territorial disputes, the constant fear of informants, and implicated people who use cannabis with other criminal behaviors.
Reference:
Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease
Cancer With A Focus In The Brain
A. The Paper
Understanding and Exploiting Cell Signaling Convergence Nodes and Pathway Cross-talk in Malignant Brain Cancer talks about the intricate molecular mechanisms of malignant brain cancer. It highlights the significance of cellular signaling pathways and their convergence points, along with the cross-talk between different pathways, in driving the progression and proliferation of cancer cells within the brain.
It is important to understand these signaling convergence nodes and pathway interactions for identifying potential therapeutic targets. By learning about the complex signaling networks involved in brain cancer, researchers can develop more effective treatment strategies that specifically target the vulnerabilities of cancer cells while minimizing damage to healthy tissue.
B. The Cancer
During our discussion, we talked about the terminology of cancer and how understanding those things can help us more in understanding the paper. I found this website very useful in learning about cancer in general: http://www.toxicologyschools.com/Free_Toxicology_Course2/a33.htm
Or this list: https://www.cancer.gov/types
Back to the paper, it discusses various signaling pathways implicated in malignant brain cancer, including those related to cell proliferation, survival, migration, and angiogenesis. We got to explore how these pathways interact and converge at specific nodes, amplifying the oncogenic signals and promoting tumor growth and invasion.
C. The Future
The paper highlights the role of emerging technologies, such as omics approaches and computational modeling, in unraveling the complexity of signaling networks in brain cancer. These tools enable researchers to analyze large-scale data sets and identify key signaling molecules and pathways driving tumor progression.
Furthermore, the paper discusses the potential therapeutic implications of targeting signaling convergence nodes and pathway cross-talk in malignant brain cancer. By disrupting the communication between different signaling pathways or targeting essential nodes within these networks, researchers can develop more precise and effective treatment strategies for combating this deadly disease.
References:
http://www.toxicologyschools.com/Free_Toxicology_Course2/a33.htm
Endocannabinoids
The endogenous cannabinoid system has opened new ways for understanding how our bodies work, over the years more research has been conducted in understanding the system. The Endocannabinoid system has two receptors CB1 and CB2. CB1 is the most common type of receptor, it is found in the CNS in areas of the hippocampus, neocortex, and brainstem, as well as other parts of the body such as the eyes and the testes. CB1 receptors are in synapses, which is where nerve cells connect. CB1 receptors interact with substances such as THC which arises from marijuana, synthetic drugs, and natural compounds produced by the body. THC plant contains over 60 different compounds that can activate CB1 and CB2 receptors, the most well-known being ∆9-THC, exposure to THC can lead to various effects in humans such as pain relief, relaxation, and discomfort.3 They’re several consequences that arise from the overuse of THC, some short-term effects are for instance when an individual smokes this, it will pass through the lungs into the bloodstream and from there travel to the brain and other organs. The high that people experience from THC is due to different parts of the brain being activated with the CB receptors and this causes changes that cause altered senses, changes in mood, and alterations in mood.1 Long-term effects include breathing problems for those who smoke it, if used while pregnant this may impact the child’s memory and problem-solving, and overusing THC can worsen symptoms in individuals who experience schizophrenia, paranoia, and temporary hallucinations.2 The CB2 receptor is found in specific parts of the brain, it is mainly related to the immune system, however in the brain CB2 receptors are found mostly in the microglia which are immune cells that play a role in inflammation. In the past, research into the involvement of CB2 receptors in drug addiction was limited. However, there has been a growing body of research shedding light on their roles in alcohol, nicotine, and cocaine addiction.3 Emmanuel Onaivi conducted research on CB2 and was one of the first to find how the receptors link to alcohol addiction, he used mice in this study and found that when given a CB2 receptor activator the mice would drink more alcohol, especially when they were stressed, when the CB2 gene was removed the mice showed a higher need for alcohol and would consume more of it. However, in involuntary drinking experiments, CB2-/- mice drank less alcohol which is an indication that more research is still needed to understand alcohol’s role. Research on cocaine found that Activating CB2 receptors in mice reduced the effects of cocaine and decreased their motivation to use the drug while blocking these receptors reduced relapse after stopping cocaine use, and reduced cocaine’s rewarding effects. Additionally, changes in CB2 receptor levels in the brain were associated with cocaine exposure and addiction development in both mice and rats. Research on Nicotine found that Activating CB2 receptors in rats reduced nicotine intake but increased motivation for nicotine while blocking these receptors had little effect on nicotine-seeking behavior. In mice lacking CB2 receptors, there was less preference for nicotine and reduced motivation to use it, and blocking these receptors decreased nicotine self-administration and withdrawal symptoms.4
What is the Endocannabinoid System and How Does it Work with Cannabis?
1Abuse, N. I. on D. (2019, December 24). Cannabis (Marijuana) DrugFacts | National Institute on Drug Abuse (NIDA). https://nida.nih.gov/publications/drugfacts/cannabis-marijuana
2Cannabis/Marijuana Use Disorder. (n.d.). Yale Medicine. Retrieved April 12, 2024, from https://www.yalemedicine.org/conditions/marijuana-use-disorder
3Kendall DA and Yudowski GA (2017) Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front. Cell. Neurosci. 10:294. doi: 10.3389/fncel.2016.00294
4 Navarrete, F., García-Gutiérrez, M. S., Gasparyan, A., Navarro, D., & Manzanares, J. (2021). CB2 Receptor Involvement in the Treatment of Substance Use Disorders. Biomolecules, 11(11), 1556. https://doi.org/10.3390/biom11111556
Metabolic Syndrome
For many years, it’s been understood that obesity triggers a chronic, low-level inflammation throughout the body, which leads to various health problems like type 2 diabetes, high cholesterol, heart disease, and even brain-related issues. Interestingly, the brain plays a significant role in this process by regulating our appetite and metabolism. Genetic factors also play a role, with many obesity-related genes affecting brain function easy access to foods with unhealthy and high-calorie foods not only affects a person externally but also has internal consequences. Research has found the hypothalamus becomes inflamed. This inflammation disrupts the brain’s ability to regulate energy balance and contributes to insulin resistance, making it harder for the body to manage blood sugar levels. The hypothalamus plays a crucial role in regulating our metabolism and appetite, it contains different types of signals such as leptin and insulin which regulate our food intake. When a person consumes a high-fat diet, the hypothalamus is triggered and doesn’t respond as well to insulin and leptin, which are both hormones that regulate sugar and control appetite, saturated fatty acids interfere with normal signaling of insulin and leptin which then leads to positive energy balance and weight gain, the inflammatory pathways in the hypothalamus become activated leading to insulin and leptin resistance. This resistance leads to weight gain and other metabolic issues.2 Leptin, as we know, regulates appetite and energy balance, when you eat a high-fat diet it leads to an increase in fat stored in the body, which then turns to higher levels of leptin being released in the bloodstream, leptins role is to tell our brain to eat less and burn more energy which then helps us maintain a healthy weight, when a person consumes a high fatty diet this leads to leptin resistance, even though the brain levels are high the brain becomes less responsive to its signals when the body becomes resistant it doesn’t do a good job in telling the brain to eat less, which can lead to more eating and weight gain.3 When a person eats a lot of high fatty diet this can make cells less sensitive and when the cells don’t respond the body makes insulin to try to compensate for it, however over time this can mess up how the body controls hunger which makes a person want to eat more high fatty foods.1 TNF-α is a protein that responds to inflammation or infection, it promotes leptin and insulin resistance by activating certain signaling pathways. When the central nervous system is exposed to low levels of TNF- α this can impair leptin and insulin function in the hypothalamus. TNF- α also increases the production of PTP1B which is a protein that that negatively regulates insulin and leptin signaling. Elevated levels of PTP1B, particularly after long-term high-fat diet consumption, impair insulin signaling by directly inhibiting key molecules involved in the process. Deleting PTP1B specifically in neurons has been shown to improve metabolic health and reduce weight gain.
1 Ilyas, Athif, et al. “The Metabolic Underpinning of Eating Disorders: A Systematic Review and Meta-Analysis of Insulin Sensitivity.” Molecular and Cellular Endocrinology, Elsevier, 28 Oct. 2018, www.sciencedirect.com/science/article/abs/pii/S0303720718302867.
2Jais, Alexander, and Jens C Brüning. “Hypothalamic Inflammation in Obesity and Metabolic Disease.” The Journal of Clinical Investigation, U.S. National Library of Medicine, 3 Jan. 2017, pubmed.ncbi.nlm.nih.gov/28045396/.
3Mendoza-Herrera, Kenny et al. “The Leptin System and Diet: A Mini Review of the Current Evidence.” Frontiers in endocrinology vol. 12 749050. 24 Nov. 2021, doi:10.3389/fendo.2021.749050