Cobbers on the Brain

Abstract by Alisha Debleye: This depicts the connection of the Gut and the inflammation on the brain. 

Let me take you on a journey that begins not in a fast food drive-thru or a grocery aisle stocked with ultra processed snacks, but inside the brain, in a small yet powerful region called the hypothalamus. It’s a place where every bite we take and every calorie we burn is carefully regulated by complex signaling systems. This tiny structure is the conductor of our body’s energy orchestra.

And for most of human history, this system worked just fine. We ate what we needed, our hormones sent signals to stop eating, and our bodies used energy efficiently. But in today’s world, with diets high in saturated fats and sugar, this ancient system is under attack. What starts on our plates ends up disrupting our brains, literally inflaming them. Therefore, obesity is no longer just a “weight issue.” It’s a neurological condition with deep consequences for public health in the United States.

A Silent Fire in the Brain

A groundbreaking study published in the Journal of Clinical Investigation reveals that obesity-related inflammation begins not in the belly or the thighs, but in the hypothalamus, the very part of the brain that regulates hunger and energy use¹.

Within just three days of starting a high-fat diet, inflammation begins to flare in this region. Before any weight is visibly gained, the hypothalamus starts to lose sensitivity to insulin and leptin, two hormones responsible for telling us when to stop eating¹. As this feedback loop breaks down, overeating begins.

Figure 1: In healthy brains, leptin and insulin suppress appetite through neurons in the arcuate nucleus (ARC). But in inflamed brains, this signal is ignored, fueling increased hunger and weight gain.

The Domino Effect

As hypothalamic inflammation sets in, it doesn’t stay put. Microglia, the brain’s immune cells, begin releasing inflammatory molecules like TNF-α and IL-6. These cytokines damage nearby neurons and spread dysfunction throughout the brain. The blood-brain barrier becomes more permeable, allowing even more inflammatory substances to enter.

The science is clear. Diet-induced inflammation impairs our ability to feel full and use energy properly, leading to a vicious cycle of overeating and weight gain¹.

And the damage isn’t limited to neurons. Astrocytes, another type of brain cell, swell and become reactive. Their once-helpful support turns toxic, and they start producing molecules that accelerate the inflammatory cascade. Over time, this neural chaos disrupts synaptic communication and even leads to neuron death, especially in the ARC region, which governs satiety.

Abstract by Alisha Debleye: Depicting the connections around the brain and how each part is a domino effect when things go wrong.

The Price We Pay

This is more than just a scientific curiosity. It’s a national crisis. In the U.S., more than 42% of adults are obese, and the medical costs are staggering, an estimated $147 billion per year².

And yet, so much of the public conversation around obesity is still framed as a moral failing, a lack of willpower. The truth is, chronic exposure to high-fat, high-sugar diets rewires our brains, making it biologically harder to stop eating.

Worse yet, this inflammation may start even before birth. Research shows that maternal obesity primes the developing brains of offspring for inflammation, setting them up for metabolic disorders later in life¹.

Hope in Reversal

But here’s where it gets hopeful.

Studies suggest that unsaturated fats, particularly omega-3 fatty acids, can reverse some of this hypothalamic inflammation¹. Exercise, too, has been shown to reduce cytokine activity in the brain, restoring insulin and leptin sensitivity. And promising new therapies target the inflammatory pathways directly, from NF-κB inhibitors to drugs that reduce endoplasmic reticulum (ER) stress.

In other words, early intervention matters. The fire in the brain can be extinguished if we act fast enough.

Why This Matters to You

This isn’t just another health scare story. It’s a wake-up call.

We need to rethink how we talk about, and treat, obesity. We need public policies that address the quality of our food supply, not just calorie counts. We need compassion, not blame. And we need research funding that prioritizes neurological and inflammatory causes of obesity.

If the brain controls the body, then protecting the brain should be the first line of defense in tackling the obesity epidemic.

So next time you hear someone say, “Just eat less,” remember: it’s not always that simple. Behind every craving, every binge, and every struggle with weight may be a brain under siege.

Let’s stop judging. Let’s start understanding. Let’s cool the fire, one neuron at a time.

References:

[1] Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. *The Journal of Clinical Investigation*, 127(1), 24–32. https://www.jci.org/articles/view/88878  
[2] CDC. (2022). Adult Obesity Facts. https://www.cdc.gov/obesity/data/adult.html

In their 2017 article, Hypothalamic Inflammation in Obesity and Metabolic Disease, researchers Jais and Brüning looked at how the hypothalamus becomes inflamed in people with obesity. The hypothalamus helps control hunger and how the body uses energy. The authors explain that when we eat too much high-fat/high-sugar food, it can trigger inflammation in this part of the brain. This inflammation makes it harder for the brain to properly regulate appetite and metabolism, which can lead to more weight gain and increase the risk of diseases like type 2 diabetes. Their work shows that obesity is not just about eating too much, but also about how the body, especially the brain, responds to what we eat [1].

Why Are We Talking About Genes and Obesity?

Obesity is a global problem, affecting millions of people [2]. While it’s easy to blame fast food or lack of exercise, scientists have found that there’s much more to the story. One important piece of that story is our genes. They are tiny instructions in our DNA that help shape how our bodies work. Some people have genetic differences that can make them more likely to gain weight, even when they try to eat well and stay active. Understanding the role of genes and brain inflammation helps explain why some people struggle more than others, and it opens the door to better, more personalized treatments.

But even though we know genes and brain inflammation play a role together, scientists still don’t fully understand how these processes work together. There are many different genes involved, and they don’t all act the same way in every person. Treatments that target inflammation in the brain are still in the early stages, and more research is needed to figure out what works and what doesn’t. This makes it a big challenge, but also an exciting area for new discoveries.

What are the Specific Genetic Defects?

Genetic obesity happens when a change in just one gene causes serious weight problems, often starting in early childhood. These changes affect parts of the brain, especially the hypothalamus, that control hunger and how the body uses energy. For example, a mutation in the LEP gene can cause a lack of leptin, a hormone that helps control appetite, leading to constant hunger and rapid weight gain. This can sometimes be treated with leptin replacement therapy. Other genes, like LEPR, stop the body from responding to leptin, even if it’s there. The MC4R gene, the most common cause of single-gene obesity, affects signals that tell the brain when you’re full. Mutations in POMC and PCSK1 can cause more complex problems, like hormone imbalances and poor energy control. All of these genes play a role in key brain pathways that manage appetite, energy use, and even how much we enjoy food [3].

Where Do We Go From Here?

Research like this shows us that obesity can be caused by more than just eating too much-  it can also be linked to brain changes and inflammation. Certain genetic differences can make some people more vulnerable to these changes. By understanding these processes, scientists can begin to develop treatments that go beyond diet and exercise. They can hopefully provide treatments that actually target the brain and genes involved. This opens up new possibilities for helping people with obesity in a way that’s more effective and more fair.

Science and Real Life

This research matters because it shifts how we think about obesity. It reminds us that weight gain isn’t just a personal failure- sometimes, it’s biology, and that changes everything. If doctors and society can better understand the real causes behind obesity, we can create more compassionate healthcare and offer personalized treatment plans, all the while reducing the stigma that people with obesity often face.

 

[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] Guideline Development Panel for Treatment of Obesity, American Psychological Association. (2020). Summary of the clinical practice guideline for multicomponent behavioral treatment of obesity and overweight in children and adolescents. The American Psychologist, 75(2), 178–188. https://doi.org/10.1037/amp0000530

[3] Abawi, O., Wahab, R. J., Kleinendorst, L., Blankers, L. A., Brandsma, A. E., van Rossum, E. F. C., van der Voorn, B., van Haelst, M. M., Gaillard, R., & van den Akker, E. L. T. (2023). Genetic Obesity Disorders: Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population. The Journal of Pediatrics, 262. https://doi.org/10.1016/j.jpeds.2023.113619

The article we have covered in a previous week, “Hypothalmic inflammation in obesity and metabolic disease” by Alexander Jais and Jens C. Brüning was an article about metabolic inflammation being connected to obesity in many surprising ways. Basically, we know already that obesity is an obstacle for the brain and it’s functioning. However, due to this feature, this is in a way how this correlation works.The topic today is why people should care about this topic and what the people must know, so without further ado let’s get reading!

The article informs us of a typical metabolic homeostasis, and then what happens to it under insulin and leptin resistance. Though, the article specifically focuses mainly on the insulin and leptin resistance aspect. As a result of this connection, we can now at least suspect the connection!

Figure one, pictured above, from the article mentioned above is especially excellent at explaining this where it was needed (excellently timed, or in other words placed well). That piece is a diagram expressing exactly this. The myriad, but consistent colors complements the black parts which either crosses something out, or is a metaphorical old-timey scale. Although, one slight problem could be that it could feel a large bunch overwhelming if you’re not too familiar with the applied terms of figure one in the Neuroscience field. This was an excellent piece to me for it is maximized simplicity because, for clear reasons, that kind of thing strongly helps. The figure may also benefit people uninvolved in Neuroscience as well because figure one uses so much brief, yet descriptive, labeling, and I find that effective myself in general because it’s easy on the eyes to track or logicate.

Now, at this point, one, such as yourself, may wonder why people really should care about all the above information. Well, let’s answer with essential basics to answer ourselves by quickly asking ourselves something simpler first; what really is metabolism? Well, the answer is absolutely nothing short of deeply important. According to Arturo Sánchez López de Nava and Avais Raja, metabolism is known as “the whole sum of reactions that occur throughout the body within each cell and that provide the body with energy.” (Arturo Sánchez López de Nava and Avais Raja 2022).^2 Considering what we know about energy, the ability to do action internally and externally, it’s no shock to pretty much anyone that such a scenario can turn serious fast. Let us put this into perspective with another topic.

In my class, I personally examined the various effects that the person with a penis has in the impact of their child’s birth via their diet. Surprisingly, I learned from the University of Tennessee Institute of Agriculture, even very specific nutritional choices have a direct effect on the child. Using protein as an example, a low amount of protein may cause a higher birth weight while high amounts of protein may lead to glucose intolerance in their child.^3 It is little short of incredible how essential our nutritional choices are, and even more so that we seemingly take little worry to what it does to us.

References:
1) “Hypothalmic inflammation in obesity and metabolic disease” by Alexander Jais and Jens C. Brüning
2)https://www.ncbi.nlm.nih.gov/books/NBK546690
3) https://animalscience.tennessee.edu/wp-content/uploads/sites/7/2022/05/Relevant-Repro-Blog-7_-Paternal-Impacts.pdf

Figure 1: Illustrates how brain inflammation contributes to leptin and insulin resistance, with unsaturated fats helping to reduce inflammation and improve metabolism. Created by Sharleen Mtesa.

We’ve all heard the saying “you are what you eat,” but when it comes to hormones like insulin and leptin, that couldn’t be more true. These two messengers have a big job: insulin helps manage your blood sugar, and leptin tells your brain when you’re full. These two hormones play a critical role in keeping our metabolism on track. And when they’re working properly, they help us maintain a healthy balance between hunger and energy.

But when our diets are high in processed foods, unhealthy fats, and sugar, these hormones can stop functioning correctly. That’s when insulin and leptin resistance kicks in leading to constant cravings, weight gain, and blood sugar issues.

Therefore, incorporating healthy unsaturated fats into your diet like those found in olive oil, avocados, nuts, and fatty fish can be a game-changer. These fats help reduce inflammation, improve hormone sensitivity, and support your body’s ability to manage hunger and energy more effectively. Let’s take a closer look at how these fats actually work to restore balance and boost your health.

How Inflammation Disrupts Insulin and Leptin Resistance.

According to the paper “Hypothalamic Inflammation in Obesity and Metabolic Disease,” a high-fat diet (HFD) triggers inflammation in the hypothalamus, impairing how the brain responds to key hormones like insulin and leptin. This inflammation leads to insulin resistance, which makes it harder for the body to manage blood sugar, and leptin resistance, which disrupts the brain’s ability to signal when you’re full, ultimately increasing hunger and food intake.[1]

The inflammatory process involves the activation of proinflammatory cytokines, like TNF-α, that interfere with insulin and leptin signaling. This damage to hormone function results in metabolic imbalances, weight gain, and constant cravings. These effects on hunger and energy regulation create a vicious cycle, making it harder to maintain a healthy weight and manage blood sugar levels

How Unsaturated Fatty Acids Help Reverse Insulin and Leptin Resistance.

Unsaturated fatty acids, particularly monounsaturated fats (MUFAs) and polyunsaturated fats (PUFAs), play a very important role in restoring metabolic balance. These healthy fats not only help with weight control but also improve the body’s response to insulin and leptin by reducing inflammation and promoting fat metabolism.

• Monounsaturated fats (MUFAs): Found in olive oil, nuts, and avocados.
• Polyunsaturated fats (PUFAs): Especially omega-3s and omega-6s, found in fatty fish, flaxseeds, and walnuts.

1. Improving Insulin Sensitivity.

Insulin helps cells absorb glucose from the blood, but when the body becomes resistant, blood sugar levels rise, contributing to type 2 diabetes. Unsaturated fats aid in restoring insulin sensitivity in the following ways:

• Better Cell Membrane Function: Unsaturated fats become part of cell membranes, making them more flexible and fluid. This improves insulin receptor function, allowing glucose to enter cells more efficiently.
• Reduced Inflammation: Chronic inflammation, often caused by a diet high in saturated fats and processed foods, disrupts insulin signaling. Omega-3s have powerful anti-inflammatory effects, reducing inflammation and improving insulin function. These omega-3s help calm the immune system, prevent activation of inflammatory receptors, and reduce the production of TNF-α, a cytokine that contributes to insulin resistance.
• Fewer Toxic Fats in Organs: Excess fat storage in organs like the liver and muscles leads to insulin resistance (lipotoxicity). Unsaturated fats help reduce fat accumulation and promote healthy fat metabolism, encouraging the body to use fat for energy instead of storing it in organs. For example, oleic acid (found in olive oil) and omega-3s help reduce diacylglycerol (DAG) buildup in the liver, which is linked to insulin resistance.
• Gene Regulation: Unsaturated fats activate proteins (like PPARs) [2] that regulate how the body uses sugar and fat, improving glucose control and reducing fat storage.

Figure 2: Insulin Signaling Pathway
This figure shows how insulin activates signaling pathways like PI3K/Akt and MAPK to promote glucose uptake, glycogen synthesis, and cell growth, while SOCS proteins regulate the response through negative feedback.[3]

2. Restoring Leptin Sensitivity

Leptin is produced by fat cells and signals the brain when you’re full. However, in leptin resistance, the brain doesn’t respond, leading to overeating and fat storage. Unsaturated fats help restore leptin sensitivity by:

• Calming Brain Inflammation: High-fat, high-sugar diets cause inflammation in the brain, especially in the hypothalamus, where leptin acts. Omega-3s help reduce this inflammation, allowing leptin signals to reach the brain effectively.
• Helping Leptin Cross the Blood-Brain Barrier: Leptin travels from the blood to the brain across the blood-brain barrier. Chronic inflammation can disrupt this process. Omega-3s help improve blood-brain barrier function, enabling leptin to reach the brain more efficiently.
• Improving Leptin Signaling: Unsaturated fats support better leptin receptor function and reduce the expression of SOCS3, a protein that blocks leptin signaling. As a result, the brain can detect leptin properly, helping to reduce hunger and cravings.[4]

Figure 3: Overview of Leptin Signaling Pathway.
This figure shows the leptin signaling pathway, where leptin activates JAK2, leading to phosphorylation of key sites (pY985, pY1138) and triggering downstream signals like STAT3, PI3K, and ERK. These pathways regulate hunger and energy balance, with SOCS3 acting as a feedback inhibitor.[5]

Feed Your Hormones Right.

When it comes to balancing your metabolism, hormones like insulin and leptin are key players and what you eat has a huge impact on how well they work. Chronic inflammation from highly-processed foods and unhealthy fats can throw these systems off, leading to cravings, weight gain, and blood sugar spikes.

But the good news? Healthy unsaturated fats like those found in olive oil, avocados, nuts, and fatty fish can help reset the system. By calming inflammation, improving hormone signaling, and supporting better fat metabolism, these fats make it easier for your body to respond to hunger and energy cues the way it’s supposed to.

So instead of fearing fat, focus on the right kinds. A few smart swaps in your daily meals can go a long way in supporting hormone health, boosting energy, and helping you feel your best from the inside out.

 

 

 

 

 

 

Footnotes

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

[2] Varga, T., Czimmerer, Z., & Nagy, L. (2011). PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochimica et biophysica acta, 1812(8), 1007–1022. https://doi.org/10.1016/j.bbadis.2011.02.014

[3],[5] Howard, J. K., & Flier, J. S. (2006). Attenuation of leptin and insulin signaling by SOCS proteins. Trends in Endocrinology & Metabolism, 17(9), 365–371. https://doi.org/10.1016/j.tem.2006.09.007

[4] Park, H. K., & Ahima, R. S. (2014). Leptin signaling. F1000prime reports, 6, 73. https://doi.org/10.12703/P6-73

 

Figure 1. Impact of stress and anxiety on pattern separation.
Created by Sharleen Mtesa. The image shows a brain with disrupted signals and emotional shadows, symbolizing how stress affects memory. Puzzle pieces and swirls represent confusion, while the background figure reflects emotional burden.

Have you ever noticed how certain memories, especially those tied to fear, stress, or strong emotions, seem impossible to forget? These moments, whether terrifying, traumatic, or deeply moving, often stay with us for life. Scientists have found that a small part of the brain called the dentate gyrus (DG) plays a major role in this [1]. The DG, located in the hippocampus, processes incoming information and helps determine which memories are stored long-term, particularly those linked to strong emotions. 

But memory isn’t just about storing emotional experiences, it’s also about keeping them distinct. When stressful or emotional events are similar, how does the brain prevent confusion between them?

Therefore, one key function of the DG is pattern separation, the brain’s ability to transform similar experiences into distinct, non-overlapping memories.

Figure 2. The location of the dentate gyrus in the brain.
This image shows where the dentate gyrus is located inside the hippocampus, a part of the brain involved in memory and emotion.[2]

How the Brain Keeps Stressful Memories Separate

According to the paper “Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways”, the DG achieves pattern separation through a very selective process. Only a small number of neurons in the DG become active during a stressful experience. This phenomenon, called sparse activation[1], helps keep memories sharp and distinct.

But this selectivity isn’t random, it’s carefully controlled by molecular switches within the brain cells. One of the most important switches is a histone tag called H3S10p-K14ac. Think of it like a key that unlocks tightly packed DNA, allowing important memory-related genes, like c-Fos and Egr-1, to be turned on. Without this tag, these genes remain inactive.[1]

Even though stress activates many parts of the brain, only DG neurons with this specific histone tag begin recording the memory. This ensures that the brain focuses its response on just a few key cells, helping to preserve the distinctiveness of each memory.

How the Dentate Gyrus Works Its Memory Magic.

The DG has some cool tricks to keep your memories sharp and organized:

1. Sparse Coding

• Only a small group of neurons fire for each experience.
• ➡️ Prevents similar memories from overlapping.
• Example: Meeting two people with similar voices? DG helps you tell them apart.

2. Input from the Entorhinal Cortex (EC)

• EC sends sensory + spatial data to the DG.
• DG reshapes it and passes it to the hippocampus.
• Ensures detailed, clear memory storage.

3. Inhibitory Microcircuits

• GABAergic interneurons = your brain’s memory traffic cops.
• Prevents too many neurons from firing at once.
• Example: Helps you remember where you actually parked today, not yesterday.

4. Neurogenesis = Fresh Memory Power

• DG keeps growing new neurons, even in adulthood.
• These newbies help make fresh, flexible, and distinct memories.
• Keeps your brain adaptable, not stuck in the past.

Figure 3. Simplified Flow of Information in the Hippocampal Formation.
This figure shows how sensory input from cortical association areas is processed by the parahippocampal and perirhinal cortices, then transmitted to the entorhinal cortex, which relays it to the hippocampus. Within the hippocampus, the dentate gyrus (DG) acts as the initial processing stage, playing a key role in pattern separation, transforming similar inputs into distinct memory representations before passing information to CA3, CA1, and the subiculum. [3]

How Stress & Anxiety Mess With the DG’s Memory Magic.

Stress doesn’t just make you feel awful, it actually affects how your brain remembers.

1. Stress Hurts Neurogenesis

• DG produces new brain cells throughout life (neurogenesis).
• Chronic stress = high cortisol (a hormone the body releases under stress) = fewer new neurons. [4]
• Fewer neurons → DG can’t keep memories separate → confusion & memory blending.

     2. HPA Axis Overdrive Weakens DG

• When stress continues for too long, the HPA axis(the body’s stress response system) stays overactive, keeping stress hormones high. [5]
• High cortisol levels weaken connections between neurons in the DG.
• ➡️ This makes it harder for the brain to separate new experiences from past ones
• Leads to anxiety, fear, and biased memory recall.

3. Pattern Completion Takes Over

• DG usually favors pattern separation.
• Under stress, it shifts to pattern completion (retrieving old memories based on partial cues).
• What that looks like:
  • Fear Overgeneralization: Mistaking safe situations for dangerous ones.
  • Exaggerated Emotional Reactions: Past trauma colors present experiences.

4. Memory Interference: Past vs. Present

• DG normally prevents interference between old and new memories.
• Stress disrupts that filter:
  • Past memories bleed into new ones.
  • Makes it hard to feel safe even when you are. [6]

How to Boost DG Function & Beat Stress

Want to keep your DG happy and your memories sharp? Try these:

• Exercise: Boosts neurogenesis + lowers cortisol
• Mindfulness & Meditation: Calms your stress response system
• Cognitive Behavioral Therapy (CBT): Helps reframe overgeneralized fears
• SSRIs/Antidepressants: Improve memory-related brain plasticity

Final Thoughts: Protecting Your Brain’s Memory Filter

The dentate gyrus may be small, but its role in shaping how we process and separate emotional memories is huge. When working well, it helps us distinguish the past from the present, keeping our memories organized and our reactions in check.

But chronic stress and anxiety can disrupt this process, blurring lines between memories, fueling fear, and making it harder to feel safe in the moment. The good news? The DG is flexible and responsive. With habits like exercise, mindfulness, therapy, and proper treatment, we can support brain health and improve memory clarity.

Because memory isn’t just about holding on, it’s about understanding, adapting, and moving forward. 

 

 

 

 

 

Footnotes:

[1] Reul J. M. (2014). Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. Frontiers in psychiatry, 5, 5. https://doi.org/10.3389/fpsyt.2014.00005

[2] Centre of Excellence for Early Childhood Development. (2008, December 5). Glossary – Brain. Encyclopedia on Early Childhood Development. https://www.child-encyclopedia.com/sites/default/files/docs/glossaire/Glossary_Brain_DG.pdf

[3] Weilbächer, R., & Gluth, S. (2016). The interplay of hippocampus and ventromedial prefrontal cortex in memory-based decision making. Brain Sciences, 7(1), 4. https://doi.org/10.3390/brainsci7010004 

[4] Schoenfeld, T. J., & Gould, E. (2012). Stress, stress hormones, and adult neurogenesis. Experimental neurology, 233(1), 12–21. https://doi.org/10.1016/j.expneurol.2011.01.008

[5] Lee, J. W., & Jung, M. W. (2017). Separation or binding? Role of the dentate gyrus in hippocampal mnemonic processing. Neuroscience & Biobehavioral Reviews, 75, 183-194. https://doi.org/10.1016/j.neubiorev.2017.01.049 

[6] Kim, E. J., Pellman, B., & Kim, J. J. (2015). Stress effects on the hippocampus: a critical review. Learning & memory (Cold Spring Harbor, N.Y.), 22(9), 411–416. https://doi.org/10.1101/lm.037291.114