Some people gain weight from chronic inflammation, while others lose weight.
The kind of inflammation you’re experiencing will determine if you gain or lose weight.
Most people will lose weight from chronic inflammation.
You might want to read the precursors to this post:
- A First Principles Approach To Obesity/Anorexia: The Big 4 Hormones
- 27 Hormones Involved in Weight Problems (not big 4)
- 29 Surprising and Science-Backed Ways To Lose Weight
The following list is different from the other posts. Believe it or not, there’s a lot more…
There’re many mechanisms in the body that alter appetite and energy storage and expenditure.
People who are over or underweight usually have a metabolic problem, assuming they’re trying to normalize their weight. And this metabolic problem is often from inflammation of various kinds.
Why Inflammation Leads to Weight Loss – The Big Picture
POMC neurons in the ARC are activated by IL-1b and CNTF and this decreases food intake. POMC-containing neurons project to several different regions of the hypothalamus that have the melanocortin MC4 receptor and are involved in appetite regulation (PVN, LH, and VMH). These second-order neurons synthesize CRH that also inhibits food intake .
So when you have a cytokine response, the body tries to reduce inflammation, and the same mechanisms by which it reduces inflammation also causes weight loss.
As long as you are having chronic inflammation (most common types), it will trigger the activation of these MC4 receptors and CRH and you will lose weight.
It’s critical to realize that psychological stress has the same effect as inflammation, which is why people often lose weight after chronic stress. When you get stressed, IL-1b is released and the same effects occur-activation of POMC neurons.
In CIRS, there is an additional mechanism by which the MC4 receptors are not being activated (because of low MSH and other mechanisms), so this is a unique chronic inflammatory issue that doesn’t necessarily result in weight loss – although it often does.
It is clear that no single cytokine is responsible for the modulation of food intake. Instead, each cytokine along with other factors involved in metabolic function, such as insulin, CCK, and ghrelin, plays a role in a concerted response that ultimately leads to the inhibition of food intake through their actions on neurons in the hypothalamus.
1) Agouti-Related Protein (AgRP)
AgRP is a protein that potently promotes weight gain.
AgRP increases appetite and decreases metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators .
So you eat more and expend less energy from increased levels of AgRP. Therefore you become fat from increased AgRP and thin from decreased levels.
Interestingly, some people will gain weight following a period of stress, while others will lose weight.
People who gain weight may be more likely to have higher NPY and cortisol, which increase in response to stress and cause appetite stimulation and produce more fat cells.
On the other hand, people who lose weight probably don’t have as much NPY and cortisol and may also experience a larger drop in AgRP. A drop in AgRP from acute stress will make you thin.
People suffering from chronic inflammation will have lower AgRP.
Higher cortisol is a signal that IL-1b is elevated in the hypothalamus.
IL-1beta inhibits the release of AgRP from hypothalamic tissue .
The appetite-stimulating effects of AgRP are inhibited by the hormone leptin and activated by the hormone ghrelin . Ghrelin significantly increased AgRP in the presence, but not absence, of Glucocorticoids .
AgRP has been demonstrated to block (inverse agonist) MC3-R and MC4-R .
When activated, MC3- and MC4 receptor activation help people lose weight. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone).
Whereas α-MSH acts broadly on most members of the MCR family (with the exception of MC2-R), AGRP is highly specific for only MC3-R and MC4-R.
In the adrenals, AgRP blocks α-MSH-induced secretion of cortisol in mice .
Loss or gain of AgRP function may result in inadequate adaptive behavioral responses to environmental events, such as stress, and have potential to contribute to the development of eating disorders .
Some studies suggest that inadequate signaling of AgRP during stress may result in binge eating .
Leptin suppresses food intake and increases energy expenditure at least partially by suppressing AgRP .
If you’re thin, it means you have low AgRP and you need to reduce your stress levels.
If you’re overweight, it means you have high AgRP and you need more sun.
2) POMC Neurons in the Hypothalamus
POMC promotes weight loss.
Leptin suppresses food intake and increases energy expenditure at least partially by activating POMC neurons .
People who have chronic inflammation and/or chronic stress will often weigh less because POMC will be elevated and activate POMC neurons.
However, people with CIRS may be an exception and have lower POMC (given that they have lower MSH).
IL-1b causes weight loss.
IL-1b is a significant cytokine in stress-induced weight loss.
In addition to suppressing eating, IL-1 inhibits the maturation of fat cells as well as the synthesis of fatty acid transport proteins in fat tissue (in vitro). It also decreases stomach emptying and gut flow, and increases leptin, glucagon, and insulin .
The higher the IL-1 concentrations in the cerebrospinal fluid, the lower the food intake in rats .
IL-1b might also be another reason why people with chronic stress have lower testosterone – because it blunts testosterone production from hCG . CRH and norepinephrine also blunt the testosterone response .
I have a full list of IL-1b inhibitors in my post on it.
TGF-beta causes weight gain.
Smad3 (which is activated by TGF) acts as a repressor of PGC-1a expression.
People with CIRS have elevated TGF-beta, which is probably one reason why they have problems with weight loss. TGF-beta also degrades muscle.
- Read my post on TGF-beta.
C3a causes weight gain.
Complement 3 (C3) generates C3a. C3a converts to ASP or acylation-stimulating-protein due to its stimulating action on triglyceride synthesis in human fat and skin cells (fibroblasts) .
ASP inhibits the action of hormone-sensitive lipase, which is linked to the pathogenesis of obesity .
C3a and the complement immune system is often elevated in CIRS.
6) MC4R and MC3R
Inflammatory cytokines from circulation or produced locally by microglia act directly on hypothalamic arcuate nucleus neurons.
The activity of POMC neurons is stimulated while the activity of AgRP/NPY neurons is inhibited. This leads to increased activation of MC4R, which results in decreased food intake and increased energy expenditure .
STAT3 causes weight loss.
Defective STAT3 results in obesity and insulin resistance in animal models.
IL-10 causes weight loss.
Chronic inflammatory states can have higher or lower IL-10.
- Read my post on IL-10.
TNF-alpha causes weight loss.
TNF suppresses food intake, but it’s less potent than IL-1 .
TNF, when administered with IL-1, acts synergistically to suppress food intake .
IL-6 causes weight loss.
IL-6 suppresses food intake when injected into the brain, but not in general circulation .
Science has discovered that exercise can help you lose weight more than by just burning calories; it changes your hypothalamus .
Nf-kB seems to cause weight gain.
Eating too much (no matter if it’s too much fat or carbs) creates insulin and leptin resistance (via activating hypothalamic NF-kB).
The fancy term is “endoplasmic reticulum stress”, which basically means we’re overloading our cells with calories.
Most studies use fat to do this, but any macronutrient can theoretically do this .
12) Interferons (IFNy, IFNa)
Interferons (IFNy and IFNa) cause weight loss.
Infusion of interferon in the rat brain decreased short-term (2-h) food intake in rats. There was a reduction of meal size and meal duration, whereas meal frequency slightly increased. Nighttime and total daily food intakes were not significantly affected .
IL-8 causes weight loss.
IL-8 causes a short-term suppression of food intake. This effect of IL-8 may contribute to reduced food intake when people get sick .
MyD88 causes weight gain in some circumstances.
When scientists inactivated part of the intestinal immune system in mice (a protein called MyD88), they were much more resistant to diabetes and obesity (diabesity) .
This MyD88 protein also causes gut permeability .
A lectin avoidance diet should reduce activation of MyD88.
IL-18 causes weight loss.
Insulin resistance seemed to be secondary to increased food intake and obesity (specifically, accumulation of body fat) because the effect only emerged after 6 months .
16) Quinolinic acid
Quinolinic acid causes weight loss.
People chronic inflammation or chronic stress have higher levels of quinolinic acid, which might be part of the reason why people in these states often weigh less.
Natural phenols such as curcumin suppress IL-18 . and EGCG reduces the neurotoxicity of quinolinic acid, via anti-oxidant and possibly calcium influx mechanisms. COX-2 inhibitors have also demonstrated protective properties against the neurotoxic effects of quinolinic acid .
Histamine causes weight loss.
Histamine and compounds that increase histamine concentrations are powerful suppressants of food intake .
Genetically obese rats have very low concentrations of hypothalamic histamine .
An action on the H1 receptor in the ventromedial hypothalamus (VMH) seems to account for these effects .
Histamine is also a powerful agent that induces drinking, whether administered systemically or directly into the hypothalamus .
PAI-1 causes weight gain.
PAI-1 results in the overgrowth of tissue (fibrosis) .
PAI-1 is believed to have a direct causal role in obesity and insulin resistance .
Presumably, CIRS will have elevated PAI-1 because of higher TGF-beta.
Curcumin also reduces PAI-1 from Angiotensin activation .
Orexin has mixed effects on weight, but overall seems to cause weight gain.
Orexin increase appetite and energy expenditure.
Inflammation shuts orexin down, which can cause us to have a lower appetite, eat less and weigh less.
Glutamate causes weight gain.
Glutamate is an excitatory neurotransmitter and it stimulates appetite .
People with chronic inflammation will have higher glutamate in various brain regions.
21) Adrenaline (Epinephrine)
Adrenaline causes weight loss.
Adrenaline is often increased in response to cytokines and inflammation.
Adrenaline is a stress hormone that underlies the fight-or-flight response.
In animal studies, adrenaline alone can decrease eating by 80%. It’s suspected that this works by increasing the metabolism of glucose, mostly by the liver .
Prolonged exercise is a good and healthy way to increase adrenaline.
Ephedrine is a protein extracted from a Chinese plant that acts similar to adrenaline and acts on the same receptors. However, this became illegal as people overdid it and it caused adverse health effects.
The adrenal glands dump adrenaline into the bloodstream, which leads to an increase in body temperature thereby burning more calories.
Adrenaline enhances the release of glucose from glycogen and enhances the release of fatty acids from adipose tissue .
Beta 2 and 3 adrenergic receptors increase fat busting (lipolysis) . These receptors are activated in response to adrenaline.
22) Norepinephrine (noradrenaline)
Noradrenaline/norepinephrine causes weight loss.
Norepinephrine is a stress hormone that underlies the fight-or-flight response. Norepinephrine increases blood pressure.
Norepinephrine influences appetite at the hypothalamic level.
Starvation decreases norepinephrine synthesis resulting in lowered appetite and lower metabolism .
An SNRI (a serotonin and norepinephrine reuptake inhibitor) called sibutramine results in weight loss, which can be caused by increase serotonin and norepinephrine .
Norepinephrine helps burn brown fat, which contributes substantially to energy expenditure by converting fatty acids and glucose into heat .
Exercise increases norepinephrine.
SOCS3 causes weight gain.
SOCS3 is often elevated in CIRS.
Read my post on SOCS3.
MMPs cause weight gain.
There is growing evidence that MMPs play an important role in causing obesity.
An MMP-2 gene was associated with the percentage of body fat in childhood obesity in New Zealand .
IL-4 causes weight loss overall, although the effects are mixed.
IL-4 is a Th2 cytokine that promotes fat busting by enhancing the activity and movement of hormone-sensitive lipase (HSL) in mature fat cells. IL-4 also inhibits fat cell creation and fat accumulation as well .
Serotonin has tissue-specific effects – it causes weight gain in the body but weight loss in the hypothalamus.
When serotonin is infused in the hypothalamus (ventromedial or lateral) of animals, they stopped eating and starvation resulted.
Low hypothalamic serotonin or dysfunctional receptors lead to increased cravings for carbs and sweets .
On the other hand, serotonin in the body (not brain) can increase weight by lessening the browning of fat and, therefore, the burning of calories .
So it seems like systemic serotonin levels may cause obesity, but hypothalamic serotonin decreases food intake.
The appetite inhibiting effects of serotonin in the brain are mediated by various serotonin receptors, some of which are increased in inflammation.
Activation of the 5HT2C receptor shuts down appetite , causes depression , anxiety  and low insulin . 5-HT2C receptor activators work, in part, via activating melanocortin-4 receptors .
The 5-HT2C receptors also increase the expression of hypothalamic NUCB2, which induces anorexia in mice .
The 5-HT2C receptor is increased by inflammation .
Ciliary neurotrophic factor (CNTF) induces weight loss. CNTF induces fever as well as inducing other aspects of the acute-phase response. CNTF is predominantly produced by astrocytes in the brain and chronic administration reduces food intake and causes weight loss . While most cytokines inhibit food intake and result in weight loss, only CNTF appears to have a long-term effect; in obese humans and rodents, weight loss is maintained even after treatment is stopped . There is evidence that this long-term effect is due to CNTF’s ability to induce neurogenesis within areas of the hypothalamus involved in energy balance . It is possible that CNTF alters the “set-point” of energy balance through long-term changes in synaptic function . In rodents, CNTF inhibits food intake and increases energy expenditure, in part through suppression of NPY . CNTF also induces cell creation in mouse hypothalamic areas that are capable of responding to leptin .
GM-CSF causes weight loss. When rats and mice were injected in the brain with the proinflammatory cytokine GM-CSF, they significantly decreased food intake and body weight . Mice without GM-CSF weighed more and had significantly higher total body fat. Energy expenditure was also decreased . (Effects are mediated through PVN and ARC) .
HMGB1 causes weight loss.
HMGB1 inhibits food intake.
HMGB1 is a cytokine that is secreted by immune cells (like macrophages, monocytes, and dendritic cells).
HMGB1 contribute to damage and tissue injury in autoimmune conditions such as arthritis, colitis, and systemic lupus erythematosus. The mechanism of inflammation and damage is binding to TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release.
Note: In fat cells, HMGB1 might contribute to obesity and indeed it was 2X higher in the fat cells of obese people .
GDF15 causes weight loss.
GDF15 is part of the TGF-beta family of cytokines.
Mice with tumors that produce too much MIC-1/GDF15 eat less. Further, weight loss can be reversed by the neutralization of these cytokines .
GDF15 probably contribute to anorexia/cachexia in humans because there is a direct correlation between the degree of blood MIC-1/GDF15 and the amount of cancer-related weight loss .
LIF causes weight loss.
LIF derives its name from its ability to reduce myeloid leukemic cells.
IL-11 causes weight loss.
Interleukin-11 is a multifunctional cytokine that is a member of the IL-6 family. It stimulates the cells that increase platelets (megakaryocytes).
It is also known under the names adipogenesis inhibitory factor (AGIF), given its role in suppressing the production of fat cells.
It has functions in many other tissues, including the brain, gut, and testis .
IL11 is important in fertility .
TLR4 causes weight gain.
Substantial evidence exists supporting the important role of Toll-Like Receptors (TLRs) in the cause of obesity.
Chronic low-grade inflammation found (in endotoxemia) has been demonstrated to be due to activation of TLR-4 by LPS.
TLR-4 activation increases inflammation in fat cells and macrophages, resulting in the development of insulin resistance and increased fat .
Mice, lacking TLR-4, have been found to be resistant to diet-induced obesity and insulin resistance .
Both TLR-2 and TLR-4 are increased in fat tissue in patients with obesity and type 2 diabetes .
A high-fat diet– or leptin deficiency-induced obesity results in higher TLR1-9 and TLR11-13 in mouse fat tissue.
TLR-4-deficient mice were protected against obesity induced by diets high in saturated fat.
VEGF causes weight gain.
Vascular endothelial growth factor (VEGF) is abundantly secreted from fat cells and plays a key role in the process of fat tissue formation through increasing angiogenesis.
A positive correlation between the concentrations of circulating VEGF levels and BMI was demonstrated in healthy male subjects under highly controlled conditions .
Angiogenesis has been associated with fat tissue (visceral and subcutaneous) in severe human obesity .
Mice treated with an angiogenesis inhibitor had smaller fat cells .
Different angiogenesis inhibitors have been shown to significantly decrease body and fat tissue weights .
VEGF-B specifically controlled the uptake of fatty acids .
Blood VEGF-A levels were significantly higher in obese patients than in lean controls, decreasing after weight loss with bariatric surgery .
VEGF genes increase susceptibility to obesity in children and adolescents .
NADPH causes weight gain.
The increase of p22phox and p47phox in fat tissue has been observed in obese subjects .
These are enzymes that use NADPH to create free radicals.
Overweight and obese adults have increased levels (vascular) of NOX-p47phox .
The reduced NOX4 is a hallmark of fat cell production .
NOX4-deficient mice show fat tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance .
Vitamin D may have a role in obesity via the suppression of NADPH expression.
Prostaglandins promote weight gain.
Prostaglandins (PGs) play a role in inflammatory processes.
PGE2 enhanced fat accumulation in the liver and caused fatty liver .
37) Nitric Oxide Synthase (NOS)
NOS causes weight gain.
Nitric oxide synthase (NOS) is an enzyme that is involved in the synthesis of nitric oxide (NO). It’s increased in inflammatory states, especially iNOS.
Platelet NO production has been significantly correlated with BMI, waist circumference, and triglyceride concentrations, thus suggesting an association between increased platelet NO production, obesity, and high triglycerides, independent of the degree of insulin-resistance .
Chronic NOS blockade in mice ameliorated diet-induced weight gain and glucose intolerance, accompanied by reduced fat tissue inflammation and improved insulin sensitivity in muscle, suggesting that NO plays a role in the development of obesity-related insulin resistance .
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