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13 Mechanisms By Which Inflammation Causes Weight Gain

Written by Joe Cohen, BS | Last updated:

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. This post will go into what types of inflammation cause weight gain.

What’s interesting is that people who are affected by environmental toxins are more likely to gain weight, and markers that are associated with weight gain are elevated.

1) TGF-b/SMAD3

TGF-beta causes weight gain.

TGF-beta is correlated with obesity in rodents and humans [1].

Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and liver damage [1].

Smad3 (which is activated by TGF) acts as a repressor of PGC-1a expression.

People with mold illness have elevated TGF-beta, which is probably one reason why they have problems with weight loss. TGF-beta also degrades muscle.

However, TGF beta is significantly elevated during starvation in Anorexia, but this could be confounded by the elevation of other cytokines [2].

2) C3a

C3a causes weight gain.

Complement 3 (C3) generates C3a. C3a converts to ASP or acylation-stimulating-protein [3].

ASP inhibits the action of hormone-sensitive lipase, which is linked to the development of obesity [3].

C3a and the complement immune system is often elevated in mold illness.

3) SOCS3

SOCS3 causes weight gain.

Suppressor of cytokine signaling 3 or SOCS3 causes leptin resistance, obesity, and glucose intolerance [4, 5].

SOCS3 is often elevated in mold illness.

4) MMPs

There is growing evidence that MMPs play an important role in causing obesity.

Human fat tissue releases MMP-2. Overweight/obese women had significantly higher MMP-2 than controls [6].

An MMP-2 gene was associated with the percentage of body fat in childhood obesity in New Zealand [7].

MMP-9 levels are found increased in obese subjects [8, 9] and are correlated with BMI [10].

MMP-9 SNPs are strongly associated with obesity [11, 12].

In one study, obese children and adolescents had higher MMP-8 [13].


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 [14].

Angiogenesis has been associated with fat tissue (visceral and subcutaneous) in severe human obesity [15].

Mice treated with an angiogenesis inhibitor had smaller fat cells [16].

Different angiogenesis inhibitors have been shown to significantly decrease body and fat tissue weights [17].

VEGF-B specifically controlled the uptake of fatty acids [18].

Blood VEGF-A levels were significantly higher in obese patients than in lean controls, decreasing after weight loss with bariatric surgery [19].

VEGF genes increase susceptibility to obesity in children and adolescents [20].

Calcitriol (active vitamin D) has been reported to inhibit angiogenesis [21], decrease the negative effects of VEGF and decrease the production of VEGF [22].

6) TLR4

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 (lipopolysaccharide).

TLR-4 activation increases inflammation in fat cells and macrophages, resulting in the development of insulin resistance and increased fat [23].

Mice, lacking TLR-4, have been found to be resistant to diet-induced obesity and insulin resistance [24].

Both TLR-2 and TLR-4 are increased in fat tissue in patients with obesity and type 2 diabetes [25].

A high-fat diet– or leptin deficiency-induced obesity results in higher TLRs in mouse fat tissue.

TLR-4-deficient mice were protected against obesity-induced by diets high in saturated fat.

Calcitriol (active vitamin D) suppresses TLR-2, 4 and 9 in human monocytes [26].

7) Prostaglandins

Prostaglandins promote weight gain.

Prostaglandins (PGs) play a role in inflammatory processes.

Cyclooxygenase (COX) participates in the conversion of arachidonic acid into prostaglandins.

PGE2 and PGD2 have shown to promote fat in mice through increase the creation of fat and preventing the breakdown of fat [27, 28].

PGE2 enhanced fat accumulation in the liver and caused fatty liver [29].

In one study, a COX-2 genetic deficiency produced in a significant reduction in total body weight and percentage of body fat [28].

8) Nf-kB

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, without the ability of the mitochondria to utilize it.

Most studies use fat to do this, but any macronutrient can theoretically do this [30].

NF-κB activity was higher in animals fed a high-fat diet. Increased stomach fat was associated with higher Nf-kB in these tissues [31].

9) MyD88

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) [32].

This MyD88 protein also causes gut permeability [32].

10) PAI-1

PAI-1 causes obesity.

Plasminogen activator inhibitor-1 (PAI-1) is present in increased levels in various disease states such as cancer, heart disease, and obesity. [33]

PAI-1 results in the overgrowth of tissue (fibrosis) [33].

Angiotensin II increases PAI-1, which causes hardening of the arteries [33].

PAI-1 is believed to have a direct causal role in obesity and insulin resistance [34].

TGF-beta increases PAI-1, which is reversed by curcumin [35].

Curcumin also reduces PAI-1 from Angiotensin activation [36].

11) Glutamate

Glutamate causes weight gain.

Glutamate is an excitatory neurotransmitter and it stimulates appetite [37].

People with chronic inflammation will have higher glutamate in various brain regions.


NADPH causes weight gain.

Nicotinamide adenine dinucleotide phosphate (NADPH).

Enzymes that use NADPH to create free radicals (p22phox and p47phox) are elevated in the fat tissue and vessels of obese subjects [38].

Spirulina and Vitamin D may help obesity via the suppression of NADPH expression.

13) 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.

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 [39].

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 [40].

Inflammation is at the root of many health issues, including weight gain, and is caused by a whole variety of different things, I have compiled all the research that has helped me reduce my chronic inflammation greatly into my book SelfHacked Secrets.

If you want to analyze your genome, SelfDecode is the best tool out there to do that.

SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thank you for your support.

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine…and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time.


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