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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. 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.


1) TGF-b/SMAD3

TGF-beta causes weight gain.

TGF-beta is correlated with obesity in rodents and humans (R).

Further, systemic blockade of TGF-β signaling protects mice from obesity, diabetes, and liver damage (R).

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 (R).

2) C3a


C3a causes weight gain.

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

ASP inhibits the action of hormone-sensitive lipase, which is linked to the development of obesity (R).

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 (RR2).

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 (R).

An MMP-2 gene was associated with percentage of body fat in childhood obesity in New Zealand (R).

MMP-9 levels are found increased in obese subjects (RR2) and is correlated with BMI (R).

MMP-9 SNPs are strongly associated with obesity (R, R2).

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



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 [R].

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

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

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

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

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

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

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

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 endoxinemia) 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 development of insulin resistance and increased fat [R].

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

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

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 [R].

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 [RR2].

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

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

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 (R).

NF-κB activity was higher in animals fed a high fat diet.  Increased stomach fat was associated with higher Nf-kB in these tissues (R).

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) (R).

This MyD88 protein also causes gut permeability (R).

10) PAI-1

PAI-1 causes obesity.

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

PAI-1 results in the overgrowth of tissue (fibrosis) (R).

Angiotensin II increases PAI-1, which causes hardening of the arteries (R).

PAI-1 is believed to have a direct causal role in obesity and insulin resistance (R).

TGF-beta increases PAI-1, which is reversed by curcumin (R).

Curcumin also reduces PAI-1 from Angiotensin activation (R).

11) Glutamate

Glutamate causes weight gain.

Glutamate is an excitatory neurotransmitter and it stimulates appetite (R).

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 [R].

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 [R].

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 [R].

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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  • Cindi Anderson

    Interesting, but nobody addresses exactly HOW inflammation causes weight gain. I don’t mean long term, but instantly. There’s a lot of people saying for example, that when you react to a food that causes you inflammation, you gain 2 pounds overnight. That can’t really be 2# of fat, right? Is it water? Then how does that eventually become fat?

    1. Nattha Wannissorn, PhD

      Yes, water. You basically swell up. If you ever have anything swollen, you’ll know that the tissue retains more water.

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