The Science of Epigenetic Obesogenic Memory

[T_Nation]

by Chris Shugart

Reprogram Your Fat Cells

Does shrunken fat tissue remember being fat? Does it try to make you fat again after you've lost weight? Yes, science says. Here's why and how to fight back.

Over 80% of people who lose fat eventually gain it back. Experts blame several things, like unsustainable fad diets, a return to unhealthy eating habits, and loss of metabolism-boosting muscle. Those are all valid reasons, but what if something else is happening, too?

I have a unique perspective on this. I was borderline obese in my early 20s. I lost over 60 pounds and have spent the rest of my life trying to keep the fat off. I gained around 30 pounds of muscle over the years and never returned to my bad eating habits. I'm part of the 20% of people who never regained their fat.

Has it been easy? Heck no, not until fairly recently at least.

Not long ago, I'd say, "It's like my body WANTS to be fat!" I also hated hearing never-been-fat trainers telling their followers to eat cheat meals. And their advice on "bulking" diets? No way. If I listened to them, I'd be fat again. I had to keep my diet and training strict, or the fat would come right back.

But a few years ago, all that changed. Biotest founder Tim Patterson walked into my office and tossed me a bottle of inky capsules, a new supplement he was working on. "This fixes sick and broken fat cells!" he said. I started taking it and, within weeks, I noticed it was easier to stay lean. I could eat carbs again, too, which helped me gain some extra muscle.

The capsules contained cyanidin 3-glucoside (Buy at Amazon) (C3G). Tim later named it Indigo-3G and marketed it as a nutrient partitioning agent. To simplify how it worked, we often said, "It causes muscle to use calories instead of storing them as fat." That's an oversimplification, but not inaccurate.

Now, recent research has shed some new light on the "broken fat cells" idea and may further explain how C3G works.

Fat Tissue Has Memories

Swiss researchers conducted several human and animal studies and concluded that adipose tissue retains an epigenetic memory of obesity even after a person loses fat. The cells "remember" their former condition, predisposing formerly chubby people to regain weight. (As a reminder, when you lose fat, the fat cells are still there; they just shrink.)

They found that obesity induces epigenetic modifications – changes in DNA methylation and histone acetylation – in adipocytes (fat cells). These alterations persist even after fat loss, leading to lasting changes in gene expression that favor fat storage and inflammation.

As part of their research, they took fat cells from previously obese folks and from people who'd never been obese. The science gets mind-numbingly complex, but they concluded that obesity induces cellular and transcriptional (obesogenic) changes in the adipose tissue, which aren't resolved after fat loss. In short, yes, fat cells remain "sick" even after weight loss.

Then the researchers took some mice, got them fat, leaned them back up, and extracted fat cells. Those fat cells absorbed more sugar and fat than cells from other mice that were never fattened up. And when the previously obese mice and the never-been-fat mice were fed a high-calorie diet, the formerly fat rodents gained 14 grams while the lean mice only gained 5 grams. The scientists called this "accelerated weight regain."

The researchers attribute all this to epigenetic obesogenic memory.

How Could C3G Help?

The scientists in the above studies weren't looking at C3G, but after pouring over their research, I was reminded of what Tim said: "C3G fixes sick and broken fat cells." Could the substance help with epigenetic obesogenic memory? Here's what I found:

• Modulation of Gene Expression: C3G influences enzymes that regulate epigenetic modifications, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), and DNA methyltransferases. These enzymes modify DNA and histones, potentially reversing obesogenic gene expression patterns. Also, by activating AMP-activated protein kinase (AMPK), C3G helps normalize gene expression related to energy metabolism, reducing the impact of epigenetic changes that promote fat storage.
• Anti-Inflammatory Effects: Chronic low-grade inflammation associated with obesity reinforces epigenetic changes that promote fat storage and insulin resistance. C3G's anti-inflammatory properties help mitigate this, creating a healthier metabolic environment less prone to obesogenic programming.
• Improved Insulin Sensitivity: C3G enhances insulin sensitivity and glucose uptake in fat cells by promoting the translocation of GLUT4 to the cell membrane. Improved insulin signaling counteracts epigenetic changes that impair glucose metabolism, helping to reduce fat accumulation.
• Promotion of Fat Oxidation: C3G boosts fat oxidation and reduces fat storage, partly by activating pathways like AMPK. This counteracts epigenetic memory that favors energy storage over expenditure. C3G also induces the browning of white fat, increasing mitochondrial activity and thermogenesis, which are impaired by epigenetic obesogenic programming.
• Reduction of Oxidative Stress: Obesogenic memory is reinforced by oxidative stress, which can lead to DNA and histone modifications. C3G's antioxidant properties reduce oxidative damage, potentially preventing further reinforcement of these epigenetic changes.
• Potential to Influence Microbiota: The gut microbiota interacts with the host epigenome and influences metabolism. C3G positively modulates gut microbiota composition, disrupting obesogenic programming reinforced by a dysbiotic (unbalanced) microbiome.
• Long-Term Metabolic Reprogramming: By improving metabolic flexibility and reducing inflammation, C3G helps sustain fat loss and prevent weight regain, even in individuals predisposed to obesity due to epigenetic memory.

Does C3G "Erase" the Memories of Fat Cells?

We can't say that yet, but it certainly helps anyone who's been fat in the past have an easier time staying lean. For whatever reason, it worked for me, and the adjacent science is supportive. If you want to give it a shot, take 300 mg of C3G daily. That's four capsules of Indigo-3G (Buy at Amazon).

Reference

1. Hinte. "Adipose tissue retains an epigenetic memory of obesity after weight loss." Nature, 18 November 2024.

[izzoacct]

@T_Nation

Hinte. “Adipose tissue retains an epigenetic memory of obesity after weight loss.”

Has this been tested on humans or just mice?

[Chris_Shugart]

@izzoacct

Has this been tested on humans or just mice?

Both. Here’s a summary of a few human studies:

1. Hinte et al. (2024) - Nature

• Human Component: This study included human subcutaneous and omental adipose tissue biopsies from individuals with obesity, collected before and after bariatric surgery (sleeve gastrectomy or Roux-en-Y gastric bypass). Lean individuals served as controls.
• Findings: Single-nucleus RNA sequencing (snRNA-seq) revealed persistent transcriptional changes in adipocytes, endothelial cells, and adipocyte progenitor cells post-weight loss compared to lean controls. These changes suggest an epigenetic memory, as the transcriptional profiles did not fully revert to those of lean individuals, indicating retained molecular alterations in adipose tissue.
• Significance: Directly demonstrates transcriptional memory in human adipose tissue, supporting the idea of epigenetic retention after weight loss.

2. Benton et al. (2015) - Genome Biology

• Human Component: The study analyzed DNA methylation in subcutaneous and omental adipose tissue from obese women before and after gastric bypass surgery.
• Findings: Significant differential methylation was observed at 485,577 CpG sites post-weight loss. Genes linked to obesity (e.g., CETP, FOXP2, HDAC4, DNMT3B, KCNQ1) showed persistent methylation changes, with some correlating with altered mRNA levels. For example, methylation at HIF3A (cg22891070) was associated with BMI and partially modifiable by weight loss, indicating lasting epigenetic marks.
• Significance: Provides evidence of DNA methylation changes in human adipose tissue that persist after weight loss, supporting the concept of epigenetic memory.

3. Multhaup et al. (2016) - Molecular Metabolism

• Human Component: The study examined adipose tissue samples from obese individuals before and after bariatric surgery.
• Findings: Post-weight loss, human adipose tissue showed persistent inflammation and incomplete restoration of insulin sensitivity in adipocytes (only 42% of patients showed improved adipocyte insulin action). While direct epigenetic profiling was not conducted, the retained inflammatory gene expression suggests an obesogenic memory, potentially linked to epigenetic mechanisms.
• Significance: Supports the persistence of an obesogenic memory in human adipose tissue, consistent with epigenetic changes observed in other studies.

Key Points:

• These human studies primarily used adipose tissue biopsies from obese individuals undergoing significant weight loss via bariatric surgery, compared to lean controls or pre-surgery states.
• The findings consistently show that transcriptional and epigenetic changes (e.g., DNA methylation, altered gene expression) in adipose tissue do not fully revert to a “lean” state after weight loss, indicating an epigenetic memory.

[burien_top_team]

Do you need to consume carbs in order for C3G to do its work vis-a-vis fat cells? In other words, would be a valuable fat-loss aid during a low-carb/keto/carnivore diet?

[Chris_Shugart]

I used SuperGrok to sum up the science in that context, and it did a pretty good job:

C3G’s primary mechanisms for influencing fat cells do not strictly depend on carbohydrate consumption, but its effects may be modulated by dietary context. Here’s how C3G interacts with fat cells and metabolism:

1. Nutrient Partitioning and AMPK Activation:

• C3G activates adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy metabolism. AMPK activation inhibits lipoprotein lipase (LPL) in fat cells, reducing fat storage, while promoting LPL activity in muscle cells, directing nutrients toward muscle for energy use rather than fat storage. This process, known as nutrient partitioning, can occur with dietary fats or proteins, not just carbs, as it relies on redirecting energy substrates (calories from any macronutrient) away from adipocytes (fat cells).[

• In studies, C3G has been shown to reduce fat accumulation and promote fat loss even in high-fat, high-sugar diets by enhancing energy expenditure and fatty acid oxidation. This suggests that C3G’s effects are not exclusively tied to carbohydrate metabolism but can influence lipid metabolism as well, which is relevant for low-carb diets.

2. Brown Adipose Tissue (BAT) Activation and Mitochondrial Biogenesis:

• C3G promotes thermogenesis in brown adipose tissue (BAT) and induces beige cell formation in white adipose tissue (WAT) by upregulating uncoupling protein 1 (UCP1) and other thermogenic genes. This increases energy expenditure, which can aid fat loss regardless of carbohydrate intake, as BAT primarily uses fatty acids for heat production, aligning well with keto or carnivore diets that are high in fat or protein.

• C3G enhances mitochondrial number and function in BAT and WAT, further supporting fat oxidation. Since keto and carnivore diets rely on fat as the primary fuel source, C3G’s ability to boost mitochondrial activity could theoretically enhance fat-burning efficiency in these contexts.

3. Insulin Sensitivity and Glucose Metabolism:

• C3G improves insulin sensitivity and glucose uptake in cells, which is often studied in the context of high-carb diets or diabetic models. On low-carb, keto, or carnivore diets, where carbohydrate intake is minimal, this mechanism may be less relevant, as these diets naturally reduce insulin levels and reliance on glucose metabolism. However, C3G’s ability to enhance insulin signaling could still benefit individuals with insulin resistance, even in low-carb settings, by improving metabolic flexibility.

4. Anti-Inflammatory and Antioxidant Effects:

• C3G reduces inflammation in fat cells by suppressing pathways like NF-κB and increasing adiponectin levels, which supports fat metabolism and reduces fat cell inflammation. These effects are independent of carbohydrate intake and could be beneficial in any dietary context, including low-carb diets, where inflammation from high-fat intake or other factors might still be present.