Change Your Body Fat Set Point. Here's How

Gene Expression, Nutrient Partitioning, and Leanness

The right training and supplement can help move your body weight set point, making it easier to get lean or build muscle.

Whether you call it a set point or a homeostasis point, it’s the same thing: your body tends to remain in about the same state. Bodyweight is one example.

It seems like a casual statement, but actually it’s a powerful thing. For example, let’s compare three people who eat and exercise identically:

  1. One might naturally stay at about 200 pounds in fairly lean condition. It would take substantive changes for his body to move far from this in either direction.
  2. The second person – eating and training the same way as the first – might tend to stay at about 220 with 40 pounds more fat than the first guy.
  3. The third person might struggle to reach a soft 180 on equal training and diet.

Different genetics might be the explanation. But sometimes it clearly isn’t. What if we were talking about the same individual at different points in time? Then genetics couldn’t be the explanation. Or at least not genetics in the usual sense of having a particular DNA code.

It’s Not Just Genetics

Often a person can improve set points of body weight, muscle mass, and body fat – independent of changes in training or nutrition – simply by being persistent with his or her current workouts.

A novice whose body tended strongly to remain at a soft 180 might easily become a 200-pound lean lifter in three years of training, even on the same macronutrient intake and training volume. His muscle gene expression adapted to support a higher set point for lean mass, and his adipose gene adapted to create a lower set point for fat mass.

It’s important to note that macronutrient intake often doesn’t stay the same. A more experienced lifter may stay muscular while consuming less protein and calories than he did earlier when having a much lower set point for muscle. Or he might consume more calories yet remain leaner. These examples show that diet isn’t the sole determinant.

Your set points can also get worse. Many find it far harder to maintain a condition that was easy for them 10 or 20 years previously. It’s easy to blame aging, but that’s a very vague explanation, and it’s not necessarily the cause of the problem. Plus, that explanation provides no solution.

But what if you improved gene expression? Now that can be a solution.

What Are Set Points Really?

Set points can be simple or complex. It’s simple enough to notice that your body tends to stay at some given weight, while at another time, it may have tended to stay at some different weight. And it’s simple enough to notice that if you don’t control calories your body fat tends to stay at a particular amount.

But let’s take a closer look: There’s no known way in which the body measures your weight and adjusts its processes to maintain that number. Instead, staying a particular weight results from many aspects of gene expression.

Of these aspects, the most important are those which control nutrient partitioning, adipose inflammation, and skeletal protein muscle synthesis i.e., muscle building.

Nutrient Partitioning: Key to Muscle and Leanness

I was first introduced to the idea of nutrient partitioning back in the 1990s from Dan Duchaine’s writings. He was huge on this point and on aspects of it, such as insulin sensitivity.

I have to admit that I really didn’t get it. With correct weight training and a reasonable diet, wouldn’t your muscles grab the nutrients they need in any case? If you want to lose fat, don’t you just need to reduce calories to less than you burn, regardless of nutrient partitioning?

Wasn’t that just a basic fact? To lose fat, eat less. Eat more than you burn and you’ll gain fat. That was about it.

Well, I was wrong. In fact, it’s enormously different being where your body regulates itself to be lean and stays lean (unless you really pig out for an extended time) versus being where your body regulates itself to be fat, and you have to kill yourself to get lean.

Meet Muscle Mike and Fat Fred

How does nutrient partitioning control leanness? To help you understand, let’s make an analogy.

Mike and Fred both work at a remote outpost. A plane drops a food package every day for the both of them to divide as they will. It has suitable protein, carbs, and fat for two people.

Fred’s a fat and lazy guy. Mike is muscular, does all the work around the place, and trains with weights.

What happens if Mike insists, “I do all the work around here, so I’ll take what I want and you pick up the scraps?” Mike’s nutrient intake will then support his weight training and work. He may gain muscle mass. As for Fred, he may lose fat.

But what if Fred grabs as much food as he wants instead, beating Mike to the plate? Mike’s likely to lose muscle mass and body weight, while Fred gets even fatter.

In either case, the fellow receiving only leftovers would be getting enough nutrition to survive. Even if it went on for years, he wouldn’t die; he’d simply stabilize at a lower body weight. Mike and Fred’s set points would be determined by who grabbed food first and how much that person tended to leave for the other.

In this analogy, Mike is your muscle and Fred is your fat. And “who grabs the food first” is your nutrient partitioning.

Vicious Cycle: Adipose Inflammation, Insulin Sensitivity, and Fat Mass

One of the main factors controlling nutrient partitioning is your insulin sensitivity, and even more specifically, the difference in insulin sensitivity between your muscle and fat cells. If you improve your nutrient partitioning, your body’s set point changes from supporting mostly body fat to supporting mostly muscle.

Insulin sensitivity is strongly related to adipose inflammation and amount of body fat. It’s a vicious cycle:

  • Impaired insulin sensitivity causes the body’s set point for fat mass to increase. That means the person will gain fat unless great and consistent care is taken.
  • The resulting increased fat mass yields increased adipose inflammation.
  • The increased adipose inflammation yields worsened insulin sensitivity, further ramping up the cycle.

Worse, many other adverse changes in gene expression occur in concert with the increase in body fat. It’s a hard cycle to break.

One answer is to just bite the bullet and lose the fat, as hard as that is to do when impaired gene expression already exists. Many have done it successfully, but far more have tried and failed or had only temporary success. A key reason for this is that after about 10% of body weight has been lost, losing even more typically slows metabolism. Some succeed despite this; many do not.

Even among those who succeed, many find themselves in a metabolically impaired situation where they can’t consume as many calories as others, can’t handle a normal carb intake, and can’t build or maintain as much muscle mass while remaining lean. All this is from gene expression.

Exercise and Gene Expression

What sorts of exercise will change your set point towards a leaner physique?

Rather than rely on biochemistry, rely on the findings of successful coaches, on the accounts of those who have followed the plans, and personal experience. But as it happens, biochemistry completely backs up what they’ve found.

And while weight training is one of the most effective ways to improve your set point, many don’t lift in an effective manner for that purpose. Are you short-changing yourself?

Brief, intensive exercise with hypertrophy-range weights taken to maximal effort will bring cellular energy levels low (or specifically, convert most of the cell’s ATP to AMP) and drive cellular oxygen levels low.

If tension is kept constant when lifting, blood flow is largely occluded. And if rest periods are kept short relative to the workload, muscle temperature increases. (About 104° F appears optimal.)

All these things improve gene expression for fat burning and elevated metabolic rate as well as muscle growth.

Does this sound like Christian Thibaudeau’s Growth Factor Training? Or even like Vince Gironda’s classic physique-transforming methods? It should. It also sounds like high-intensity interval training (HIIT), and it should.

Coaches have long said to train this way, but frankly, it’s hard. Many pump their reps, lose tension at the top or bottom of reps, do more sets of easier work, and allow too much rest time between sets. Or they do exclusively heavy work for low reps, which always leaves considerable cellular energy reserves. If you want to reset your physique to be naturally lean, don’t train like that.

Modulate Your Gut Bacteria for a Leaner Set Point?

Yes, your gut bacteria can have a profound effect on your set point for body fat. Unfortunately, presently available probiotics won’t help much. For now, be aware that there’s indeed a great relevance, and for now, a good diet is your best way of favorably modulating your gut bacteria.

Could a Supplement Create A Leaner Set Point?

Can we change gene expression towards fat loss without inducing metabolic impairment, or even better, while improving metabolism? Yes. Among the gene expression changes we’d want are:

  • Reductions in inflammatory IL-6, IL-1β, and TNF-α
  • Reduction in inflammation-promoting TLR-4 and MCP-1
  • Increase in anti-inflammatory adiponectin
  • Increase in GLUT-4 to increase nutrient transport into muscle
  • Increase in metabolic-rate-speeding uncoupling proteins

As a consequence of gene expression changes, we’d like to see proof of reduced systemic inflammation as shown by reduced C-reactive protein, and lower response to LPS, a fat-promoting endotoxin produced by some of the normal gut bacteria.

And, of course, we want to see results in practice where people’s set points improve dramatically! Too much to ask for? Not at all.

Cyanidin 3-Glucoside (C3G) Creates A Leaner Set Point

C3G, sold as Indigo-3G (on Amazon), is always described in terms of the effects people see for themselves. Improved gym performance, improved muscle gain, improved fat loss, and – for those with impaired ability to handle carbs – improved carb tolerance.

What’s rarely discussed is Indigo-3G’s origin. Why did Biotest ever decide to research cyanidin 3-glucoside, at doses never before tried?

Part of the answer is gene expression. Cyanidin 3-glucoside was clearly the most potent available nutritional agent for favorably modulating gene expression. Every mechanism I discussed above, cyanidin 3-glucoside (the active anthocyanin in Indigo-3G) is proven able to do.

You lose body fat on Indigo-3G (on Amazon) not because of receptor stimulation (as with typical “fat burners”) but because your set point becomes one of lower body fat for your given diet and exercise level. The effect remains even on discontinuance.

Natural, Sustained Leanness

Focusing your efforts on improved gene expression – through better diet, better exercise, and better supplementation – is the way to natural, sustained fat loss. Change your set point to a favorable one rather than push endlessly against an unfavorable set point.



Well stated article. The only other thing that I would like to know about, being a hard loser and needing extreme caloric restriction, is the role of thyroid. Particularly if the t4/t3 isn’t binding to the TBG and TTR properly. And what, if any, supplements or nutritional advice would be advised for such issues.


Thank you for your training recommendations - as you say coaches see results from these practices, as CT’s training has demonstrated.

The proposed physiology to explain these effects however seems problematic, not least the “set point” idea and the framing as about nutrition partitioning.

For example,
You likely know that the concept of a “set point” in nutrition (taken from psychology) was tested in the 90s along with and has since been abandoned.
For example as early as 2001, this paper " Multiple neural systems controlling food intake and body weight" overviews how set point was laid to rest at least in nutrition.

It’s also not clear to me anyway how your analogy about fred and mike is supposed to be about nutrient partitioning. If a sedentary person grabs out on food (fred) and eats as much as he wants, then he’s more likely to get fat - no matter the composition of the food. Energy density regardless of nutrient uptake. As to whether Scraps guy would go to a lower stabilisation point? A lower body weight with insufficient nutrients and calories to maintain a health metabolism is called malnutrition.

The who grabs the food first - perhaps you’re trying to say - is based on what the body’s homeostatic needs are at the time of food consumption?

You seem to suggest that insulin sensitivity is a reason for what grabs what first.
recent research is challenging that correlation "Scientific evidence is however largely disagreeing with an adverse effect of postprandial hyperinsulinemia on fuel partitioning. "

For fat to have a blocking effect on insulin sensitivity, we’re talking obsesity, where the normal kinds of storage of excess fuel into adipose tissue is effectively broken (eg this paper from 2016 is a good overview). In other words these effects around insulin sensitivity don’t get to this place of pro inflmmatory and dysfunctional response outside of these extreme metabloic conditions - increasingly normal, but still extreme in terms of human phsyisology.

So i guess i’d suggest when you talk about “increased body fat” - what kinds of increase are we talking about?

Likewise for HIIT and fat loss - the literature is kinda mixed.
Once again the research tends to focus on obese - one paper shows no difference between groups doing more mid/continuous range exercise and HIIT. Suggesting it’s whatever you enjoy and stick with.

Another papers says mixing it up is good for your metabolism and your heart.

Most recent review of younger cohorts seems to show similar results.

Again, your suggestions on practice show good results - better eating for better gut; getting moving with loads to support repairing metabolism - all well supported.

Hope perhaps these more recent research findings may be of use in thinking about mechanisms - and how that science is being refined it seems daily.

thank you


This is a sales letter for Indigo, not a scientific article…the claim to question here is: does it alter gene expression?


oh that’s so funny! Thank you

as for gene expression the claim at the end of the article is:

" You lose body fat on Indigo-3G® not because of receptor stimulation (as with typical “fat burners”) but because your set point becomes one of lower body fat for your given diet and exercise level. The effect remains even on discontinuance."

To that point, since set point is not a valid framing for body it’s like ether - been discredited.

if you’re asking just about the compound used in the supplement - can’t find any human trials

in mice studies sure it affects gene expression (lack of sleep affects gene expression too)

Here’s a recent review - so it may be early days to see this used in humans for effect - outside that is the presence of these polyphenol molecules in food

and thanks again for the pointer.

I posted this question on the Indigo-3G store page, but it never got posted.
It doesn’t make much sense to take before my biggest meal, where I have at least three big meals in a day. So, will this product better serve me if I took it at each meal? If so, should I take the three recommended caps, or less? Currently, I try to take this at every larger meal, two to three times a day — altering the quantity of caps from one to three, based on the meal size. It’s pricey, but if it works…
Thanks for the good article.

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I love T-Nation’s informative ads. I have bought Indigo3 twice already, but these articles are still ads.

I’d like to mention that when I restrict calories, I have found my Uric Acid levels to rise considerably. My levels go from normal (<6) to 8-10 within 5-10 days depending on the degree of restriction. Uric acid is know to cause inflammatory insulin resistance. It takes raises insulin levels and also downregulates thyroid function, There is no doubt that after restriction, daily caloric expenditure drops even without muscle loss, and certain anti-inflammatory agents can reduce the rise in Uric Acid. I don’t equate this with set point theory, but metabolism clearly drops with restriction and the body actually is as likely to regain fat as muscle if you go back up to your old maintenance level right away because of the residual insulin resistance from the effects of Uric Acid.

Most people process carbs just fine, but new research has demonstrated that certain low GI carbs like who grain wheat, beans, and some others, while they produce a low rise in blood sugar, actually require 150-200% as much total insulin to manage over 6-12 hours as faster carbs like rice and potatoes. The associated proteins like gluten, and other non-proteins in the low GI carbs raise the release of glucose from the liver for many hours while they are passing through the intestine, and broken down by intestinal bacteria. Research with high gluten wheat for example showed double the release of insulin on a per carb gram basis as for white rice. In effect the reason low GI carbs are low GI is because they provoke much more insulin release so blood sugar doesn’t go high, but the effect on insulin exposure is high. Point is that people handle glucose just fine but may have varied inflammatory responses to certain complex carb sources that result in a bi-mechanistic form of insulin resistance, (1. increased counter-regulatory hormone levels, 2. Increased insulin exposure and downregulation of insulin sensitivity at the receptor level).

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What specific kind of markers (blood or otherwise) can someone track to objectively determine that Indigo3G is working? I have used it many times in hopes of seeing a positive change, but never notice anything significant subjectively to justify the cost. With so many variables available in our quest to improve, its often difficult to determine if only one or which one(s) is making a difference. How much bodyfat should I reasonably expect to lose with IG3? Would an insulin blood lab be a good reference indicator? My insulin lab runs high even though my last A1C was excellent at 4.8. Thanks

Seems like any blood glucose tests would be fair comparators, but I really don’t know. It’s a good question. When you’ve taken it in the past, did you have any A1C labs close enough before and after to compare?

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