FAT LOSS & FAT TISSUE ADAPTATIONS

(Adipose) Fat Tissue Adaptations

The adaptations that occur within the Fat tissue in response to weight loss and caloric restriction are perhaps the most fascinating of all.

 It was long believed that Fat tissue was a biologically inert tissue. That is, it was believed that Fat tissue only existed as a storage depot for energy, mainly in the form of triacylglycerides (TAGs), which occupy the vast majority of adipocyte volume. 

We now know that Fat tissue is an organ that integrates hormonal signals and secretes its own hormones (like leptin) called “adipokines,” which communicate with other tissues of the body including the brain.*1 

Research has demonstrated that fat tissue itself plays a large role in the self-defense system. During energy restriction, adipocyte volume decreases, signaling a reduction in nutrient availability and an energy gap. 

This is conveyed to the brain via decreased leptin (hunger hormone) secretion from adipose, a reduction in circulating insulin (insulin levels are inversely related to adipocyte volume), and possibly decreased sympathetic nervous system (SNS) tone.*2

Signals to the brain reflect not only long-term nutrient availability but short-term nutrient availability as well. Thus, the body senses not only how much energy is currently stored, but the direction and intensity of energy fluctuation across the fat cell .*3

This is demonstrated by the ability of short-term overfeeding to restore leptin levels even though pre-diet body fat levels have not been achieved.*4

 For example, even at high levels of body fat when your fat cells are plenty big, you may notice a pretty good surge in hunger in the first few days after you begin dieting. 

This short-term increase in hunger is likely triggered by the short-term drop in leptin due to decreased fluctuation of glucose and fats in the fat cells. 

In contrast, even at lower levels of body fat, hunger may be temporarily reduced by short-term increases in leptin due to refeeding as the fluctuation of glucose and fats into the fat cell is high even though the fat cells are smaller. 

That said, it’s the overall size of the fat cells that seem to have the biggest impact on overall energy expenditure and satiety, in most cases (there may be an exception, which I’ll discuss later).

These short- and long-term signals integrate into the hindbrain and hypothalamus, which serve as the control center for energy balance regulation.*5

In response to these signals of reduced energy reserves from the fat cells, energy expenditure decreases and appetite increases through increased expression of peptides like neuropeptide Y, agouti-related peptide, and decreased expression of proopiomelanocortin.*6*7

This produces the previously referred to as “energy gap” where more energy is desired than required. It’s not just the hormonal and neuro-endocrine signals that impact the energy gap. The actual structure of the fatty tissue seems to make an impact, as well. 

As fat mass is lost and the fat cells shrink, the extracellular matrix must be remodeled around them to accommodate the change. It has been hypothesized that weight loss places a strain on the extracellular matrix of adipocytes, which results in an altered metabolic profile that favors weight regain to relieve the cellular stress and mechanical strain on the adipocyte.*8

This fits with the theme of the body’s self-defense system setting you up for weight regain even while you’re still dieting.

Perhaps even more interesting is the notion that massive refeeding in the immediate post-diet period may increase the production of small fat cells called pre-adipocytes.

This was first demonstrated by MacLean, who noted the formation of a population of small fat cells produced from a process called pre-adipocyte differentiation (a process by which pre-adipocytes turn into fully formed adipocytes) during overfeeding in early weight regain in the post-diet period.

 This resulted in an increase in total fat cell number by almost 50%.*9Normally, total fat mass is a reflection of the size of the adipocytes, and the total cell number does not change. 

This is not to say that adipocytes stay around forever once they’re formed. In fact, we now know that there is fat cell turnover where new adipocytes are produced and mature adipocytes are cleared at a rate of about 8-10% per year—but this turnover is under extremely tight regulation that normally prevents changes in cell number.*10*11

That regulation can be overridden under certain circumstances, including morbid obesity when the maximum capacity of the adipocyte to store lipids is exceeded, thought to be around 100 micrometers in diameter per cell. 

As the fat cells approach this size, new fat cells can be formed through the differentiation of pre-adipocytes into fully formed fat cells to provide more storage for additional energy.*12

Interestingly, it appears that this increase in fat cell number can also occur even when the maximal cell size is not approached, specifically in the early post-diet period when weight relapse begins.*13

MacLean noted that the unique hormonal milieu (low T3, increased TSH, low leptin, low insulin) combined with decreased SNS (sympathetic nervous system) tone and severely reduced rates of fatty acid oxidation created an environment that favored pre-adipocyte differentiation into fully formed adipocytes when subjects engaged in rapid weight regain in the post-diet period.*14

Both SNS and T3 have an inhibitory effect on pre-adipocyte differentiation, and these hormones are reduced during the early post-diet period from the previous energy restriction. During this early post-diet period, it has also been suggested that signals reflecting short-term nutrient availability play a more critical role in pre-adipocyte differentiation than long-term energy storage signals.*15

That is, during the immediate post-diet period, if massive amounts of energy are made available, it may override the existing adipocytes’ ability to effectively clear the nutrients (namely glucose and fatty acids) due to 

1) the unique milieu previously mentioned and 

2) the drastically decreased rates of fat oxidation in adipocytes (fats literally being stuffed into adipocytes way faster than they can oxidize them). 

This could theoretically trigger pre-adipocyte differentiation in an attempt by the body to preemptively create a greater capacity for storage of energy rather than wasting it.

Now, we know that was a whole lot of science crammed in there for you. If I lost you in the milieu, let me explain. 

Essentially, what I was saying is that if you regain weight too fast in the early post-diet period, you might actually increase your fat cell number. 

This is potentially a huge problem for weight regain and may, at least in part, explain the phenomenon of body fat overshooting. Remember my discussion of body fat setpoint? The setpoint is thought to reflect the size of the individual fat cells. 

Thus, even though one may have regained the total amount of fatback after massive refeeding post-diet, their individual fat cells may now be smaller due to an increase in overall fat cell number, and this may signal to the body that the setpoint hasn’t been met. 

As a result, leptin levels may not be as high as they were previously at the same body fat level, and it may drive your body to continue gaining fat until the adipocytes each return to their previous cell size.*16

While the current data demonstrating this phenomenon is in animals (since demonstrating it in humans is problematic), there is evidence that this process occurs across species based on some human data.*17

This is the final and perhaps most powerful Part of the self-defense system. Increasing the total number of fat cells (hyperplasia) would make future weight loss efforts even more difficult and cause the body to defend a new, higher body fat setpoint. 

This is a major reason I spend so much time on the diet after the diet— because if you don’t get that part of the equation correct, it can really screw you up. 

Now imagine what several yo-yo dieting cycles could do, when weight is repeatedly regained too quickly. Yikes. 

I want to be clear, however, that this is a unique situation (post-diet dynamic rapid weight regain) where fat cell hyperplasia may take place. This is not going to happen to someone who regains all their body fat but does so at a slowed pace. 

This situation likely only occurs in those who lose significant weight, then aggressively gain a significant amount back in a short period (likely a few weeks or less). I know some of my readers may be feeling extremely disheartened and angry reading this section of the blog.

 In fact, you may identify with this exact scenario and be convinced that you’ve added more fat cells and things are now hopeless. Maybe you did, maybe you didn’t, but all you can do now is move forward—and I’ll do my best to arm you with the tools to facilitate long-term healthy weight reduction.

 Other readers may now think that liposuction is the best option—but this procedure has its own drawbacks. Liposuction has been shown to have similar relapse statistics as normal weight loss, only the fat comes back in different, sometimes odd places.*18

Recall that fat cells are constantly being turned over and produced thus if weight is regained post-surgery, the new, small fat cells are more than eager to dispose of the nutrients. It’s very difficult to fool mother nature, and almost everything has a price. 

Why Do We Get Fat?

Now that you’ve read this blog on the body’s self-defense system, some of you may be wondering: Why do we get fat? If body fat set point is so highly regulated, then how do we exceed it and gain weight past our set point? 

A researcher named Speakman proposed an interesting answer to this question. Essentially, regulation of body fat setpoint weighs human survival at risk of starvation (low end of setpoint) versus. the risk of predation (exceeding the setpoint).*19*20 

That is the power of your body’s self-defense system to prevent you from starving to death versus your body’s self-defense system for letting you get so fat that you can’t avoid a predator.

He argues that a substantial reduction in predatory risk within the human population over the last several thousand years has caused a substantial genetic shift. So much so that there is a significantly less robust defense against weight gain than against weight loss. While this is only a theory, we think it makes sense and tends to agree with him. 

These data have led some people to speculate that genetics drives the obesity crisis, but that’s unlikely. Large-scale changes in genetics take many generations, but obesity became a crisis in less than a generation; a “blink of an eye” when put in terms of evolution. 

Therefore it’s extremely unlikely that all or most people who become obese simply have “bad genes.” It’s more likely that genetics can predispose us to obesity, and when you combine that with an obesogenic (promoting excessive weight gain) environment; free access to highly palatable, cheap, and calorie-dense foods; and a sedentary lifestyle, the obesity epidemic arrives. 

 “Genetics can only load the gun for obesity, behavior pulls the trigger.”

It’s not all just physiological, however. Overeating isn’t just driven by physiology; it’s also psychology and sociology. Portion sizes are bigger pretty much across the board. 

If you examined a dinner plate from the 1800s, you’d notice it’s about 50-60% the size of current dinner plates. Also, consider instructions for you to always “clean your plate.” Or eating out and feeling like you got a good value if you got a lot of food for the price.

Heaven forbid you to go to an all-you-can-eat place because that typically turns into “eat all you can.” Finally, consider the last time you went to a social event that didn’t have food?

How would you feel if you went to a social event that didn’t have something to eat? Probably like it wasn’t well planned, right? 

These are just a few examples demonstrating how ingrained food is into our culture, and why overeating isn’t as simple as physiology. 

Evolution has helped us develop an elaborate, repetitious, and powerful self-defense system that defends us against starvation. 

Unfortunately, this self-defense system also pre-disposes us towards weight regain and reduces the chance of future dieting success. 

Therefore, we need to heed the advice of MacLean, who stated: “To ensure success, the regain prevention strategies will likely need to be just as comprehensive, persistent, and repetitious, as the biological adaptations they are attempting to counter.” 

The purpose of this blog is to lay out what I know about weight loss, weight regains, and the best ways to counter weight-regain and produce lasting weight loss. 

Now that the bad news is out of the way, it’s time to start talking about how to lose weight—and how to keep it off.

*1 (n.d.). Narrative Review: The Role of Leptin in Human Physiology – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829242/

*2 (n.d.). The role for adipose tissue in weight regain after weight loss.. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/25614203

*3 (2011, June 15). Biology’s response to dieting: the impetus for weight regain. – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/21677272

*4 (n.d.). The role for adipose tissue in weight regain after weight loss.. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/25614203

*5 (n.d.). Brain regulation of energy balance and body weight. – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/23990408

*6 (n.d.). Chronic exercise lowers the defended body weight gain … – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/14695115

*7 (n.d.). Increased hypothalamic melanin-concentrating hormone gene …. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/15165723

*8 (n.d.). Human biology of weight maintenance after weight loss. – NCBI. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/22472972

*9 (n.d.). Biology’s response to dieting: the impetus for weight regain. – NCBI – NIH. Retrieved September 11, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/21677272

*10 (n.d.). Adipocyte turnover: relevance to human adipose tissue morphology.. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/19846802

*11 (n.d.). Dynamics of human adipose lipid turnover in health and … – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/21947005

*12 (2010, June 22). Single-cell analysis of insulin-regulated fatty acid uptake … – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/20570821

*13 (2008, February 20). Weight regain after sustained weight reduction is … – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/18287221

*14 (2008, February 20). Weight regain after sustained weight reduction is … – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/18287221

*15 (n.d.). Biology’s response to dieting: the impetus for weight regain. – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/21677272

*16 (2008, February 20). Weight regain after sustained weight reduction is … – NCBI – NIH. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/18287221

*17 (n.d.). Long-term prospective and controlled studies demonstrate adipose …. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/16131581

*18 (2011, April 7). Fat redistribution following suction lipectomy: defense of body fat and …. Retrieved September 12, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/21475140

*19 (n.d.). Thrifty genes for obesity, an attractive but flawed idea, and an … – NCBI. Retrieved September 11, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/18852699

*20 (n.d.). If body fatness is under physiological regulation, then how … – NCBI. Retrieved September 11, 2018, from https://www.ncbi.nlm.nih.gov/pubmed/24583765