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Saturday, February 25, 2012

Fat Tissue Expansion: Part III ~ Fat Cell Number

Before reading you may wish to read:  Part I ~ Terminology , Part II ~ Overview of How it Can Happen

As mentioned in Part II, fat tissue expands by an increase (proliferation) of fat cells and/or a growth of the individual fat cells.  This installment concerns the number of fat cells and is likely the least "actionable" in this series in terms of diet, unless you're planning to have a child and/or have young children.   This does, however, lend some assistance to those formerly obese who are considering liposuction or more drastic surgery that may involve fat cell removal.  Bottom line, the number of fat cells we have is virtually completely out of our control as adults (according to current understanding). 

So this post will be rather short, and I plan to expand on the data we have regarding fat tissue development in infancy, puberty and other periods of childhood in subsequent installments.  It would appear that the number of fat cells we are born with is determined somewhat later in gestation.  At right is the progression of the formation of mature adipocytes.    From this article

A single fertilized egg gives rise to nearly 200 different cell types that make up the multiple developmental lineages and multicellular organism. The full developmental program of preadipose tissue from fertilized egg is unknown. However, the pluripotent fibroblasts (stem cells) are known to have mesodermal origins) and can differentiate into committed preadipocytes, cartilage, bone or muscle tissue. In humans, preadipocytes begin to differentiate into adipose tissue during late embryonic development, with a majority of the differentiation occurring shortly after birth. This enables the newborn to cope more efficiently with intervals between nutrient intake.
It would seem that whatever the pregnant mother can do dietarily to influence tissue composition, it would be very late in the pregnancy and/or in early life nutrition (breastfeeding or formula).  I note that the embryonic cell line from which fat cells are derived is also a precursor for various lean tissues.  Continued:
Rat and mouse preadipocytes do not begin conversion into adipose tissue until after birth. All species have the ability to differentiate preadipocytes throughout their life spans in response to the body’s fat storage demands.
Yes, humans are different from mice, but the differentiation patterns in other animals would indicate that to the degree this differentiation occurs in humans before birth, it is likely quite late in gestation.  More:
In vivo study of preadipocyte differentiation is difficult. Fat tissue within animals consists of approximately one third adipocytes. The remaining two thirds are a combination of small blood vessels, nerve tissue, fibroblasts and preadipocytes in various stages of development. The distinction between preadipocytes and fibroblasts is difficult to make, and the inability to align preadipocytes at similar developmental stages confounds detailed in vivo studies. 
I plan to look at that bold/italicized statement there vis a vis obesity in adulthood.  Are they talking on average?  For cell type or mass/volume?  Stay tuned ...  In any case, given that fat cells can enlarge significantly, BUT cannot expand indefinitely, obesity and susceptibility to associated diseases has a significant component rooted in the number of fat cells.  (Note, the citation is from 2000.  If anyone knows of a more recent one with information differing from that presented here, I would appreciate the heads up.)

I have been unsuccessful if finding any direct studies on the number of fat cells in human infants and subsequent body weight later in life.  All of what I've been able to find concerns fat tissue/proportion.  Still, in light of the information above, one can presume that when we "lay down fat" in greater amounts in late gestation/early infancy, we do so by relatively rapid differentiation of mature adipocytes which have greater receptor (insulin and ASP) levels than preadipocytes for triglyceride storage.  Therefore it seems a logical conclusion that this period is one that is crucial to determining fat cell number.  Consider then, this considerably older (1973) study who looked at obese and non-obese adults.
ABSTRACT:  The cellular character of the adipose tissue of 21 nonobese and 78 obese patients has been examined. Adipose cell size (lipid per cell) was determined in three different subcutaneous and deep fat depots in each patient and the total number of adipose cells in the body estimated by division of total body fat by various combinations of the adipose cell sizes at six different sites. Cell number has also been estimated on the basis of various assumed distribution of total fat between the subcutaneous and deep fat depots.
Obese patients, as a group, have larger adipose cells than do nonobese patients; cell size, however, varies considerably among the fat depots of individuals of either group. The variation in cell size exists not only between, but also within subcutaneous and deep sites. Estimates of total adipose cell number for a given individual based upon cell size can, therefore, vary by as much as 85%. On the basis of these studies it is suggested that the total adipose number of an individual is best and most practically estimated, at this time, by division of total body fat by the mean of the adipose cell sizes of at least three subcutaneous sites.
Irrespective of the method by which total adipose cell number is estimated, two patterns of obesity emerge with respect to the cellular character of the adipose tissue mass of these patients: hyperplastic, with increased adipose cell number and normal or increased size, and hypertrophic, with increased cell size alone. These two cellular patterns of obesity are independent of a variety of assumed distributions of fat among the subcutaneous and deep depots. When these different cellular patterns are examined in terms of various aspects of body size, body composition, and the degree, duration, and age of onset of obesity, only the latter uniquely distinguishes the hyperplastic from the hypertrophic: hyperplastic obesity is characterized by an early age of onset, hypertrophic, by a late age of onset. These studies indicate that there are two distinct periods early in life during which hypercellularity of the adipose tissue are most likely to occur: very early within the first few years, and again from age 9 to 13 yr.

This study indicates the cell number may well increase throughout childhood:

Adipocyte size and number were determined in 288 subjects ranging in age from 4 mo to 19 yr. The study was performed in 110 obese and 178 non-obese subjects. 4-yr, longitudinal, follow-up studies were also performed in 132 subjects. The results demonstrate that the contribution of cell number and size to the growth of the fat depot in nonobese children varies with age. Deviations from this normal development were observed in obese children shortly after 1 yr of age.  By 11 yr of age obese children exceeded the mean cell number found in nonobese adults. Indeed, obese subjects displayed more rapid and earlier elevations in both cell number and size, which were maintained throughout the study. Thus obese children display both quantitative and qualitative differences in fat tissue development when compared to nonobese children. The data indicate that the rate and type of adipose tissue cellular development one encounters in children may play a role in the development of the enlarged fat depots found in obese subjects.
The  emphasized statement would be in contrast to some of the information on fat levels in early infancy and obesity risk that I will discuss in an upcoming installment.  What is not evident from these studies is what comes first -- does some predisposition towards obesity, perhaps caused by some propensity to adipocyte differentiation, cause fat tissue expansion due to more "hungry fat cells" causing a child to "overeat"?  Or does overeating during childhood cause fat tissue to expand by both modes -- cell number and cell size?  I have yet to come across the answer to this question and it would be difficult to determine in humans.  At least in rats, the increase in fat cells can be induced by overfeeding ... and overfeeding of fat to the DIO-susceptible Osborne-Mendel strain caused significantly greater adipocyte number in one depot.  The Zucker rat is another obesity prone strain.  In this rat:
Zucker obese (fafa) and nonobese (Fafa) male rats were over- or underfed prior to weaning by placement in large or small litters, respectively.  During the first 30 days of life the nutritional effect and not the genotype was the predominant influence on the animals' growth. By 12 weeks of age, genotypic differences became the major determinant of body weight. While early overfeeding significantly increased adipocyte number in both obese and nonobese rats, early underfeeding reduced adipocyte number only in the nonobese. 
I think we can all agree that mass genetic mutation is not underlying the obesity epidemic.  Still, there's no accounting for the mental state of the Zucker rats.  Are those underfed from weaning going around hungry all day?  After 12 weeks of age, that the genotype takes over is this because of some underlying genetic influence on fat cell size or number?  This paper does discuss how insulin secretion is higher in the obese (someone run and tell the nearest TWICHOOB) rats, so again I must remind twice in one paragraph that all sides have ruled out en masse mutation.  So is adult obesity somewhat predetermined, but if nutrition is controlled in development can it be mitigated somewhat?   Or could it be that humans are genetically predisposed to obesity after all, but in the past we haven't bombarded our genome with so many obesogenic foods?  
Note that most of the human studies look at subcutaneous and "deep fat", which is not necessarily "visceral fat".  I wonder if the number of visceral fat cells cannot increase into adulthood.  But that is just that, my own wondering out loud based on a hunch, not anything I've found to confirm (nor refute).  The other limitation is determination of brown fat (BAT) stores which are relatively high in early infancy and do seem to fluctuate throughout life and/or can be produced in adulthood in certain circumstances.  The recent studies on the BAT forming compound being produced during exercise lends us to believe we may be able to increase the "fat burning fat", but I remain skeptical of this being possible to any large degree unless I were to keep my home at 55 degrees or something like that. 

Reversing Obesity & Fat Cell Number

Here's where it gets depressing.  Whether you're older or younger ... just trying  now to lose weight or been trying for decades ... this much is agreed upon (again, current state of knowledge):  Adipocyte number is established by some time in our mid-to-late teens and you're stuck with what you got.  On the plus side you can't really make more, but on the minus side, your body won't kill them off even if they are no longer needed.  This may well be at the root of why reversing obesity in the long run is so difficult.  As I stated earlier, this may be psychologically helpful to those who lose a lot of weight but are left with stubborn patches of fat in addition to that loose skin (sorry folks but lots of what we think is loose skin is really still fat) to alleviate guilt they may associate with surgery.  I don't understand the stigma for the very obese who lose weight then going the extra mile with corrective surgery.  Well, I do from the formerly obese perspective -- because whenever I've mentioned it to friends and family they think I'm nuts and should just accept what I'm left with.   But I don't think these well-meaning others have a clue in this regard. 

Enter liposuction.  The good news is that liposuction is successful at permanent weight/fat reduction locally.  Proof positive that the distribution of fat cells in our bodies definitely impacts the distribution of fat tissue.  While i don't think this should surprise anyone, I think the bastardizing of the interpretation of lipodystrophies has confused many unnecessarily.  Yes, I'm talking about Taubes' repeated use of the poor woman with emaciated upper torso and ample hips and thighs to convince you that "conventional wisdom" cannot explain her condition.  Sure it can Gary.  She has more fat cells in her lower half, and if this condition occurs later in life, perhaps there is some local fat cell death or dysfunction that leads to atrophy of the adipose tissue in that location.  Unfortunately for this woman, starving herself would lead to further emaciation on top and she'll never wear a proportional size on the bottom.  But it is ridiculous to show that slide and say that those who believe in the laws of thermodynamics are saying her top undereats/is sedentary and her bottom overeats/moves more.  It was this sort of stuff that early on demonstrates just how intellectually insincere Taubes really is.  Because we all have seen very thin people with disproportionately "fat" areas -- these tend to be tummies in men, butts in women -- as well as very fat people with the same disproportionality.  This doesn't mean that overall adiposity is totally out of our control or that just because our fat likes to distribute to Area X that most of us can't at least keep that area in reasonable proportion.  Emphasis on reasonable. 

Enter that somewhat infamous liposuction study published last spring:  Fat Redistribution Following Suction Lipectomy: Defense of Body Fat and Patterns of Restoration (sorry, abstract only, more lay-friendly discussion here).  From the lay-friendly article:
''All the fat is back by one year," says researcher Robert H. Eckel, MD, professor of medicine, physiology and biophysics at the University of Colorado Anschutz Medical Campus. However, it does not return to the spot that has been operated on. "The fat comes back in different places," Eckel tells WebMD. In his study, the women had liposuction of the lower abdomen, hips, or thighs and were followed for a year. "The reaccumulation of fat was in the upper abdomen and triceps."
Now granted this was a small study and not done in the post-obese, but the almost universal interpretation of these results seemed to be that bodyweight was regulated beyond our control, and other razzle dazzle, and therefore any attempts to change it consciously are futile.  I disagree, and here's why.  IF body fat is regulated by the fat tissue itself or insulin levels, then this study is the proverbial black swan.  All of these women had fat cells removed.  We know new ones to replace them are not made so they don't get fat again in the same areas they were predisposed to accumulate fat.  But now, fat cells that weren't hypersensitive to insulin, or whatever you think is the means by which you accumulate fat, somehow wake up despite no change in behavior?  I don't think so.  To me the key is that they didn't change behavior.  It is highly unlikely that liposuction reduced enough fat to significantly lower adipokines (leptin most specifically, and I would add ASP to the mix) or that sans change in diet, insulin levels changed at all.  So why now did these women gain in the upper abdomen and backs of their arms?  I'm just going to throw this out there -- they ate the same amount which was a caloric surplus for the lower bodyfat content.  They gain back by storing the excess elsewhere until caloric balance is once again attained.

Does this mean you're doomed?  I think not.  Have the lipo or the more invasive "tuck" here or there where fat tissue is inevitably removed, but be forewarned that you will have to exercise vigilance to avoid regain.  But I think there's something to the "call of the deflated fat cell" to the difficulties of maintenance.  However, in adulthood, our fat cells do turn over, and the larger ones (and likely the "old" deflated formerly large ones) are going to be killed off first and replaced by young, insulin sensitive, healthy little baby fat cells.  And this folks, is not a bad thing where metabolic health is concerned -- quite the contrary. 

(Perhaps I'll include a discussion of pharmaceutical alteration on fat cell number at some future time)

In Part IV I'll discuss fat tissue growth in late-gestation, early infancy


Geoff 99 said...

Not sure if you are aware of this study - but it does have some very interesting implications concerning metabolic health and adipocyte numbers, especially for those on a high fat diet (and for mutant mice).

"Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome"

In part ...

"The aim of the present study was to determine the relationship between adipocyte storage capacity and two major components of the metabolic syndrome in rodents, T2D, and lipotoxic cardiomyopathy (14). It has long been accepted that the primary function of adipocytes is to store fuel for distribution to nonadipose tissues in times of need, as during a famine (18). The present study suggests a second function of adipocytes, namely, the compartmentalization into adipocytes of the surplus calories consumed during over-nutrition so as to protect non-adipose organs from lipid-induced trauma(3). Indeed, the recent demonstration by Kim et al. ( 10) that expansion of the fat mass of congenitally obese mice improves their metabolic profile lends further credence to the idea."

...and ...

"Thus, contrary to popular belief, obesity protects, at least temporarily, against T2D and metabolic syndrome by buffering the effects of over-nutrition on ectopic lipid deposition."

Galina L. said...

You did huge job! Wow! It gives many facts for thoughts. I wonder do people with different types of fat sells would need different diets?
It also looks like some people have an impaired capacity to store fat under skin, and it gets worse with age.

Geoff 99 said...

An interesting follow on. This review examines the role of PUFA in gene transcription and activation of fat cells.

"Polyunsaturated Fatty Acid Regulation of Gene Expression"

Two observations stand out:

1. PUFA down-regulates lipogenesis within mature fat cells (reducing individual cell storage capacity)
2. PUFA activates genes involved in the differentiation of pre-adipocytes into regular adipocytes (making more fat cells available)

The authors note:

"Taken together, current data suggest two opposing roles for PUFA in adipocytes. Although fat synthesis and accumulation in mature adipocytes is down-regulated by PUFA of both the (n-6) and (n-3) series, the formation of new adipose cells is regulated by the (n-6) series through PPARg2 and possibly other transcription factors. This seemingly paradoxical circumstance can be explained by the physiologic state of dietary fat excess. The adipocyte responds to increased dietary fat by shutting off its mechanisms that would lead to adipose hypertrophy. These are the lipogenic genes that are suppressed by PUFA. However, the same molecules that sense abundance of fat enable the organism to provide more space for storage by regulating the differentiation of the preadipocytes into adipocytes."

... Taken at face value this reveals quite a dynamic interaction between dietary fat and body fat stores, with a strong emphasis on maintaining adequate storage capacity.


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