How do fat cells protect you from metabolic risk?

In his post yesterday, Peter has discussed the counter-intuitive idea that having too little fat, rather than too much, causes many of the metabolic problems of obesity.  Today I thought it would be good to continue on with this theme and to focus on some of the mechanisms that explain this strange relationship.  Let’s begin where Peter ended off:

Currently, the emerging theory of why obesity is associated with metabolic disease risk suggests that it is not the excess amount of fat that results in problems – but rather, it is the inability of the fat tissue (specifically subcutaneous) to expand enough via the development of numerous, healthy adipocytes or fat cells to store all the excess calories being ingested.

Fat tissue is made up of many small fat cells, called adipocytes , each of which stores a single droplet of lipid. When we say that there are problems with having too little fat, we really mean thatthere are problems with having too few adipocytes.  For the purposes of this discussion, the most important categories of adipocytes are subcutaneous (those found just below the skin),visceral (those found inside of the abdominal wall) and intermuscular (between muscles). I’ve taken the figure below from my Master’s thesis, which shows where each of these types of cells can be found within the body.

What’s interesting about these different types of adipocytes is that they differ in their rates of lipolysis  – essentially how rapidly they release fat into the blood stream.  In comparison to subcutaneous adipocytes, visceral adipocytes have higher rates of lipolysis and decreased sensitivity to the anti-lipolytic effects of insulin.  What this means is that visceral adipocytes are very quick to give up the fat they store, while subcutaneous adipocytes (especially those found in the lower body) hold onto fat, and really resist letting it into the bloodstream.  When visceral adipocytes give up their fat, it circulates through the bloodstream where it can accumulate within the liver, heart, and skeletal muscle, resulting in insulin resistance and metabolic dysfunction.  In contrast, subscutaneous adipocytes hold tightly onto their fat, preventing it from doing any damage to the rest of the body (click here  for a fantastic in-depth review of the differences between visceral and subcutaneous adipose tissue by Bernardo Wajchenberg).

Let’s say that you’re a lean, healthy individual, but for one reason or another you begin to consume more calories than you burn.  You are going to start storing fat in your subcutaneous adipocytes.   As Peter suggested, so long as you are able to continue storing fat in those subcutaneous adipocytes, you are likely to be metabolically healthy However, if you continue to gain weight, you will eventually exceed the storage capacity of your subcutaneous adipocytes, at which point fat will start to “overflow” into visceral adipocytes.  As mentioned earlier, these visceral adipocytes already have high rates of lipolysis, which is bad enough.  But as they enlarge, visceral adipocutes become increasingly insulin resistant, resulting in the release of even higher amounts of fat into the bloodstream, rapid accumulation of fat within the liver and other organs, and increased metabolic risk.

The simple differences in visceral and subcutaneous adipocytes can help to make sense of the “outliers” that Peter discussed in his post on Friday.  Individuals with lipodystrophy (who have very few adipocytes) appear lean, but with no place to safely store their fat, it rapidly accumulates within the heart, liver, and muscles, resulting in increased health risk.  Similarly, TZD treatment results in an increase in the number of subcutaneous adipocytes , which essentially suck up circulating lipid and reduce metabolic risk accordingly (unfortunately TZDs have some other nasty side effects).  This is also why it can be so difficult to reduce the amount of fat stored in your hips and thighs – those subcutaneous adipocytes just do not want to release the fat that they are storing!  It may be frustrating, but it’s terrific from a health perspective!

So, what is the clinical utility of these differences?  Unfortunately, not much.  We really have no control over where we store our body fat.  And the simple fact is that a large proportion of obese individuals have large amounts of visceral fat, resulting in increased health risk (this is a big driver of the relationship between BMI and health risk, as imperfect as it may be).  But I still find it incredibly interesting that, far from being the scourge that people often expect, fat cells are actually extremely important to the healthy function of the human body.

Travis

Today’s post was originally published on March 22, 2010, during our time on Scienceblogs.

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14 Responses to How do fat cells protect you from metabolic risk?

  1. Fascinating pair of posts. It may not have direct clinical utility yet, but it does potentially make a big difference to the way we think about health I think. It further distinguishes our concern with being fat from our concern with being unhealthy. If we are really concerned about health, then the priorities are nutrition and fitness first, and then obesity. If we are honestly more concerned about being fat then our focus would change to things that most impact body composition rather than health. The finding that these two are not synonymous does potentially have a real impact on our thinking I believe.

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  2. А я, наверное, именно таких слов ждал

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  3. LAFONTAN Max says:

    Good idea to pinpoint the heterogeneity of fat deposits.
    It is nice to refer to the review of Bernardo Wajchenberg (Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 21: 697-738, 2000).
    Some recent ones contain more actualized informations with mechanistic proposals.
    See:
    Lafontan M, and Berlan M. Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol Sci 24: 276-283, 2003.
    Manolopoulos KN, Karpe F, and Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. International journal of obesity 34: 949-959, 2010. Important for all the surgeons who propose to remove this fat deposit for aesthetic purposes!!
    I have a problem with TZDs. I utilize these drugs to stimulate differentiation of human fat cells progenitors. Excellent tools. Although TZDs increase the number of small fat cells (and possess transitory beneficial metabolic action)…. small fat cells will become large fat cells on the long-term….Thus TZD are promoting fattening on the long term. Is it a good deal for a type 2 diabetic?
    I read your blogs with pleasure. Sincerely.

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    • Travis Saunders, MSc, CEP says:

      Thanks for the comment and additional references Max!

      I know a very limited amount about TZDs (or pharmacological agents more generally), and I know that they have some pretty significant side effects aside from their impact on adipocytes. However, I don’t know that I would be concerned about having *more* adipocytes – for any given amount of body fat, having *more* adipocytes should be better than having less, all else being equal. I’m not sure that there is any research on this specifically, but that would be my initial thought.

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      • Dave Bridges says:

        Depends on whether you want to combat hyperglycemia (TZD good) or obesity (TZD bad). Same goes with injecting insulin.

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  4. I agree with Todd here. I’m very glad you posted these two posts. If you wanted to grab sensationalist headlines, you could lead with something like “If you weren’t getting fatter, your” [/everybody's] “junky diet would be much more likely to kill you outright”…

    I’m going to wander off into the deep end of the pool here, and I’m a Civil Engineer, not a biochemist, not a doctor, so I’m just spouting some opinions without much scientific basis. But it’s interesting how these articles remind us that fat, aesthetics aside, evolved as a layer of protection. Reminds me of that article you quoted from JP Chaput back last spring. We all know (or believe) that the stored energy in fat is supposed to be a protection from famine. The Chaput article also reminded us that fat is supposed to be a cushion against injury and trauma.

    One could argue in this case that adipose cells sequestering excess fat from the bloodstream are protecting your body in a way roughly analogous to how a bear’s fat is supposedly able to protect them from rattlesnake bites and so forth. The snake’s fangs can’t penetrate through the bear’s fat, so the injected poison just sits there, sequestered from the bear’s metabolism, until the venom loses its potency and is eventually disposed of safely.

    Makes me wonder whether the “holistic/alternative” medicine guys may have the glimmerings of a point that is ignored by the medical establishment. Those guys are always saying we need to “detoxify” from the modern environment. Makes me wonder if one reason (among many) for the modern obesity epidemic, is because our bodies are gaining fat in order to sequester suspicious artificial chemicals away from our metabolism, like the bear’s fat does. Even if all the weird pesticides and plastomers etc. pervading modern life are totally safe — even if we accept the industry-sponsored testing that these things are not toxic to humans at the levels they occur in the modern built environment, it might nevertheless be possible that our bodies are mis-identifying the artificial substances as toxins, and accumulating fat in order to sequester the suspicious substances.
    Well, just a thought.

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    • Travis Saunders, MSc, CEP says:

      I appreciate the speculation, Thomas :) There is some evidence that endocrine disrupting chemicals are associated with weight gain, although my perception is that it’s due more to dysfunction, rather than being an actual physiological coping mechanism. And since these chemicals tend to be fat soluble, it’s also possible that as you gain fat tissue you simply have more place to store the chemicals (e.g. rather than protecting us from the chemicals, fat tissue might be providing them with a handy hiding spot within our bodies).

      All that being said, the whole pollutant/obesity issue is still pretty new, and I don’t think it’s particularly well understood. I’m always hesitant to give credence to something like “detoxification” since it’s almost always promoted by charlatans, but the idea that pollutants are in some way linked with obesity is a legitimate area of study.

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      • majkinetor says:

        Why are you focusing on charlatans when detox is in question ? Charlatans exist in any sphere, perhaps they are more visible here.

        Toxins and obesity are known to be connected. For one, the worst toxins are lipid soluble so fat, as in case with bears, is ‘storing’ toxins so they do not circulate around the body and cause more harm. This is one of the reasons some people get detox symptoms and poisoning after loosing weight (it was even topic of one House episode).

        So its not that bad hypothesis, that the body will use hypertrophy of specific tissue when the demand for it is higher (i.e. higher toxin load, poor liver status etc.).

        That toxins indeed can cause obesity is also apparent from MSG case – MSG induced obesity is typical laboratory procedure on animals. And that is just one case. BPA as encocrine disruptor and fetal programming agent is also suspected to lead to obesity.

        More closer to earth example is fructose – is it a toxin or not is matter of controversy but it sure as hell promotes obesity.

        Third, detoxin agents like Vitamin C, Choline, N-Acetyl-Cystein etc are known to influence obesity.

        So, while it might not be dominant factor, its still is factor. And I strongly suggest anybody on wight loss diet to use “detoxing” agents – just try to inform yourself what is scientifically evidenced among those, and what is fad.

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        • Travis Saunders, MSc, CEP says:

          This is one of the problems with throwing around a term like toxin – it can be so broad as to be essentially meaningless (e.g. considering fructose to be a toxin). Anything is toxic when given in sufficient quantities (water, oxygen, etc), which I find makes it very hard to have a meaningful discussion about “toxins” generally.

          Also, I don’t know of any evidence that Vitamin C or other “detoxin agents” influence obesity. As I said before, there is some interesting evidence for a few specific pollutants, but even there things are far from clear. I reviewed all the evidence for endocrine disrupters in a paper 2 years ago, and the evidence just isn’t that strong:

          http://www.isrn.com/journals/pediatrics/2011/917684/ (skip to section 10 for the section on pollutants)

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          • majkinetor says:

            Indeed, most people don’t understand that toxin is contextual definition. But that is something clearly understood in scientific circles. The dose, the genetics, the environment, the microbiota etc.. all influence how will substance finish in the body. And more importantly, the “toxin treashold” is probably very dynamic on almost daily bases (depending on system status, i.e. acute infection/stress, hydration status etc.). But that doesn’t prevent one to have meaningful discussion, I think.

            Here is some evidence for Vitamin C influencing obesity (and some related studies). I have papers for other mentioned nutrients but I think this will suffice for now.

            Campión, J, F I Milagro, D Fernández, and J A Martínez. “Diferential Gene Expression and Adiposity Reduction Induced by Ascorbic Acid Supplementation in a Cafeteria Model of Obesity.” Journal of Physiology and Biochemistry 62, no. 2 (June 2006): 71–80. http://www.ncbi.nlm.nih.gov/pubmed/17217161.

            “Vitamin C Supplementation Influences Body Fat Mass and Steroidogenesis-related Genes When Fed a High-fat Diet.” International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Für Vitamin- Und Ernährungsforschung. Journal International De Vitaminologie Et De Nutrition 78, no. 2 (March 2008): 87–95. http://www.ncbi.nlm.nih.gov/pubmed/18791977.

            García, O. P, D. Ronquillo, M. del Carmen Caamaño, M. Camacho, K. Z Long, and J. L Rosado. “Zinc, Vitamin A, and Vitamin C Status Are Associated with Leptin Concentrations and Obesity in Mexican Women: Results from a Cross-sectional Study.” Nutrition & Metabolism 9, no. 1 (2012): 59. http://www.nutritionandmetabolism.com/content/pdf/1743-7075-9-59.pdf.

            Garcia-Diaz, D F, J Campion, F I Milagro, N Boque, M J Moreno-Aliaga, and J A Martinez. “Vitamin C Inhibits Leptin Secretion and Some Glucose/lipid Metabolic Pathways in Primary Rat Adipocytes.” Journal of Molecular Endocrinology 45, no. 1 (July 2010): 33–43. http://www.ncbi.nlm.nih.gov/pubmed/20400526.

            Huck, Corey J., Carol S. Johnston, Bonnie L. Beezhold, and Pamela D. Swan. “Vitamin C Status and Perception of Effort During Exercise in Obese Adults Adhering to a Calorie-reduced Diet.” Nutrition (June 2012). http://www.nutritionjrnl.com/article/S0899-9007(12)00080-9/abstract.

            Johnston, Carol S, Bonnie L Beezhold, Bo Mostow, and Pamela D Swan. “Plasma Vitamin C Is Inversely Related to Body Mass Index and Waist Circumference but Not to Plasma Adiponectin in Nonsmoking Adults.” The Journal of Nutrition 137, no. 7 (July 2007): 1757–1762. http://www.ncbi.nlm.nih.gov/pubmed/17585027.

            Johnston, Carol S, Corinne Corte, and Pamela D Swan. “Marginal Vitamin C Status Is Associated with Reduced Fat Oxidation During Submaximal Exercise in Young Adults.” Nutrition & Metabolism 3 (2006): 35. http://www.ncbi.nlm.nih.gov/pubmed/16945143.

            Naylor, G J, L Grant, and C Smith. “A Double Blind Placebo Controlled Trial of Ascorbic Acid in Obesity.” Nutrition and Health 4, no. 1 (1985): 25–28. http://www.ncbi.nlm.nih.gov/pubmed/3914623.

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  5. I see toxicity as a model rather than a fad. Essentially the idea is to treat substances as if they become seriously harmful at some level. And one version is to see this as dose dependent, with the same substance being beneficial or even essential at other doses. Not unreasonable to treat nutrients in that manner I think, as a possible general framework. F you take that view, the goal seems to be to figure out the range where each type of nutrient is helpful and where it becomes harmful, or else to use the inability to find such a range as evidence against the framework.

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    • majkinetor says:

      That range is already known for majority of nutrients although controversies do exist (for instance vitamin A, the one that is especially important in obesity).

      However, the effect is not that simple because of nutrient and toxin synergies.

      But, almost anything can be treated with adequate nutrient usage (orthomoleculars claim that for decades and later nutrigenetics) including obesity. The problem is not if such solution exists, because we are almost certain it does, but to find what is adequate nutrient mix for specific person.

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