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Grow More Fat and Improve Metabolic Health: Insights from TZD Treatment of Obese

Monday, November 16, 2009 Posted by Peter Janiszewski, PhD

By now, readers of Obesity Panacea (which just celebrated its 1 year anniversary!) have hopefully learned that excess weight is not directly predictive of health risk, and that excess fat mass is not in itself unhealthy. Recall that approximately 30% of individuals who are classified as obese by their body weight turn out to be metabolically healthy, and in fact seem not to get much metabolic benefit (or may even get worse) when they lose weight. Also consider that individuals who have NO fat tissue (e.g. lipodystrophy) have extremely elevated metabolic risk factors, meanwhile others who can apparently indefinitely grow more fat mass (multiple symmetric lipomatosis – think Michelin man) have metabolic profiles we’d all like to have.

The emerging theory of why obesity is associated with 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, or under the skin fat) to expand enough to store all the excess calories being ingested. In other words, if obese and metabolically unhealthy individuals could somehow develop more subcutaneous fat tissue, they could theoretically become healthier.

That’s right – get fatter and yet healthier.

While these notions surely seem like heresy or simply void of logic to many of you reading, a study just published ahead of print in the journal Obesity, beautifully illustrates the theoretical argument I just described.

In the study, 12 overweight or obese and metabolically unhealthy subjects were given a drug (Pioglitazone) for a duration of 12 weeks. While the exact actions of this drug, and more generally the thiazolidinediones (TZD) class of drugs are beyond the scope of this post, it is important to understand that these drugs seem to upregulate the production of healthy new fat cells (a process known as adipogenesis) – that is they make you fatter. By doing so, these drugs increase the storage capacity of your fat tissue – something that is limited in unhealthy obese individuals.

And that is precisely what happened in these subjects following 3 months of Pioglitizone administration. First, they gained about 2kg of body weight. Their amount of subcutaneous fat in the belly went up by about 10% and that in their butt/thigh by about 24%. Interestingly, their amount of dangerous visceral fat decreased by about 11%. (Some suggest that visceral fat really begins to accumulate and potentially lead to metabolic problems when benign subcutaneous fat runs out of storage space. Thus, not surprising to see an increase in storage capacity of subcutaneous fat and yet a reduction in visceral accumulation).

Also, a fat biopsy from the belly of the subjects showed that the increase in fat mass was due to an increase in the number of small and healthy adipocytes (fat cells) which are better able to take up more circulating fat.

Alright, so people with excess fat and metabolic problems took drugs for 12 weeks which apparently made them fatter, and what happened to their insulin sensitivity (a major metabolic marker of diabetes risk)?

Their insulin sensitivity improved by over 28%!

That’s right – they got fatter and yet healthier.

Interestingly, the authors were able to show a close correlation between the relative increase in new subcutaneous fat cells and insulin sensitivity – the more new fat cells a subject developed, the more their insulin sensitivity improved.

Still believe the “fat is bad” mantra? As this study illustrates, matters related to excess fat and health risk are much more nuanced than what many would have you believe.

Brief note: Our annual Canadian Society for Exercise Physiology conference is now over and Travis and I are en route back to Toronto as I write this post. Travis is sitting directly behind me and two rows ahead of me is one of the stars (Brent Butt) of the Canadian sitcom “Corner Gas”. Catching up with friends and colleagues at the conference was quite nice. Our respective presentations went very well, and we attended some very interesting talks on topics ranging from the regulation of natural health foods or supplements, to video games for enhancing lifestyle, to a debate on whether waist circumference is superior to body mass index as a predictor of obesity related health risk. Thanks to all for another great meeting!


McLaughlin, T., Liu, T., Yee, G., Abbasi, F., Lamendola, C., Reaven, G., Tsao, P., Cushman, S., & Sherman, A. (2009). Pioglitazone Increases the Proportion of Small Cells in Human Abdominal Subcutaneous Adipose Tissue Obesity DOI: 10.1038/oby.2009.380

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3 Response to "Grow More Fat and Improve Metabolic Health: Insights from TZD Treatment of Obese"

  1. Darya Said,

    Very interesting! I still worry about cancer, but this is a really fascinating study. Thanks for pointing it out.

    Posted on November 16, 2009 at 12:28 PM

  2. red rabbit Said,

    Ok, but the TZDs are also linked to increased all-cause mortality in most studies, particularly from congestive heart failure.

    I think it's an interesting side note, but it's not going to get me prescribing anything out of that class to my patients.

    Posted on March 22, 2010 at 6:13 PM

  3. Travis Saunders Said,

    @ Red Rabbit,

    I wasn't aware of a link between heart failure and TZDs - do you have links to those studies? I did a quick search and found a recent meta analysis suggesting that TZDs may increase the risk of heart failure, but not mortality. Any idea on the mechanism linking the two?


    Posted on March 22, 2010 at 9:45 PM


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We are PhD students in the School of Kinesiology and Health Studies at Queen's University in Kingston, Ontario. Our research focuses on the relationships between obesity, physical activity, and health risk. This blog is our attempt to consider the many "cures" for obesity that we read about on a daily basis. Enjoy.


The opinions expressed here belong only to Peter and Travis and do not reflect the views of any organization. Any medical discussion on this page is intended to be of a general nature only. This page is not designed to give specific medical advice. If you have a medical problem you should consult your own physician for advice specific to your own situation.

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