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

By now, readers of Obesity Panacea 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.


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

This post was originally published on on November 16, 2009.

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Pioglitazone has long been associated with 3-5 kg weight gain when used in diabetics. Prior speculation or studies have tended to blame fluid inceasese.

Thiazolidinediones like pioglitazone have long been known as peripheral insullin sensitizers, so the increased insulin sensitivity here is no surprise. [Metformin, in contrast, works in the liver predominantnly, so it's known as a central insulin sensitizer.]

What seems to be new in the study at hand is that fat cell numbers (and size?) increased. Many of us think you get fat from an increase in the amount stored in existing fat cells, not from production of new fat cells.


So the takeaway message is that 'excess' fat (whatever than means for any given individual) and metabolic disorders are both the result of nutrient oversupply, rather than the latter being caused by the former. Correlation =/= causation.

Hmm. If that's so, does liposection make you unhealthier? (Real question; just trying to see whether the mechanism works in reverse.)

By speedwell (not verified) on 26 Jun 2010 #permalink

@ Steve Parker,

There was a significant increase in the % of cells that were "small", as well as the ratio of small cells to large cells, but not - suggesting that the TZD's resulted in an increased number of healthy, small adipocytes (the diameter of large cells increased as well, but I don't really know how to interpret that). It is very interesting since as you suggest, in general weight gain results from simply increasing the size of existing fat cells as you suggest - which has negative health consequences. So it's very interesting that this medication that causes weight gain could actually be improving health. It's a bit counter-intuitive at first, but it really drives home the idea fat cells are not the enemy that many people assume.

@ LKL,

Yes and no. Consuming more calories than you are burning will result in increased deposition as fat. But once those fat cells become large they become insulin resistant, as well as secreting inflammatory proteins, both of which cause all sorts of havoc. Since there was no weight loss in this study (a small weight gain actually), it is unlikely that individuals were simply consuming less nutrients - the changes were most likely due to changes in fat cell numbers. That being said, simple lifestyle can result in improved health independent of adipocyte size as well.

@ Speedwell,

Good question. In general, liposuction does *NOT* make you healthier, and there are some very plausible reasons to think it makes an individual less healthy. For example, liposuction often results in an enlargement in breast size, which may be a marker for increased visceral fat (more on that here). So it seems that it really does work in reverse: increasing subcutaneous fat cell number = good, reducing subcutaneous fat cell number = bad.

I thought the number of fat cells in adults is fixed, sometime in late adolescence.

The increase in insulin sensitivity only pertains to the new fat cells, which aren't (yet) programmed to be insulin insensitive, correct? I doubt muscle cell sensitivity is altered.

Interesting article discussion - thanks!