Thiazolidinediones and Weight Gain: Implications for Obesity Research

The robust association between therapy with thiazolidinediones (TZDs) and body weight gain in patients tells us something profound about why people gain and lose fat.

The Caloric Balance Hypothesis tells us that "Calories In" and "Calories Out" control fat metabolism. Thus, TZDs can cause weight gain only by somehow causing patients to overeat and/or under exercise.

Our alternative hypothesis, Lipophilia, tells us something very different. In order for medications like thiazolidinediones to cause weight gain, they must act on the fat tissue itself and somehow disturb its hormonal regulation.

So what does the evidence tell us?

First of all, many legitimate sources tell us that thiazolidinediones can lead to weight gain in patients, apparently absent changes in dietary therapy or physical activity.

1. Consider: "Effect of thiazolidinediones and body weight on patients with diabetes mellitus."[1]

The authors note: "treatment of diabetes mellitus with medications, including insulin, sulfonylurea, and thiazolidinediones (TZDs), often leads to weight gain through a variety of mechanisms."

2. Also, consider this abstrusely titled article: "Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids."[2]

The authors say that a certain receptor known as PPAR gamma "plays a key role in adipogensis in adipocyte gene expression and is the receptor for the thiazolidinedione class of insulin sensitizing drugs."

To translate, the word adipogenesis means the "creation of fat." So here we have some authors from places like Harvard Medical School telling us that TZDs work on a receptor that plays a "key role" in the creation of new fat. They're not talking about "Calories In" or "Calories Out." They're talking about what's going on at the level the fat tissue!

They continue: "PPAR gamma to MRNA levels is an additional level of regulation for the control of adipocyte development and function, and could provide a molecular mechanism for alterations in adipocyte number and function in obesity."

Again, this is just speculation, but if clinicians can find molecular mechanisms in the fat tissue that control obesity, why then are they so wedded to the idea that "Calories In" and "Calories Out" alone control fat accumulation? It absolutely makes no sense.

Reading articles like this one, one can't help but come away with the notion that obesity must be hormonally regulated, just like science writer Gary Taubes and other advocates of the Lipophilia Hypothesis have been telling us.

3. Here is another interesting article: "Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes."[3]

The researchers found that TZDs affected intra abdominal fat differently than they did total body fat. They thus concluded that TZDs' "potentially variable effect points to a differential action on insulin sensitivity in different adipose tissue depots."

So TZDs create insulin sensitivity in the fat tissue? This is exactly what the Lipophilia Hypothesis would tell us, and it perfectly explains why patients on TZDs might be gaining weight. Again, notice that we are not taking about appetite or exercise. We are taking about what's going on at the level of the fat tissue.

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References


1. Fonseca V. "Effect of thiazolidinediones and body weight on patients with diabetes mellitus." Am J Med. 2003 Dec 8;115 Suppl 8A:42S-48S.

2. A J Vidal-Puig, R V Considine, M Jimenez-Liñan, A Werman, W J Pories, J F Caro, and J S Flier. "Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids." J Clin Invest. 1997 May 15; 99(10): 2416–2422.

3. I E Kelly, T S Han, K Walsh and M E Lean."Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes." Diabetes Care February 1999 vol. 22 no. 2 288-293.

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