New insights into body fat tissue and weight gain induced by type 2 diabetes drugs
Studying two forms of a master molecular regulator of body fat tissue, PPARγ, researchers discovered that, in mice, one form is associated with weight-gain side effects of a type 2 diabetes drug—a finding with implications for new treatment strategies. PPARγ is central to fat tissue development in mice and humans and is involved in other biological processes related to diabetes and metabolism. It is also the target of type 2 diabetes drugs called thiazolidinediones (TZDs), which activate PPARγ to improve blood glucose (sugar) levels but lead to unwanted weight gain. The two forms of PPARγ in mice and humans, PPARγ1 and PPARγ2, differ slightly in structure. While there were hints of other differences from earlier research, specific functional distinctions were not clear. Hoping for new insights that could lead to improved therapies, a team of researchers set out to study these two forms of PPARγ more closely.
For their research, the scientists designed a series of experiments and generated male mice that were deficient in one or the other form of PPARγ to identify any differences. Because PPARγ is known to control the activity of many genes, the researchers examined gene regulation in the mice and found that PPARγ1 and PPARγ2 regulate distinct sets of genes in various body fat tissues. They also identified other functional differences between PPARγ1 and PPARγ2. Most intriguingly, when the researchers gave a TZD drug to mice deficient in PPARγ1, they discovered that the mice had improved blood glucose levels without the usual drug-induced weight gain. Although deficient in PPARγ1, these mice still had PPARγ2, so the researchers concluded that PPARγ2 is sufficient for the drug’s benefits, while PPARγ1 must be responsible for the weight-gain side effect.
This research in mice brings to light previously unknown features of fat tissue and new understanding of weight gain caused by some type 2 diabetes drugs. If further studies show that PPARγ1 and PPARγ2 function similarly in humans, researchers may be able to develop drugs that specifically target one of PPARγ’s forms to treat diabetes with fewer side effects.
Hu W, Jiang C, Kim M, ...Lazar MA. Isoform-specific functions of PPARγ in gene regulation and metabolism. Genes Dev 36: 300-312, 2022.