The study also suggests that two already approved drugs restore leptin sensitivity, which may provide a novel treatment for obesity. The study is the first to be successful in sensitizing obese mice fed a high-fat diet to leptin. So far, studies have failed to find ways of making obese mice and people respond to the hormone leptin.
However, the underlying reason why obese individuals become leptin resistant in the first place remained open to question. This new study has shed some light on that issue.
Recent studies have showed that a condition known as endoplasmic reticulum (ER) stress in peripheral organs plays an important role in obesity-induced insulin resistance and type 2 diabetes. Within the ER, molecular substances facilitate the folding and transport of proteins. When the these substances can't keep up, a stress response is triggered, known as the unfolded protein response (UPR).
It may be that ER stress and the UPR response lead to leptin resistance in the brain's hypothalamus. The hypothalamus is the primary brain region that responds to leptin, sending a signal that curbs appetite. Mice engineered to have reduced ER capacity or increased ER stress throughout their bodies do gain more weight on a high-fat diet, according to earlier studies.
Obese mice manipulated to have increased ER stress only in the hypothalamus show less response to leptin. The animals are not only more leptin resistant, but they also grow significantly more obese on a high-fat diet.
The question then became whether the animals could be resensitized by treating them with either of two pre-existing drugs (4-Phenyl Butyric Acid [PBA] and Tauroursodeoxycholic acid [TUDCA]) that act as ER stress reducers. It seems that the answer is yes.
Normal mice treated with the drugs dropped some weight and quickly rebounded, but the knockout mice [that were genetically predisposed to ER stress in the brain] continued to lose weight. It shows that ER stress relievers are leptin sensitizers.
That makes PBA and TUDCA the first leptin sensitizers, which may lead to new ways of treating obesity.
