In the 1990s, it was discovered that genetically obese mice have mutations in the leptin gene, or in the gene for the leptin receptor. Leptin is a hormone, produced mainly by adipose tissue, that acts on receptors in the brain to produce a feeling of satiety and reduce appetite. Daily injections of leptin to leptin-deficient mice led to a dramatic reduction in food intake and body weight, leading to hopes that leptin treatment would have similar effects in obese people. Obese individuals, however, often have unusually high circulating leptin levels rather than suffering from a leptin deficiency, leading to the hypothesis that these people are insensitive to the effects of leptin.
Hopes that leptin could be used to treat obesity have now been revived by scientists at the Children’s Hospital in Boston who have found a way to increase leptin sensitivity in mice. They showed that obesity increases endoplasmic reticulum (ER) stress and initiates the unfolded protein response in the hypothalamus, leading to inhibition of leptin receptor signalling. The resulting leptin resistance, which led to increased obesity, was reversed by the known chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA) which improve ER function and decrease the accumulation and aggregation of misfolded proteins. The study is published in the January 7th issue of the journal Cell Metabolism.