Rodent of the Week: New hope for leptin

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Leptin is an appetite-suppressing hormone that was discovered in 1995 and set the obesity-treatment field on fire as a potential drug to help people lose weight. Leptin signals the brain to stop eating, and researchers had high hopes that giving obese people leptin would help them lose weight. That promise fizzled out over the years as studies show that obese people’s brains have a resistance to the hormone. New research in mice, however, suggests there may be a way to use leptin’s natural powers.

Researchers at Children’s Hospital in Boston have shown that two medications already on the market may be useful to re-sensitize the brain to leptin. The study, published this week in the journal Cell Metabolism, found that obese mice have increased stress in the endoplasmic reticulum. This is a structure within cells where proteins are assembled and prepared for their various tasks. In the presence of obesity, the endoplasmic reticulum functions poorly and becomes stressed. The resulting stress triggers a cascade of signals aimed at relieving the stress by increasing the levels of ‘molecular chaperones,’ which are molecules that assist in the assembling of proteins.

To make a long story short, the study showed that using drugs that reduce endoplasmic reticulum stress can re-sensitize the brain to leptin and allow the body’s normal appetite response to function properly. The chemical chaperones tested were Buphenyl, which is used in urea cycle disorders and cystic fibrosis treatment, and tauroursodeoxycholic acid (or TUDCA), which is a traditional Chinese medicine used to treat some liver diseases. In a group of obese mice pretreated with either drug, leptin sensitivity increased as much as 10-fold, and the mice had a significant weight loss with leptin treatment even when fed a high-fat diet.

The researchers said they hope to begin studies with human volunteers.

‘Most humans who are obese have leptin resistance,’ said Dr. Umut Ozcan, the lead author of the study, in a news release. ‘Leptin goes to the brain and knocks on the door, but inside, the person is deaf ... I think our study will bring new hope for the treatment for obesity.’

The two leptin sensitizers tested are both oral medications with good safety profiles, he noted.

-- Shari Roan