First agents to sensitise leptin-resistant brains to help the obese lose weight identified

January 7th, 2009 - 12:14 pm ICT by ANI  

Washington, January 7 (ANI): Researchers at Children’’s Hospital Boston claim to have identified the first agents that can help do away with leptin resistance in the brain, and thereby make obese people responsive to this appetite-suppressing hormone.
Dr. Umut Ozcan, of Children’’s Division of Endocrinology, revealed that the research team made this discovery while experimenting with mice.
During the study, the researchers observed that it is due to increased stress in a structure within the cell called the endoplasmic reticulum (ER) where proteins are assembled, folded into their appropriate configurations, and dispatched to do jobs for the cell that leptin action in the brain gets blocked.
They also observed that using chemical chaperones to reduce ER stress could re-sensitise the brain to leptin, and lead to weight loss when used in conjunction with leptin.
“I think our study will bring new hope for the treatment for obesity,” said Ozcan.
Working first with mice made obese through a high-fat diet, the researchers showed that the animals developed ER stress in the hypothalamus, the main area of the brain where leptin signals. That, according to the team, initiated the unfolded-protein response and rendered the mice extremely leptin-resistant.
The researchers also created a strain of mice whose ER was weakened in the brain through deletion of a gene called XPB1 specifically in the neurons, that developed ER stress and leptin resistance, and also became obese despite having some of the highest leptin levels ever reported. The mice also ate more and gained more weight.
However, when the researchers pre-treated either group of mice with a chemical chaperone (either 4-PBA or TUDCA) leptin sensitivity increased as much as 10-fold, and the animal had significant weight loss with leptin treatment even when fed a high-fat diet.
The researchers are hoping to eventually move their discovery to human trials, as both 4-PBA and TUDCA are safe in humans and already FDA-approved for clinical use.
An article describing their study has been published in the journal Cell Metabolism. (ANI)

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