Knocking out key protein in mice boosts insulin sensitivity

Nov 10, 2011
This is human adipose tissue (fat). Credit: UC San Diego School of Medicine

By knocking out a key regulatory protein, scientists at the University of California, San Diego School of Medicine and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland dramatically boosted insulin sensitivity in lab mice, an achievement that opens a new door for drug development and the treatment of diabetes.

The research, published in the November 11 issue of the journal Cell, reveals a new and previously unsuspected role for nuclear receptor corepressor (NCoR), a transcriptional coregulatory protein found in a wide variety of cells.

"Different transcription factors stimulate genes, turning them on and off, by bringing in co-activators or co-repressors," said Jerrold M. Olefsky, MD, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego and senior author of the paper. "All transcriptional biology is a balance of these co-activators and co-repressors."

Olefsky and colleagues focused their attention on NCoR, which was known to be a major co-repressor of Peroxisome Proliferator-Activated Receptor gamma or PPAR-gamma, a ubiquitous protein that regulates fatty acid storage and , but which also appeared to act on other receptors as well.

"It seemed to be a general purpose co-repressor," said Olefsky. "It's unusual for one protein to do so many things. It's not very efficient and you don't see it too much in biology."

The scientists created a knock-out mouse model whose adipocytes or lacked NCoR. Though bred to be obese and prone to diabetes, Olefsky said the improved in the NCoR knock-out mice. Moreover, they displayed enhanced in liver, muscle and fat, and decreased . Resistance to insulin, a hormone central to regulating carbohydrate and fat metabolism, is a hallmark of diabetes, as is .

"When NCoR was deleted, insulin sensitivity in the whole animal increased dramatically compared to normal obese mice, which remained insulin resistant. The sensitivity occurred not just in adipocytes, but in all cells," said Olefsky. "With NCoR knocked out of adipocytes, PPAR-gamma becomes active. This produces a robust increase in systemic insulin sensitivity."

Phosphorylation is a biochemical process in which a phosphate group is added to a protein or other organic molecule, activating or deactivating many enzymes. It turns out that NCoR facilitates phosphorylation of PPAR-gamma, so that without NCoR, the receptor remains unphosphorylated and active.

In related work also published in the same issue of Cell, EPFL scientists found that knocking out NCoR in muscle cells produced a surprising effect. It did not repress PPAR-gamma, but rather generated a different phenotype or set of results.

"In adipocytes, NCoR repressed PPAR-gamma, but in other cells, it appears to repress other transcription factors," Olefsky said. "That's a new principle: A repressor that's found in many cells, but performs a specific, different function depending on the cell type."

Though NCoR's role as a major co-repressor was known, it was considered a poor drug target because inhibiting it could cause unwanted de-repression in some cell types, producing adverse side effects. Olefsky said the newly discovered specificity of NCoR revitalizes the idea that NCoR may be an excellent drug target for type 2 diabetes and other insulin resistant diseases.

"If researchers can make a drug that's tissue-specific, repressing NCoR could be a powerful way to boost insulin sensitivity. It's doable. Already, we can create drugs that specifically target fat and liver cells. That might be good enough to produce a system-wide benefit."

Explore further: Earliest stages of ear development involve a localized signaling cascade

Related Stories

Why fish oils work swimmingly against diabetes

Sep 02, 2010

Researchers at the University of California, San Diego School of Medicine have identified the molecular mechanism that makes omega-3 fatty acids so effective in reducing chronic inflammation and insulin resistance.

Scientists find 'dual switch' regulates fat formation

Apr 08, 2011

New research by scientists at The Scripps Research Institute and collaborating institutions has identified a key regulator of fat cell development that may provide a target for obesity and diabetes drugs.

Killing 'angry' immune cells in fat could fight diabetes

Oct 07, 2008

By killing off "angry" immune cells that take up residence in obese fat and muscle tissue, researchers have shown that they can rapidly reverse insulin resistance in obese mice. The findings reported in the October Cell Me ...

Macrophage protein has major role in inflammation

Nov 02, 2010

Researchers at the University of California, San Diego School of Medicine have discovered that a multi-tasking protein called FoxO1 has another important but previously unknown function: It directly interacts with macrophages, ...

Recommended for you

Genomes of malaria-carrying mosquitoes sequenced

Nov 27, 2014

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing ...

How calcium regulates mitochondrial carrier proteins

Nov 26, 2014

Mitochondrial carriers are a family of proteins that play the key role of transporting a chemically diverse range of molecules across the inner mitochondrial membrane. Mitochondrial aspartate/glutamate carriers are part of ...

Team conducts unprecedented analysis of microbial ecosystem

Nov 26, 2014

An international team of scientists from the Translational Genomics Research Institute (TGen) and The Luxembourg Centre for Systems Biomedicine (LCSB) have completed a first-of-its-kind microbial analysis of a biological ...

Students create microbe to weaken superbug

Nov 25, 2014

A team of undergraduate students from the University of Waterloo have designed a synthetic organism that may one day help doctors treat MRSA, an antibiotic-resistant superbug.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.