We are working to understand human metabolism and what happens when this biological system breaks down. The problem is more important than ever, given the increasing burden that diabetes and other metabolic dysfunctions have on human health and society.



Nature Chemical Biology

Discovery Of “Outlier” Enzymes Could Offer New Diabetes Treatments

Scientists at the Salk Institute and The Scripps Research Institute (TSRI) discovered two enzymes that could someday be targeted to treat type 2 diabetes and inflammatory disorders, as detailed in Nature Chemical Biology on March 28, 2016.

The discovery is unusual because the enzymes do not bear a resemblance—in their structures or amino-acid sequences—to any known class of enzymes, according to co-senior authors Alan Saghatelian, Salk professor, and Benjamin Cravatt, chair of TSRI’s Department of Chemical Physiology.

These “outlier” enzymes, called AIG1 and ADTRP, appear to break down a class of lipids Saghatelian uncovered in 2014 called fatty acid esters of hydroxy fatty acids (FAHFAs). Saghatelian had found that boosting the levels of one FAHFA lipid normalizes glucose levels in diabetic mice. In principle, inhibitors of AIG1 and ADTRP could be developed into FAHFA-boosting therapies that reduce inflammation as well as improve glucose levels and insulin sensitivity.

The labs are collaborating on further studies of the new enzymes and potential benefits of inhibiting them in mouse models of diabetes, inflammation and autoimmune disease.

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Genetic Switch Turned On During Fasting Helps Stop Inflammation

A molecular pathway activated in the brain during fasting halts the spread of intestinal bacteria into the bloodstream, according to work published May 2016 in the Proceedings of the National Academy of Sciences.

Salk Professor Marc Montminy, in collaboration with the labs of John Thomas and Janelle Ayres, uncovered this brain-gut signal in fruit flies, which could eventually inform the treatment of inflammatory bowel diseases in people.

To detail this pathway, first author Run Shen and colleagues studied a genetic switch in the brain called Crtc. They found that the guts of fruit flies without Crtc expressed molecules indicating that the immune system was keyed up, suggesting that without Crtc, bacteria leak from the gut into the fly’s circulation.

John Thomas, Marc Montminy and Janelle Ayres
From Left: John Thomas, Marc Montminy and Janelle Ayres

The normal role of Crtc is to fortify the barriers of the gut to prevent bacteria from entering the bloodstream and awakening the immune system. Without Crtc, the connections between cells that line the gut tube became disrupted, causing bacteria to leak out, activating the immune response and depleting energy reserves. The team also discovered that without the protein sNPF (found in the fly brain and with a human equivalent), the flies showed signs of gut inflammation similar to those flies missing Crtc. What’s more, the normally tight seals along the GI tract were broken down, letting bacteria out. Conversely, flies expressing more than the normal amounts of Crtc or sNPF in their neurons were able to survive longer without food and showed less disruption to the tight junctions that maintain their GI barriers. The team is conducting more experiments to understand how the neuropeptides activate the gut receptors that help protect it from bacterial invasion.

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Genes & Development

Salk Scientists Uncover How A Cell’s “Fuel Gauge” Promotes Healthy Development

Salk Professor Reuben Shaw’s lab revealed how a cellular “fuel gauge” responsible for managing energy processes—a protein complex called AMPK—has an unexpected role in development. The work was published March 2016 in Genes & Development.

Shaw, first author Nathan Young and colleagues discovered that embryonic stem cells without a functioning AMPK pathway don’t execute the development process properly, creating more of one germ layer than another. This lapse turns out to be due to a loss of lysosomes, structures responsible for degrading and reusing cellular components. By turning on lysosomal genes, the team was able to restore normal development in the AMPK-deficient cells.

According to Shaw, the connection between AMPK and lysosomes reveals more about cellular growth and metabolism.

Currently, lysosome inhibitors are in dozens of clinical trials for certain cancers, even though the exact link between lysosomes and tumors is not understood. “We are decoding underlying connections that might indicate when and how cancer drugs might be useful,” says Shaw. “This work may help us make better, more specific ways of targeting lysosomes in cancer.”

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Powering Up the Circadian Rhythm

At noon every day, levels of genes and proteins throughout your body are drastically different than they are at midnight. Disruptions to this 24-hour cycle of physiological activity are why jet lag or a bad night’s sleep can alter your appetite and sleep patterns for days—and even contribute to conditions like heart disease and cancers.

Now, scientists led by Ronald Evans have discovered a key player—a protein called REV-ERB—that controls the strength of this circadian rhythm in mammals. The discovery, published May 2016 in Cell, is unusual in the field, as most circadian genes and proteins only shift the timing or length of the daily cycle.

The study’s first author Xuan Zhao, Evans and colleagues analyzed levels and molecular characteristics of REV-ERB in the livers of mice. After the protein’s levels peaked during the day, two other proteins, CDK1 and FBXW7, reduced REV-ERB to a low point by the middle of the night. When the team targeted these proteins to block the degradation of REV-ERB, normal daily fluctuations in gene expression were suppressed, but the timing of the cycles wasn’t affected. Altering the strength of the gene expression oscillations profoundly affected metabolism, disrupting the levels of fats and sugars in the blood. What’s more, mice that lacked REV-ERB developed fatty liver disease, stressing the importance of regulating the intensity of the cycle.

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