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INSIDE SALK

SUMMER 2016

WWW.SALK.EDU

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

onMarch 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.

DISCOVERY

OF “OUTLIER”

ENZYMES

COULD OFFER

NEW DIABETES

TREATMENTS

From left: John Thomas, Marc Montminy and Janelle Ayres

Amolecular pathway activated in the

brain during fasting halts the spread of

intestinal bacteria into the bloodstream,

according to work publishedMay 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.

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.

GENETIC SWITCH TURNED ON

DURING FASTING HELPS STOP

INFLAMMATION