We recently celebrated the end of summer with tacos and cake. Happy Labor Day weekend! -JZL
We published our PM20D1-KO mouse last week in PNAS! Key to the success of this project was wonderful help from colleagues in the Nomura, Spiegelman, and Banks labs, and a special help from Amanda Roberts. This paper describes our continued efforts to understand the physiologic functions of N-acyl amino acid signaling. We found that PM20D1-KO mice display bidirectional dysregulation of endogenous N-acyl amino acid levels and a variety of metabolic phenotypes including altered thermoregulation and diet-induced insulin resistance.
In addition to metabolism, we also used PM20D1-KO mice to explore other areas of physiology that might be controlled by N-acyl amino acid signaling. For instance, individual members of this lipid family have putative roles in pain sensation, bone function, and vascular homeostasis. We found that PM20D1-KO mice exhibit robust anti-nociceptive behaviors in inflammatory pain models. Guided by these phenotypes, we identify C18:1-Gln as a key PM20D1-regulated lipid that antagonizes certain members of the TRP channels including TRPV1. Our observations add to the growing body of evidence that N-acyl amino acids likely signal through polypharmacologic mechanisms to regulate diverse aspects of organismal physiology.
Projecting forward, we anticipate that more extensive phenotyping of PM20D1-KO mice will likely uncover additional physiologic processes regulated by N-acyl amino acid signaling. Towards this end, we have now deposited the PM20D1-KO to JAX (stock #032193) to help disseminate these mice to the broader scientific community. -JZL
Stephanie Terrell and Joon Kim have started in the lab as research associates. Ryan Cardiff has also started as a Chemistry Undergraduate Summer Research Fellow. Welcome! -JZL
Our new collaborative paper between four (!) laboratories is out today in J. Med. Chem. With help from the Nomura, Spiegelman, Griffin, and Kamanecka groups, we have performed a comprehensive structure-activity relationship study of the N-acyl amino acids and their chemical uncoupling bioactivity. You can read more about it here.
I wanted to use this opportunity to describe the context of this work in a little more detail. Chemical uncoupling is a powerful and proven strategy for increasing energy expenditure and reducing weight in humans. Discovered nearly 100 years ago, chemical uncouplers like 2,4-dinitrophenol (DNP) are still used off label today as "diet pills." Of course, their narrow therapeutic index (which can lead to overheating and death) severely limits their general utility for weight loss.
Recently, there has been renewed interest in other structural scaffolds that might be useful for chemical uncoupling. For instance, there are reports of DNP derivatives with potentially wider therapeutic ratios or structurally distinct "mild" chemical uncouplers. Our own work relates to a class of endogenous metabolites, the N-acyl amino acids. In our original report, we discovered that N-acyl amino acids can act as endogenous chemical uncouplers. Furthermore, the previously unknown circulating enzyme PM20D1 is a key enzymatic regulator of this lipid class.
We were curious about whether N-acyl amino acids might be diversifiable by chemical synthesis to produce new analogs with potentially improved properties. In this JMC paper we describe these synthetic efforts. In fact, we stumbled upon a class of unnatural, isoindoline containing N-acyl amino acids that exhibit improved uncoupling bioactivity and resistance to degradation. Importantly, these isoindoline derivatives are also bioactive uncouplers in diet-induced obese (DIO) mouse models. Ultimately more work will be needed to determine whether these compounds are significantly "better" (e.g., safer or more potent) in vivo than the natural N-acyl amino acids. Nevertheless, the main takeaway is that diversification of N-acyl amino acid structures can yield improved uncouplers that might also serve as useful tool compounds for N-acyl amino acid biology.
This work represents some of the last few things I was doing during my time with Bruce at DFCI/HMS prior to transitioning to Stanford. We have another manuscript in the works on the biology of N-acyl amino acids. Check back soon for more updates! -JZL
The lab has finally caught up with 2018 and we now have a twitter account. You can follow us at @LongLabStanford! -JZL
Unexpected discovery about a family of previously unknown cholesterol-binding proteins and their roles in non-vesic… https://t.co/zItK3KiRAn
Still using GAPDH as your loading control? Yet additional lines of evidence to suggest that you should think again… https://t.co/3iJIs11WCO
what a great looking group! https://t.co/UKij4O4XUh
The doors to the laboratory will open January 2018! We are actively looking for passionate individuals to join our team. We recruit from diverse backgrounds and believe that this philosophy promotes creativity in our science. In the meantime, the lab website is now up and going. Please check back often for updates about our people and our science. -JZL