Abstract
The endocannabinoidome (expanded endocannabinoid system, eCBome)-gut microbiome (mBIome) axis plays a fundamental role in the control of energy intake and processing. The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently identified molecule acting as an antagonist of the ghrelin receptor and hence a potential effector of energy metabolism, also at the level of the gastrointestinal system. Here we investigated the role of the eCBome-gut mBIome axis in the control of the expression of LEAP2 in the liver and, particularly, the intestine. We confirm that the small intestine is a strong contributor to the circulating levels of LEAP2 in mice, and show that: (1) intestinal Leap2 expression is profoundly altered in the liver and small intestine of 13 week-old germ-free (GF) male mice, which also exhibit strong alterations in eCBome signaling; fecal microbiota transfer (FMT) from conventionally raised to GF mice completely restored normal Leap2 expression after 7 days from this procedure; in 13 week-old female GF mice no significant change was observed; (2) Leap2 expression in organoids prepared from the mouse duodenum is elevated by the endocannabinoid noladin ether, whereas in human Caco-2/15 epithelial intestinal cells it is elevated by PPARγ activation by rosiglitazone; (3) Leap2 expression is elevated in the ileum of mice with either high-fat diet—or genetic leptin signaling deficiency—(i.e., ob/ob and db/db mice) induced obesity. Based on these results, we propose that LEAP2 originating from the small intestine may represent a player in eCBome- and/or gut mBIome-mediated effects on food intake and energy metabolism.
Highlights
The liver-expressed antimicrobial peptide 2 (LEAP2) was originally isolated from human hemofiltrates [1]
In 4 week-old male mice, we observed a significant decrease in Leap2 mRNA expression in the liver, and a non-significant increase in the jejunum and ileum, in GF vs. conventionally raised (CR) mice, whereas there were no trends in the duodenum (Figure 1A)
Levels of circulating LEAP2 protein showed a decrease at 4 weeks (Figure 1B), whereas there was a significant increase in 13 week-old male mice (Figure 1B)
Summary
The liver-expressed antimicrobial peptide 2 (LEAP2) was originally isolated from human hemofiltrates [1]. The murine Leap RNA encodes for a 76 amino acid protein, the mature LEAP2 peptide is composed of 40 amino acid residues [1]. The peptide is positively charged and shows similar characteristics to other cationic peptides with antimicrobial activity in vitro. It is composed of an N-terminal (1–14 amino acids) and a C-terminal (15–40 amino acids) domain and two disulfide bonds. LEAP2 shares structural characteristics with antimicrobial peptides such as defensins and LEAP1/hepcidin [1]. The antimicrobial activity of LEAP2 was suggested to be dependent on the amino-terminal domain and not on the induction of membrane destabilization and/or pore formation under physiological conditions [3], indicating that the peptide may bind to an intracellular target to exert this activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
