# Enzyme-Activated Self-Assembling Peptides Mimicking Adiponectin Multimers for Nonalcoholic Fatty Liver Disease Therapy

## TL;DR

Scientists created self-assembling peptides that mimic the structure of adiponectin to treat nonalcoholic fatty liver disease by reducing fat buildup and improving metabolic health.

## Contribution

The novel peptides self-assemble in ALP-rich liver tissue to mimic multimeric adiponectin, enhancing therapeutic efficacy.

## Key findings

- Peptides 1P and 2P self-assemble into nanofibers in ALP-overexpressing liver tissue, improving structural stability and receptor engagement.
- Treatment with the peptides reduced body weight, blood glucose, and hepatic steatosis in a NAFLD mouse model.
- Transcriptomic analysis showed modulation of inflammation, lipid synthesis, and metabolism pathways.

## Abstract

Adiponectin is a
multifunctional adipokine that regulates
metabolic
homeostasis, particularly lipid metabolism, through activation of
adiponectin receptors (AdipoRs). Its high molecular weight (HMW) form
exhibits the greatest biological activity, yet therapeutic peptides
derived from adiponectin typically exist as monomers or aggregates,
limiting their efficacy. To mimic the multimeric architecture of adiponectin
and enhance peptide efficacy, we developed two alkaline phosphatase
(ALP)-activated self-assembling peptides, 1P and 2P, based on a conserved
adiponectin sequence (148GKFH­CNIPGL­YYFAY162). These peptides undergo in situ self-assembly into stable
nanofibers in ALP-overexpressing liver tissue, enhancing structural
stability and receptor engagement. The assembled peptides effectively
bind AdipoRs and reduce lipid accumulation in vitro. In a high-fat
diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) mouse
model, treatment with these peptides led to significant reductions
in body weight, blood glucose levels, and hepatic steatosis. Transcriptomic
analysis further revealed modulation of key pathways involved in inflammation,
lipid synthesis, and metabolism. This study offers a promising strategy
for mimicking multimeric adipokine structures and advancing peptide-based
therapeutics for NAFLD.