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A multitarget angiogenesis inhibitor, CTT peptide-endostatin mimic-kringle 5, prevents diet-induced obesity

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Abstract

Adipose tissue vasculature has been considered an attractive target for prevention and treatment of obesity. AARP (CTT peptide-endostatin mimic-kringle 5) is a novel multitarget fusion protein against tumor angiogenesis. This study aimed to examine the effects of AARP on diet-induced obesity and its possible molecular mechanism. Treatment with AARP markedly prevented weight gains, improved metabolic disturbances, and decreased adipose tissue angiogenesis in diet-induced obese mice without noticeable toxicities. In addition to its potent antiangiogenic and MMP-2/9 inhibitory activities, AARP administration also significantly increased energy expenditure, influenced the metabolic and angiogenic gene expression profiles, and attenuated obesity-induced inflammation, demonstrating its systemic beneficial effects. Importantly, AARP exhibited no effect on mice fed with standard normal mouse diet. Furthermore, the AARP-treated HFD-fed mice experienced a significant increase in lifespan during the posttreatment observation period, compared with untreated HFD-fed mice. Our results suggest that AARP might be pharmacologically useful for treatment of obesity or obesity-related metabolic disorders in humans.

Key messages

What is already known

• More effective and safe therapies for obesity are in urgent need.

• AARP is a novel multitarget fusion protein against tumor angiogenesis.

What this study adds

• AARP prevents obesity, improves metabolic disorders in mice fed high-fat diet.

• AARP increases energy expenditure, decreases adipose tissue angiogenesis, and increases lifespan.

• AARP is well tolerated and exhibits no observable toxicity.

Clinical significance

• AARP may be a promising therapeutic agent against obesity or obesity-related metabolic disturbances.

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Data availability

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Abbreviations

AARP:

CTT peptide-endostatin mimic-kringle 5

ACC:

Acetyl-CoA carboxylase

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

BAT:

Brown adipose tissue

CPT1a:

Carnitine palmitoyltransferase 1a

EC:

Endothelial cell

ECM:

Extracellular matrix

FAS:

Fatty acid synthase

FGF:

Fibroblast growth factor

FGF-2:

Fibroblast growth factor-2

FFA:

Free fatty acid

GTT:

Glucose tolerance test

HFD:

High-fat diet

HDL-c:

High-density lipoprotein cholesterol

HGF:

Hepatocyte growth factor

HUVEC:

Human umbilical vein endothelial cell

ITT:

Insulin tolerance test

LCAD:

Long-chain acyl-CoA dehydrogenase

SD:

Standard normal mouse diet

LDL-c:

Low-density lipoprotein-cholesterol

MCAD:

Medium-chain acyl-CoA dehydrogenase

MMP:

Matrix metalloproteinase

NAFLD:

Nonalcoholic fatty liver disease

PGC1α:

Peroxisome proliferator-activated receptor gamma coactivator 1α

PPAR-γ:

Peroxisome proliferator-activated receptor-gamma

RER:

Respiratory exchange ratio

TG:

Triglyceride

TC:

Total cholesterol

VEGF:

Vascular endothelial growth factor

WAT:

White adipose tissue

SREBP-1c:

Sterol regulatory element binding protein-1c

TNF-α:

Tumor necrosis factor-alpha

VEGF-A:

Vascular endothelial growth factor-A

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Funding

This work was supported by the grants from Ministry of Science and Technology, China (2016ZX09102).

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Authors and Affiliations

  1. State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, China

    Houbin Wang & Jun Gu

  2. Radiology department of Third Surgery Ward, Shaanxi Baoji Traditional Chinese Medicine Hospital, Baoji, China

    Yijie Shi

Authors
  1. Houbin Wang
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  2. Yijie Shi
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  3. Jun Gu
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Contributions

H. B.W and J. G designed the study. H. B.W and Y.J.S performed the study. H. B.W and J. G analyzed the data. H.B.W wrote the manuscript.

Corresponding author

Correspondence to Jun Gu.

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The authors declare that they have no conflicts of interest.

Ethics approval and consent to participate

This study was performed according to the Guide for Care and Use of Laboratory Animals as adopted by the National Institute of Health and approved by the PeKing University Institutional Animal Care and Use committee (#2016010205).

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Not applicable.

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Wang, H., Shi, Y. & Gu, J. A multitarget angiogenesis inhibitor, CTT peptide-endostatin mimic-kringle 5, prevents diet-induced obesity. J Mol Med 98, 1753–1765 (2020). https://doi.org/10.1007/s00109-020-01993-w

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  • DOI: https://doi.org/10.1007/s00109-020-01993-w

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