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Edited by Tadamitsu Kishimoto, Immunology Frontier Research Center, Osaka University, Suita, Japan, and approved September 10, 2014 (received for review August 19, 2014)
Significance
The etiology and mechanisms underlying the age-related high incidence of metabolic diseases such as type 2 diabetes are not fully understood. In this paper, we show that blood vasculatures in the adipose tissues experience continuous changes during aging and VEGF is a key angiogenic factor controlling microvessel numbers and functions. Surprisingly, targeting VEGF and VEGF receptor 2 by specific blocking drugs produces different and sometimes opposing effects on white adipocytes, resulting in marked differences in insulin sensitivity in different age groups. These findings demonstrate that vascular changes in white adipose tissues are the key determinant for modulation of adipocyte metabolism and insulin sensitivity and provide valuable information for treatment of obesity and diabetes by targeting the vasculature.
Abstract
Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.
Footnotes
- ↵1To whom correspondence should be addressed. Email: yihai.cao{at}ki.se.
Author contributions: Y.C. designed research; J.H., T.S., H.I., and C.F. performed research; J.L., N.J.S., and J.Z. contributed new reagents/analytic tools; J.H., T.S., H.I., C.F., S.L., and Y.C. analyzed data; and J.H. and Y.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1415825111/-/DCSupplemental.
Adipose vasculature modulates insulin sensitivity
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