Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity

doi:10.1073/pnas.0305905101

Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity

^*Department of Nutritional Sciences and Toxicology and ^§Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

Edited by Roger H. Unger, University of Texas Southwestern Medical Center, Dallas, TX, and approved February 1, 2004 (received for review September 13, 2003)

Abstract

Adipocyte-specific secretory factor (ADSF)/resistin is a small cysteine-rich protein secreted from adipose tissue that belongs to a gene family found in inflammatory zone (FIZZ) or found in resistin-like molecule (RELM). ADSF has been implicated in modulating adipogenesis and insulin resistance. To examine the long-term function of ADSF in adipogenesis and glucose homeostasis, we constructed an expression vector for a dominant inhibitory form of ADSF by fusing it to the human IgGγ constant region (hFc). ADSF-hFc not only homodimerizes but heterooligomerizes with ADSF/resistin and prevents ADSF/resistin inhibition of adipocyte differentiation of 3T3-L1 cells in a dominant negative manner. Transgenic mice overexpressing ADSF-hFc in adipose tissue show increased adiposity with elevated expression of adipocyte markers as well as enlarged adipocyte size. This finding clearly demonstrates in vivo the inhibitory role of ADSF in adipogenesis. ADSF-hFc transgenic mice with impaired ADSF function exhibit improved glucose tolerance and insulin sensitivity either on chow or high-fat diets. Because of the enhanced adipocyte differentiation, the ADSF-hFc transgenic mice show increased expression of leptin and adiponectin in adipose tissue. The elevated circulating levels for these adipocyte-derived hormones with decreased plasma triglyceride and free fatty acid levels may account for the improved glucose and insulin tolerance in these transgenic mice.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: hsul{at}nature.berkeley.edu.
↵ † Present address: Department of Medicine, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226.
↵ ‡ Present address: Department of Animal Sciences and Biotechnology, Jinju National University, Jinju, Kyong Nam 660-788, Korea.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: ADSF, adipocyte-specific secretory factor; FIZZ, found in inflammatory zone; RELM, resistin-like molecule; hFc, human IgGγ constant region; PPARγ, peroxisome proliferator-activated receptor γ; Pref-1, preadipocyte factor 1; HA, hemagglutinin; aFABP, adipocyte fatty acid-binding protein; GTT, glucose tolerance test; ITT, insulin tolerance test.