Lack of “immunological fitness” during fasting in metabolically challenged animals

Ingrid Wernstedt Asterholm; John McDonald; Pierre-Gilles Blanchard; Madhur Sinha; Qiang Xiao; Jehangir Mistry; Joseph M. Rutkowski; Yves Deshaies; Rolf A. Brekken; Philipp E. Scherer

doi:10.1194/jlr.M021725

Lack of “immunological fitness” during fasting in metabolically challenged animals[S]

^*Touchstone Diabetes Center, Departments of Internal Medicine and
^**Departments of Internal Medicine Cell Biology
^††Hamon Center for Therapeutic Oncology Research and Division of Surgical Oncology
^†University of Texas Southwestern Medical Center, Dallas, TX 75390; Bioscience Division, Millipore Corporation, St. Charles, MO 63304; and
^§Laval Hospital Research Center, Faculty of Medicine, Laval University, Québec, Canada

Abstract

Subclinical inflammation is frequently associated with obesity. Here, we aim to better define the acute inflammatory response during fasting. To do so, we analyzed representatives of immune-related proteins in circulation and in tissues as potential markers for adipose tissue inflammation and modulation of the immune system. Lipopolysaccharide treatment or high-fat diet led to an increase in circulating serum amyloid (SAA) and α1-acid glycoprotein (AGP), whereas adipsin levels were reduced. Mouse models that are protected against diet-induced challenges, such as adiponectin-overexpressing animals or mice treated with PPARγ agonists, displayed lower SAA levels and higher adip-sin levels. An oral lipid gavage, as well as prolonged fasting, increased circulating SAA concurrent with the elevation of free FA levels. Moreover, prolonged fasting was associated with an increased number of Mac2-positive crown-like structures, an increased capillary permeability, and an increase in several M2-type macrophage markers in adipose tissue. This fasting-induced increase in SAA and M2-type macrophage markers was impaired in metabolically challenged animals. These data suggest that metabolic inflexibility is associated with a lack of “immunological fitness.”

Footnotes

↵1 To whom correspondence should be addressed. e-mail: Philipp.Scherer{at}utsouthwestern.edu
Abbreviations:

AGP

α1-acid glycoprotein

ASP

acylation-stimulating protein

CLS

crown-like structures

FACS

fluorescence-activated cell sorting

FFA

free FA

HFD

high-fat diet

LPS

lipopolysaccharide

SAA

serum amyloid

tg

transgenic

TLR4

Toll-like receptor-4
This work was supported by National Institutes of Health Grants R01-DK-55758, R01-CA-112023, RC1-DK-086629, and P01-DK-088761-01 (P.E.S.), DK-081182 (Jay Horton), and the Effie Marie Cain Scholarship in Angiogenesis Research (R.A.B.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. I.W.A. was also supported by a fellowship from the Throne-Holst Foundation and the Swedish Research Council (2006-3931) and by a VINNMER Fellowship from the VINNOVA Foundation. J.M.R. was supported by NIH Postdoctoral Fellowship F32-DK085935.
↵[S] The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one table and two figures.