Role of β-adrenergic receptors in the oral activity of zinc-α2-glycoprotein (ZAG)

Steven T. Russell, Michael J. Tisdale

Research output: Contribution to journalArticle

Abstract

Zinc-a2-glycoprotein (ZAG) is an adipokine with the potential as a therapeutic agent in the treatment of obesity and type 2 diabetes. In this study we show that human ZAG, which is a 41-kDa protein, when administered to ob/ob mice at 50 µg/d-1 orally in the drinking water produced a progressive loss of body weight (5 g after 8 d treatment), together with a 0.5 C increase in rectal temperature and a 40% reduction in urinary excretion of glucose. There was also a 33% reduction in the area under the curve during an oral glucose tolerance test and an increased sensitivity to insulin. These results were similar to those after iv administration of ZAG. However, tryptic digestion was shown to inactivate ZAG. There was no evidence of human ZAG in the serum but a 2-fold elevation of murine ZAG, which was also observed in target tissues such as white adipose tissue. To determine whether the effect was due to interaction of the human ZAG with the ß-adrenergic (ß-AR) in the gastrointestinal tract before digestion, ZAG was coadministered to ob/ob mice together with propanolol (40 mg/kg-1), a nonspecific ß-AR antagonist. The effect of ZAG on body weight, rectal temperature, urinary glucose excretion, improvement in glucose disposal, and increased insulin sensitivity were attenuated by propanolol, as was the increase in murine ZAG in the serum. These results suggest that oral administration of ZAG increases serum levels through interaction with a ß-AR in the upper gastrointestinal tract, and gene expression studies showed this to be in the esophagus.

LanguageEnglish
Pages4696-4704
Number of pages9
JournalEndocrinology
Volume153
Issue number10
Early online date17 Aug 2012
DOIs
Publication statusPublished - 1 Oct 2012

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Receptors, Adrenergic, beta
Zinc
Glycoproteins
Glucose
Propranolol
Adrenergic Agents
Insulin Resistance
Digestion
Serum
Body Weight
White Adipose Tissue
Upper Gastrointestinal Tract
Temperature
Adrenergic Antagonists
Adipokines
Glucose Tolerance Test
Drinking Water
Type 2 Diabetes Mellitus
Esophagus
Area Under Curve

Cite this

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Role of β-adrenergic receptors in the oral activity of zinc-α2-glycoprotein (ZAG). / Russell, Steven T.; Tisdale, Michael J.

In: Endocrinology, Vol. 153, No. 10, 01.10.2012, p. 4696-4704.

Research output: Contribution to journalArticle

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