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ß-Adrenergic Regulation of IL-6 Release from Adipose Tissue: In Vivo and in Vitro Studies

Departments of Medicine (V.M.-A., L.F., R.G.) and Cardiovascular Genetics (S.E.H.), University College London Medical School, Whittington Hospital, London N19 3UA, United Kingdom; Harvard School of Public Health (V.M.-A., J.S., G.H.), Boston, Massachusetts 02115; Pennington Biomedical Research Center (D.A.Y., J.P.), Louisiana State University, Baton Rouge, Louisiana 70808-4124; and Department of Medicine, Diabetes, and Endocrinology Research Group (J.P.), University of Liverpool, University Hospital Aintree, Liverpool L9 7AL, United Kingdom

Address all correspondence and requests for reprints to: Jonathan Pinkney, M.D., University of Liverpool, Department of Medicine, Clinical Sciences Centre, Longmoor Lane, Liverpool L9 7AL, United Kingdom. E-mail: jpinkney{at}liverpool.ac.uk

Abstract

Circulating IL-6 levels are elevated in obesity. Although IL-6 is expressed in adipose tissue, neither its regulation nor cell of origin is well characterized. Here we investigated the ß-adrenergic regulation of IL-6 release in a combination of studies on humans and animals in vivo and cultured adipocytes in vitro. Human in vivo study: Human volunteers were infused with isoproterenol, norepinephrine, or saline {4 M:4F; mean (SD) age 35.5 (5.8) yr; body mass index 24.6 (4.2) kg/m^-2}. Plasma IL-6 levels increased during a 3-h infusion of isoproterenol (P = 0.01) and fell 2 h post infusion (P = 0.05). IL-6 levels did not change significantly with either norepinephrine or saline. Murine in vivo study: C57BL6/J male mice were injected ip with dobutamine (ß₁ agonist), clenbuterol (ß₂), CL316243 (ß₃), or saline placebo. Plasma IL-6 levels at 3 h were increased by clenbuterol (P = 0.02) and CL316243 (P = 0.02) but not dobutamine (P = 0.51), compared with placebo. In vitro studies: In human peripheral blood cells, lipopolysaccharide treatment enhanced secretion of IL-6 (vs. controls; P < 0.001), whereas isoproterenol inhibited IL-6 secretion (P = 0.012) and norepinephrine had no significant effect. In contrast, isolated human adipocytes and differentiated 3T3F442A adipocytes all rapidly secreted IL-6 in response to adrenergic agonists (P < 0.01, compared with untreated cells). We conclude that ß2/ß3 adrenoceptor stimulation on adipocytes, rather than macrophages, may be responsible for the increases in plasma IL-6 concentrations observed during sympathetic activation and in obesity.

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